WO2002051432A1 - A novel pharmaceutical compound and methods of making and using same - Google Patents

A novel pharmaceutical compound and methods of making and using same Download PDF

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Publication number
WO2002051432A1
WO2002051432A1 PCT/US2001/043115 US0143115W WO02051432A1 WO 2002051432 A1 WO2002051432 A1 WO 2002051432A1 US 0143115 W US0143115 W US 0143115W WO 02051432 A1 WO02051432 A1 WO 02051432A1
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WO
WIPO (PCT)
Prior art keywords
active agent
polypeptide
release
amino acid
composition
Prior art date
Application number
PCT/US2001/043115
Other languages
French (fr)
Inventor
Thomas Piccariello
Original Assignee
New River Pharmaceuticals Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by New River Pharmaceuticals Inc. filed Critical New River Pharmaceuticals Inc.
Priority to PCT/US2001/043115 priority Critical patent/WO2002051432A1/en
Publication of WO2002051432A1 publication Critical patent/WO2002051432A1/en
Priority to US10/923,088 priority patent/US7427600B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to diacetylmorphine, as well as methods for protecting and administering diacetylmorphine.
  • This novel compound referred to as a CARRIERWANETM Molecular Analogue (CMA)
  • CMA CARRIERWANETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxymorphone, as well as methods for protecting and administering oxymorphone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to dihydrocodeine, as well as methods for protecting and administering dihydrocodeine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine, guaifenesin and pseudoephidrine, as well as methods for protecting and administering codeine, guaifenesin and pseudoephidrine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to aspirin, carisoprodol, and codeine, as well as methods for protecting and administering aspirin, carisoprodol, and codeine.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to acetaminophen and hydrocodone, as well as methods for protecting and administering acetaminophen and hydrocodone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to guaifenesin and hydrocodone, as well as methods for protecting and administering guaifenesin and hydrocodone.
  • This novel compound referred to as a CARRIERWAVETM Molecular Analogue (CMA)
  • CMA CARRIERWAVETM Molecular Analogue
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid . are used to provide timed release of human O 02/051432
  • Diacetylmorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems also provide the ability to control the release of the active agent.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems also provide the ability to control the release of the active agent.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • Variable molecular weights have unpredictable diffusion rates and pharmacokinetics.
  • High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes.
  • High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • This prodrug formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines.
  • the released dexamethasone active agent was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream.
  • Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker.
  • HARs highly ordered lipid films
  • Dihydromorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Methyldihydromorphinone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
  • the novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists.
  • the novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration.
  • Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Codeine, phenylephrine and promethazine is a known pharmaceutical agent that is used in the treatment of coughs and colds.
  • the structure of codeine is shown in Figure 1.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Abso ⁇ tion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Inco ⁇ orating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent.
  • copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone.
  • a wide range of pharmaceuticals pu ⁇ ortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids.
  • Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
  • peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration.
  • timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine.
  • Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • Abso ⁇ tion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers.
  • Inco ⁇ orating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes.
  • Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent.
  • Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation.
  • Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
  • Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target.
  • active agent biologically active agent
  • the importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique.
  • Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching diacetylmorphine to a side chain of an amino acid to form an active agent/amino acid complex;
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, diacetylmo ⁇ hine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the invention also provides a method for protecting hydromo ⁇ hone from degradation comprising covalently attaching it to a polypeptide.
  • the present invention provides covalent attachment of the active agent (hydrocodone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the invention also provides a method for delivering hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • hydrocodone is released from the composition by an enzyme-catalyzed release.
  • hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release.
  • the composition further comprises a microencapsulating agent and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • the invention provides a composition comprising a polypeptide and oxymo ⁇ hone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Oxymo ⁇ hone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting oxymo ⁇ hone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering oxymo ⁇ hone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • oxymo ⁇ hone is released from the composition by an enzyme-catalyzed release.
  • oxymo ⁇ hone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and oxymo ⁇ hone is released from the composition by dissolution of the microencapsulating agent.
  • oxymo ⁇ hone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxymo ⁇ hone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, oxymo ⁇ hone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • Dihydrocodeine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • NCA N-carboxyanhydride
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the invention also provides a method for protecting dihydromo ⁇ hine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering dihydromo ⁇ hine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • dihydromo ⁇ hine is released from the composition by an enzyme-catalyzed release.
  • dihydromo ⁇ hine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering methyldihydromo ⁇ hinone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • methyldihydromo ⁇ hinone is released from the composition by an enzyme-catalyzed release.
  • methyldihydromo ⁇ hinone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • N-carboxyanhydride N-carboxyanhydride
  • the present invention provides covalent attachment of the active agent (codeine and promethazine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine and promethazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising codeine and promethazine microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and codeine and promethazine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Codeine and promethazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition further comprises a microencapsulating agent and codeine and promethazine is released from the composition by dissolution of the microencapsulating agent.
  • codeine and promethazine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine and promethazine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the present invention provides a pharmaceutical composition comprising codeine, phenylephrine and promethazine microencapsulated by a polypeptide.
  • the invention also provides a method for protecting codeine, phenylephrine and promethazine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine, phenylephrine and promethazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine, phenylephrine and promethazine is released from the composition by an enzyme- catalyzed release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention provides a composition comprising a polypeptide and codeine and guaifenesin covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Codeine and guaifenesin preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the invention also provides a method for protecting codeine and guaifenesin from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine and guaifenesin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine and guaifenesin is released from the composition by an enzyme-catalyzed release.
  • codeine and guaifenesin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and codeine and guaifenesin is released from the composition by dissolution of the microencapsulating agent.
  • codeine and guaifenesin is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine and guaifenesin is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • NCA active agent/amino acid complex N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, codeine and guaifenesin and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the invention provides a composition comprising a polypeptide and codeine, guaifenesin and pseudoephidrine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting codeine, guaifenesin and pseudoephidrine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering codeine, guaifenesin and pseudoephidrine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • codeine, guaifenesin and pseudoephidrine is released from the composition by an enzyme- catalyzed release.
  • codeine, guaifenesin and pseudoephidrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and codeine, guaifenesin and pseudoephidrine is released from the composition by dissolution of the microencapsulating agent.
  • codeine, guaifenesin and pseudoephidrine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • codeine, guaifenesin and pseudoephidrine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, codeine, guaifenesin and pseudoephidrine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (aspirin, carisoprodol, and codeine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching aspirin, carisoprodol, and codeine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the present invention provides a pharmaceutical composition comprising aspirin, carisoprodol, and codeine microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and aspirin, carisoprodol, and codeine covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the • microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching it to a polypeptide.
  • the composition further comprises a microencapsulating agent and aspirin, carisoprodol, and codeine is released from the composition by dissolution of the microencapsulating agent.
  • aspirin, carisoprodol, and codeine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • aspirin, carisoprodol, and codeine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, aspirin, carisoprodol, and codeine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • the adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the composition further comprises a microencapsulating agent and himatropine and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • himatropine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • himatropine and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, himatropine and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • hydrocodone and phenylpropanolamine to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone and phenylpropanolamine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Hydrocodone and phenylpropanolamine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting hydrocodone and phenylpropanolamine from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering hydrocodone and phenylpropanolamine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • hydrocodone and phenylpropanolamine is released from the composition by an enzyme- catalyzed release.
  • hydrocodone and phenylpropanolamine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and hydrocodone and phenylpropanolamine is released from the composition by dissolution of the microencapsulating agent.
  • hydrocodone and phenylpropanolamine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • hydrocodone and phenylpropanolamine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent
  • hydrocodone and phenylpropanolamine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • acetaminophen and hydrocodone to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching acetaminophen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising acetaminophen and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and acetaminophen and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Acetaminophen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting acetaminophen and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering acetaminophen and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • acetaminophen and hydrocodone is released from the composition by an enzyme-catalyzed release.
  • acetaminophen and hydrocodone is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and acetaminophen and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • acetaminophen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • acetaminophen and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching acetaminophen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
  • NCA N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, acetaminophen and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (chlo ⁇ heniramine, hydrocodone and pseudoephedrine) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chlo ⁇ heniramine, hydrocodone and pseudoephedrine to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • Chlo ⁇ heniramine, hydrocodone and pseudoephedrine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering chlo ⁇ heniramine, hydrocodone and pseudoephedrine to a patient, the patient being a human or a non- human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by an enzyme-catalyzed release.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by dissolution of the microencapsulating agent.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition by a pH-dependent unfolding of the polypeptide.
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent
  • chlo ⁇ heniramine, hydrocodone and pseudoephedrine and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching guaifenesin and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for delivering guaifenesin and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • guaifenesin and hydrocodone is released from the composition by an enzyme-catalyzed release.
  • guaifenesin and hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and guaifenesin and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • guaifenesin and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • guaifenesin and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (ibuprofen and hydrocodone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ibuprofen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising ibuprofen and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and ibuprofen and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Ibuprofen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-deperident manner.
  • the composition further comprises a microencapsulating agent and ibuprofen and hydrocodone is released from the composition by dissolution of the microencapsulating agent.
  • ibuprofen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • ibuprofen and hydrocodone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching ibuprofen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, ibuprofen and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • chlo ⁇ heniramine and hydrocodone to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chlo ⁇ heniramine and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • the present invention provides a pharmaceutical composition comprising chlo ⁇ heniramine and hydrocodone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and chlo ⁇ heniramine and hydrocodone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Chlo ⁇ heniramine and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting chlo ⁇ heniramine and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering chlo ⁇ heniramine and hydrocodone to a patient, the patient being a human or a non-human animal, comprising
  • chlo ⁇ heniramine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, chlo ⁇ heniramine and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients .
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of:
  • N-carboxyanhydride N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, chlo ⁇ heniramine and hydrocodone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate.
  • the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
  • the present invention provides covalent attachment of the active agent (naltrexone) to a polymer of peptides or amino acids.
  • the invention is distinguished from the above-mentioned technologies by virtue of covalently attaching naltrexone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide.
  • the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection.
  • delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide.
  • indigenous enzymes Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for abso ⁇ tion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
  • the present invention provides a pharmaceutical composition comprising naltrexone microencapsulated by a polypeptide.
  • the invention provides a composition comprising a polypeptide and naltrexone covalently attached to the polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • Naltrexone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide.
  • the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide.
  • the active agent is an amine and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide.
  • the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
  • the composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient.
  • the microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • an adjuvant preferably activates an intestinal transporter.
  • the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension.
  • the active agent can be conformationally protected by folding of the polypeptide about the active agent.
  • the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
  • the invention also provides a method for protecting naltrexone from degradation comprising covalently attaching it to a polypeptide.
  • the invention also provides a method for delivering naltrexone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • naltrexone is released from the composition by an enzyme-catalyzed release.
  • naltrexone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release.
  • the composition further comprises a microencapsulating agent and naltrexone is released from the composition by dissolution of the microencapsulating agent.
  • naltrexone is released from the composition by a pH-dependent unfolding of the polypeptide.
  • naltrexone is released from the composition in a sustained release.
  • the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide.
  • the adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
  • the invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide.
  • the method comprises the steps of: (a) attaching naltrexone to a side chain of an amino acid to form an active agent/amino acid complex;
  • N-carboxyanhydride N-carboxyanhydride
  • NCA N-carboxyanhydride
  • steps (a) and (b) are repeated prior to step (c) with a second active agent.
  • steps (a) and (b) are repeated prior to step (c) with a second agent, naltrexone and a second active agent can be copolymerized in step (c).
  • the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination.
  • the thermodynamics of protein folding and unfolding are defined by the free energy of a particular condition of the protein that relies on a particular model.
  • the process of protein folding involves, amongst other things, amino acid residues packing into a hydrophobic core.
  • the amino acid side chains inside the protein core occupy the same volume as they do in amino acid crystals.
  • the folded protein interior is therefore more like a crystalline solid than an oil drop and so the best model for determining forces contributing to protein stability is the solid reference state.
  • Detailed 501 Page 7 be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.
  • Preparation of Poly[ ⁇ -Alkyl Glutamate] ⁇ - Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight).
  • the product can be isolated from the solution by pouring it into water and filtering.
  • the product can be purified using GPC or dialysis.
  • the resultant peptide-ethylmo ⁇ hine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and ethylmo ⁇ hine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 1 wherein said polypeptide is capable of releasing ethylmo ⁇ hine from said composition in a pH-dependent manner.
  • a method for controlling release of ethylmo ⁇ hine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching ethylmo ⁇ hine to said polypeptide.
  • a method for delivering ethylmo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ethylmo ⁇ hine covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize diacetylmo ⁇ hine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of diacetylmo ⁇ hine.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises diacetylmo ⁇ hine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • diacetylmo ⁇ hine is covalently attached to the polypeptide via a ketal bond.
  • the resultant peptide-diacetylmo ⁇ hine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and diacetylmo ⁇ hine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting diacetylmo ⁇ hine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering diacetylmo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and diacetylmo ⁇ hine covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydromo ⁇ hone and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydromo ⁇ hone.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • the composition of the invention comprises hydromo ⁇ hone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • hydromo ⁇ hone is covalently attached to the polypeptide via the hydroxyl group.
  • the resultant peptide-hydromo ⁇ hone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and hydromo ⁇ hone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein hydromo ⁇ hone is conformationally protected by folding of said polypeptide about said active agent.
  • composition of claim 1 wherein said polypeptide is capable of releasing hydromo ⁇ hone from said composition in a pH-dependent manner.
  • a method for protecting hydromo ⁇ hone from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of hydromo ⁇ hone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching hydromo ⁇ hone to said polypeptide.
  • a method for delivering hydromo ⁇ hone to a patient comprising administering to said patient a composition comprising: a polypeptide; and hydromo ⁇ hone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydrocodone and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydrocodone.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises hydrocodone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • hydrocodone is covalently attached to the polypeptide via a ketal bond.
  • the resultant peptide-hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and hydrocodone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing hydrocodone from said composition in a pH-dependent manner.
  • a method for protecting hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting dihydromo ⁇ hine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering dihydromo ⁇ hine to a patient comprising administering to said patient a composition comprising: a polypeptide; and dihydromo ⁇ hine covalently attached to said . polypeptide.
  • composition of the invention comprises methyldihydromo ⁇ hinone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-methyldihydromo ⁇ hinone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and methyldihydromo ⁇ hinone covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 1 wherein said polypeptide is capable of releasing methyldihydromo ⁇ hinone from said composition in a pH-dependent manner.
  • a method for delivering methyldihydromo ⁇ hinone to a patient comprising administering to said patient a composition comprising: a polypeptide; and methyldihydromo ⁇ hinone covalently attached to said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize codeine and promethazine and prevent its digestion in the stomach.
  • composition of the invention comprises codeine and promethazine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing codeine and promethazine from said composition in a pH-dependent manner.
  • a method for protecting codeine and promethazine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for delivering codeine and promethazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
  • codeine and promethazine is released from said composition by an enzyme-catalyzed release.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize codeine, phenyleplirine and promethazine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of codeine, phenylephrine and promethazine.
  • active agents can be combined to produce synergistic effects.
  • abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises codeine, phenylephrine and promethazine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine, phenylephrine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine, phenylephrine and promethazine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein codeine, phenylephrine and promethazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of the invention comprises codeine and guaifenesin covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein said polypeptide is capable of releasing codeine and guaifenesin from said composition in a pH-dependent manner.
  • a method for protecting codeine and guaifenesin from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of codeine and guaifenesin from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching codeine and guaifenesin to said polypeptide.
  • a method for delivering codeine and guaifenesin to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and guaifenesin covalently attached to said polypeptide.
  • codeine and guaifenesin is released from said composition by an enzyme-catalyzed release.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • composition of the invention comprises codeine, guaifenesin and pseudoephidrine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-codeine, guaifenesin and pseudoephidrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • a pharmaceutical composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein codeine, guaifenesin and pseudoephidrine is conformationally protected by folding of said polypeptide about said active agent.
  • a method for delivering codeine, guaifenesin and pseudoephidrine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • composition of claim 1 wherein said composition is in the form of an oral suspension.
  • composition of claim 1 wherein aspirin, carisoprodol, and codeine is conformationally protected by folding of said polypeptide about said active agent.
  • a method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of aspirin, carisoprodol, and codeine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching aspirin, carisoprodol, and codeine to said polypeptide.
  • a method for delivering aspirin, carisoprodol, and codeine to a patient comprising administering to said patient a composition comprising: a polypeptide; and aspirin, carisoprodol, and codeine, covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 1 further comprising an adjuvant.
  • composition of claim 13 further comprising a pharmaceutically acceptable excipient.
  • composition of claim 1 wherein said composition is in the form of an ingestable tablet.
  • composition of claim 1 wherein said composition is in the form of an intravenous preparation.
  • a method for protecting himatropine and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
  • a method for controlling release of himatropine and hydrocodone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching himatropine and hydrocodone to said polypeptide.
  • a method for delivering himatropine and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and himatropine and hydrocodone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize hydrocodone and phenylpropanolamine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of hydrocodone and phenylpropanolamine.
  • active agents can be combined to produce
  • a pharmaceutical composition comprising: a polypeptide; and hydrocodone and phenylpropanolamine covalently attached to said polypeptide.
  • composition of claim 1 wherein said polypeptide is an oligopeptide.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 further comprising an adjuvant.
  • a method for controlling release of hydrocodone and phenylpropanolamine from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching hydrocodone and phenylpropanolamine to said polypeptide.
  • composition of the invention comprises acetaminophen and hydrocodone covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-acetaminophen and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 further comprising a microencapsulating agent.
  • composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
  • PEG polyethylene glycol
  • composition of claim 1 wherein said polypeptide is capable of releasing acetaminophen and hydrocodone from said composition in a pH-dependent manner.
  • a method for controlling release of acetaminophen and hydrocodone from a composition wherein said composition comprises a polypeptide said method comprising covalently attaching acetaminophen and hydrocodone to said polypeptide.
  • a method for delivering acetaminophen and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and acetaminophen and hydrocodone covalently attached to said polypeptide.
  • composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
  • the present invention provides several benefits for active agent delivery.
  • the invention can stabilize chlo ⁇ heniramine, hydrocodone and pseudoephedrine and prevent its digestion in the stomach.
  • the pharmacologic effect can be prolonged by delayed release of chlo ⁇ heniramine, hydrocodone and pseudoephedrine.
  • active agents can be combined to produce synergistic effects. Also, abso ⁇ tion of the active agent in the intestinal tract can be enhanced.
  • the invention also allows targeted delivery of active agents to specifics sites of action.
  • composition of the invention comprises chlo ⁇ heniramine, hydrocodone and pseudoephedrine covalently attached to a polypeptide.
  • the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • the resultant peptide-chlo ⁇ heniramine, hydrocodone and pseudoephedrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
  • composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
  • composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
  • composition of claim 1 wherein chlo ⁇ heniramine, hydrocodone and pseudoephedrine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.

Abstract

The present invention relates to novel pharmaceutical compositions comprising a polypeptide and an active agent attached to the polypeptide. The active agent is preferably covalently attached to the polypeptide. The compositions of the invention are useful in accomplishing enhancement of chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; and targeted delivery to a particular tissue/cell type.

Description

A NOVEL PHARMACEUTICAL COMPOUND AND METHODS OF MAKING AND USING SAME
FIELD OF THE INVENTION
(501) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ethylmorphine, as well as methods for protecting and administering ethylmorphine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(502) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to diacetylmorphine, as well as methods for protecting and administering diacetylmorphine. This novel compound, referred to as a CARRIERWANE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(503) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to hydromorphone, as well as methods for protecting and administering hydromorphone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(504) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to hydrocodone, as well as methods for protecting and administering hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(505) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to oxymorphone, as well as methods for protecting and administering oxymorphone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(506) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to dihydrocodeine, as well as methods for protecting and administering dihydrocodeine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(507) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to dihydromorphine, as well as methods for protecting and administering dihydromorphine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (508) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to methyldihydromorphinone, as well O 02/051432
as methods for protecting and administering methyldihydromorphinone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(509) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine and promethazine, as well as methods for protecting and administering codeine and promethazine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (510) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine, phenylephrine and promethazine, as well as methods for protecting and administering codeine, phenylephrine and promethazine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (511) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine and guaifenesin, as well as methods for protecting and administering codeine and guaifenesin. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (512) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to codeine, guaifenesin and pseudoephidrine, as well as methods for protecting and administering codeine, guaifenesin and pseudoephidrine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (513) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to aspirin, carisoprodol, and codeine, as well as methods for protecting and administering aspirin, carisoprodol, and codeine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(514) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to himatropine and hydrocodone, as well as methods for protecting and administering himatropine and hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(515) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to hydrocodone and phenylpropanolamine, as well as methods for protecting and administering hydrocodone and phenylpropanolamine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(516) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to acetaminophen and hydrocodone, as well as methods for protecting and administering acetaminophen and hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(517) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to chlorpheniramine, hydrocodone and pseudoephedrine, as well as methods for protecting and administering chlorpheniramine, hydrocodone and pseudoephedrine. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (518) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to guaifenesin and hydrocodone, as well as methods for protecting and administering guaifenesin and hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(519) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to ibuprofen and hydrocodone, as well as methods for protecting and administering ibuprofen and hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness. (520) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to chlorpheniramine and hydrocodone, as well as methods for protecting and administering chlorpheniramine and hydrocodone. This novel compound, referred to as a CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
(521) The present invention relates to a novel pharmaceutical compound that comprises a polypeptide that is preferably covalently attached to naltrexone, as well as methods for protecting and administering naltrexone. This novel compound, referred to as a
CARRIERWAVE™ Molecular Analogue (CMA), has the benefit of taking a known effective pharmaceutical agent that is both well studied and occupies a known segment of the pharmaceutical market, and combining it with a carrier compound that enhances the usefulness of the pharmaceutical agent without compromising its pharmaceutical effectiveness.
BACKGROUND OF THE INVENTION (501) Ethylmorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the * stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid.are used to provide timed release of human O 02/051432
growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(502) Diacetylmorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance. Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(503) Hydromorphone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns. (504) Hydrocodone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight miciOspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(505) Oxymorphone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(506) Dihydrocodeine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(507) Dihydromorphine is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drug delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(508) Methyldihydromorphinone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor. Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drug delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(509) Codeine and promethazine are known pharmaceutical agents used in the treatment of coughs. The structure of codeine is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absorption; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance. Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incorporating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals purportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incorporation of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drug delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incorporates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absorption through the brush-border membrane of the intestines is limited to less than 5 microns.
(510) Codeine, phenylephrine and promethazine is a known pharmaceutical agent that is used in the treatment of coughs and colds. The structure of codeine is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance. Absorption of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in β the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brash-border membrane of the intestines is limited to less than 5 microns.
(511) Codeine and guaifenesin is a known pharmaceutical agent that is used in the treatment of coughs. The structure of codeine is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drug delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(512) Codeine, guaifenesin and pseudoephidrine are used in the treatment of coughs and colds. The structure of codeine is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor. Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, pplyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(513) Aspirin, carisoprodol, and codeine are used in the treatment of pain. The structure of codeine is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drug delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(514) Himatropine and hydrocodone is a known pharmaceutical agent that is used in the treatment of pain. The structure of hydrocodone is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(515) Hydrocodone and phenylpropanolamine are used in the treatment of coughs and colds. The structure of hydrocodone is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals pmportedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(516) Acetaminophen and hydrocodone is a known pharmaceutical agent that is used in the treatment of pain. The chemical name of acetaminophen is N-acetyl-p- aminophenol. The structure of hydrocodone is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach. Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(517) Chloφheniramine, hydrocodone and pseudoephedrine are used in the treatment of coughs and colds. The structure of hydrocodone is shown in Figure 1. The structure of pseudoephedrine is:
Figure imgf000046_0001
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance. Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations. Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(518) Guaifenesin and hydrocodone is a known pharmaceutical agent that is used in the treatment of coughs. The structure of hydrocodone is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor. Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drug and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrug formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(519) Ibuprofen and hydrocodone are used in the treatment of pain. The structure of hydrocodone is shown in Figure 1. The structure of ibuprofen is:
Figure imgf000051_0001
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drugs rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drug is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drug attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration. It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
(520) Chloφheniramine and hydrocodone is a known pharmaceutical agent that is used in the treatment of pain. The structure of hydrocodone is shown in Figure 1. The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor.
Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance. Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release.
In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drag conjugates of this class of drug delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drug delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drags, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns. (521) Naltrexone is a known pharmaceutical agent that is used in the treatment of pain. Its structure is shown in Figure 1.
The novel pharmaceutical compound of the present invention is useful in accomplishing one or more of the following goals: enhancement of the chemical stability of the original compound; alteration of the release profile of an orally administered product; enhanced digestion or absoφtion; targeted delivery to particular tissue/cell type; and provision for an oral dosage form when none exists. The novel pharmaceutical ' compound may contain one or more of the following: another active pharmaceutical agent, an adjuvant, or an inhibitor. Active agent delivery systems are often critical for the effective delivery of a biologically active agent (active agent) to the appropriate target. The importance of these systems becomes magnified when patient compliance and active agent stability are taken under consideration. For instance, one would expect patient compliance to increase markedly if an active agent is administered orally in lieu of an injection or another invasive technique. Increasing the stability of the active agent, such as prolonging shelf life or survival in the stomach, will assure dosage reproducibility and perhaps even reduce the number of dosages required which could improve patient compliance.
Absoφtion of an orally administered active agent is often blocked by the harshly acidic stomach milieu, powerful digestive enzymes in the GI tract, permeability of cellular membranes and transport across lipid bilayers. Incoφorating adjuvants such as resorcinol, surfactants, polyethylene glycol (PEG) or bile acids enhance permeability of cellular membranes. Microencapsulating active agents using protenoid microspheres, liposomes or polysaccharides have been effective in abating enzyme degradation of the active agent. Enzyme inhibiting adjuvants have also been used to prevent enzyme degradation. Enteric coatings have been used as a protector of pharmaceuticals in the stomach.
Active agent delivery systems also provide the ability to control the release of the active agent. For example, formulating diazepam with a copolymer of glutamic acid and aspartic acid enables a sustained release of the active agent. As another example, copolymers of lactic acid and glutaric acid are used to provide timed release of human growth hormone. A wide range of pharmaceuticals puφortedly provide sustained release through microencapsulation of the active agent in amides of dicarboxylic acids, modified amino acids or thermally condensed amino acids. Slow release rendering additives can also be intermixed with a large array of active agents in tablet formulations.
Each of these technologies imparts enhanced stability and time-release properties to active agent substances. Unfortunately, these technologies suffer from several shortcomings. Incoφoration of the active agent is often dependent on diffusion into the microencapsulating matrix, which may not be quantitative and may complicate dosage reproducibility. In addition, encapsulated drags rely on diffusion out of the matrix, which is highly dependant on the water solubility of the active agent. Conversely, water-soluble microspheres swell by an infinite degree and, unfortunately, may release the active agent in bursts with little active agent available for sustained release. Furthermore, in some technologies, control of the degradation process required for active agent release is unreliable. For example, an enterically coated active agent depends on pH to release the active agent and, as such, is difficult to control the rate of release. In the past, use has been made of amino acid side chains of polypeptides as pendant groups to which active agents can be attached. These technologies typically require the use of spacer groups between the amino acid pendant group and the active agent. The peptide-drug conjugates of this class of drag delivery system rely on enzymes in the bloodstream for the release of the drag and, as such, are not used for oral administration. Examples of timed and targeted release of injectable or subcutaneous pharmaceuticals include: linking of norethindrone, via a hydroxypropyl spacer, to the gamma carboxylate of polyglutamic acid; and linking of nitrogen mustard, via a peptide spacer, to the gamma carbamide of polyglutamine. Dexamethasone has been covalently attached directly to the beta carboxylate of polyaspartic acid without a spacer group. This prodrag formulation was designed as a colon-specific drag delivery system where the drag is released by bacterial hydrolytic enzymes residing in the large intestines. The released dexamethasone active agent, in turn, was targeted to treat large bowel disorders and was not intended to be absorbed into the bloodstream. Yet another technology combines the advantages of covalent drag attachment with liposome formation where the active ingredient is attached to highly ordered lipid films (known as HARs) via a peptide linker. Thus, there has been no drag delivery system, heretofore reported, that incoφorates the concept of attaching an active ingredient to a polypeptide pendant group with its targeted delivery into the bloodstream via oral administration.
It is also important to control the molecular weight, molecular size and particle size of the active agent delivery system. Variable molecular weights have unpredictable diffusion rates and pharmacokinetics. High molecular weight carriers are digested slowly or late, as in the case of naproxen-linked dextran, which is digested almost exclusively in the colon by bacterial enzymes. High molecular weight microspheres usually have high moisture content which may present a problem with water labile active ingredients. Particle size not only becomes a problem with injectable drugs, as in the HAR application, but absoφtion through the brush-border membrane of the intestines is limited to less than 5 microns.
SUMMARY OF THE INVENTION
DI The present invention provides covalent attachment of the active agent (ethylmoφhine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ethylmoφhine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising ethylmoφhine microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and ethylmoφhine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Ethylmoφhine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting ethylmoφhine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering ethylmoφhine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ethylmoφhine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ethylmoφhine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ethylmoφhine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ethylmoφhine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ethylmoφhine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching ethylmorphine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ethylmoφhine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DII The present invention provides covalent attachment of the active agent (diacetylmoφhine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching diacetylmoφhine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising diacetylmoφhine microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and diacetylmoφhine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Diacetylmoφhine preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner. The invention also provides a method for protecting diacetylmoφhine from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering diacetylmoφhine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, diacetylmoφhine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, diacetylmoφhine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and diacetylmoφhine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, diacetylmoφhine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, diacetylmoφhine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching diacetylmorphine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, diacetylmoφhine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a fhioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
Dili The present invention provides covalent attachment of the active agent (hydromoφhone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydromoφhone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising hydromoφhone microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and hydromoφhone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Hydromoφhone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting hydromoφhone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering hydromoφhone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, hydromoφhone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, hydromoφhone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and hydromoφhone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, hydromoφhone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, hydromoφhone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching hydromorphone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, hydromoφhone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DIV The present invention provides covalent attachment of the active agent (hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. Alternatively, the present invention provides a pharmaceutical composition comprising hydrocodone microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting hydrocodone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme- catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane. a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DV The present invention provides covalent attachment of the active agent
(oxymoφhone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching oxymoφhone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. Alternatively, the present invention provides a pharmaceutical composition comprising oxymoφhone microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and oxymoφhone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Oxymoφhone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner. The invention also provides a method for protecting oxymoφhone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering oxymoφhone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, oxymoφhone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, oxymoφhone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and oxymoφhone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, oxymoφhone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, oxymoφhone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching oxymoφhone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, oxymoφhone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DVI The present invention provides covalent attachment of the active agent
(dihydrocodeine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching dihydrocodeine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising dihydrocodeine microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and dihydrocodeine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Dihydrocodeine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting dihydrocodeine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering dihydrocodeine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, dihydrocodeine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, dihydrocodeine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and dihydrocodeine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, dihydrocodeine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, dihydrocodeine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching dihydrocodeine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, dihydrocodeine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DVII The present invention provides covalent attachment of the active agent (dihydromoφhine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching dihydromoφhine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising dihydromoφhine microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and dihydromoφhine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Dihydromoφhine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting dihydromoφhine from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering dihydromoφhine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, dihydromoφhine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, dihydromoφhine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and dihydromoφhine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, dihydromoφhine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, dihydromoφhine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients. The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching dihydromorphine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, dihydromoφhine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DVIII The present invention provides covalent attachment of the active agent (methyldihydromoφhinone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching methyldihydromoφhinone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising methyldihydromoφhinone microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and methyldihydromoφhinone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Methyldihydromoφhinone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting methyldihydromoφhinone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering methyldihydromoφhinone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, methyldihydromoφhinone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, methyldihydromoφhinone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and methyldihydromoφhinone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, methyldihydromoφhinone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, methyldihydromoφhinone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients. The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching methyldihydromorphinone to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, methyldihydromoφhinone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DIX The present invention provides covalent attachment of the active agent (codeine and promethazine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine and promethazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising codeine and promethazine microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and codeine and promethazine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Codeine and promethazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner. The invention also provides a method for protecting codeine and promethazine from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering codeine and promethazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, codeine and promethazine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, codeine and promethazine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and codeine and promethazine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, codeine and promethazine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, codeine and promethazine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching codeine and promethazine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, codeine and promethazine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DX The present invention provides covalent attachment of the active agent (codeine, phenylephrine and promethazine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine, phenylephrine and promethazine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising codeine, phenylephrine and promethazine microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and codeine, phenylephrine and promethazine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. Codeine, phenylephrine and promethazine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N- terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting codeine, phenylephrine and promethazine from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering codeine, phenylephrine and promethazine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, codeine, phenylephrine and promethazine is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, codeine, phenylephrine and promethazine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and codeine, phenylephrine and promethazine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, codeine, phenylephrine and promethazine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, codeine, phenylephrine and promethazine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching codeine, phenylephrine and promethazine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, codeine, phenylephrine and promethazine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXI The present invention provides covalent attachment of the active agent (codeine and guaifenesin) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine and guaifenesin to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. Alternatively, the present invention provides a pharmaceutical composition comprising codeine and guaifenesin microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and codeine and guaifenesin covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Codeine and guaifenesin preferably is covalently attached to a side chain, the N- terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting codeine and guaifenesin from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering codeine and guaifenesin to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, codeine and guaifenesin is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, codeine and guaifenesin is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and codeine and guaifenesin is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, codeine and guaifenesin is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, codeine and guaifenesin is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching codeine and guaifenesin to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, codeine and guaifenesin and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the sideschain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DXII The present invention provides covalent attachment of the active agent (codeine, guaifenesin and pseudoephidrine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching codeine, guaifenesin and pseudoephidrine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising codeine, guaifenesin and pseudoephidrine microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and codeine, guaifenesin and pseudoephidrine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Codeine, guaifenesin and pseudoephidrine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N- terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting codeine, guaifenesin and pseudoephidrine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering codeine, guaifenesin and pseudoephidrine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, codeine, guaifenesin and pseudoephidrine is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, codeine, guaifenesin and pseudoephidrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and codeine, guaifenesin and pseudoephidrine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, codeine, guaifenesin and pseudoephidrine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, codeine, guaifenesin and pseudoephidrine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients. The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching codeine, guaifenesin and pseudoephidrine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, codeine, guaifenesin and pseudoephidrine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXIII The present invention provides covalent attachment of the active agent (aspirin, carisoprodol, and codeine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching aspirin, carisoprodol, and codeine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. Alternatively, the present invention provides a pharmaceutical composition comprising aspirin, carisoprodol, and codeine microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and aspirin, carisoprodol, and codeine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Aspirin, carisoprodol, and codeine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The •microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering aspirin, carisoprodol, and codeine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, aspirin, carisoprodol, and codeine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, aspirin, carisoprodol, and codeine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and aspirin, carisoprodol, and codeine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, aspirin, carisoprodol, and codeine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, aspirin, carisoprodol, and codeine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients. The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching aspirin, carisoprodol, and codeine to a side chain of an amino acid to form an active agent/amino acid complex; (b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, aspirin, carisoprodol, and codeine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXIV The present invention provides covalent attachment of the active agent (himatropine and hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching himatropine and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising himatropine and hydrocodone microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and himatropine and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Himatropine and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter. Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner. The invention also provides a method for protecting himatropine and hydrocodone from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering himatropine and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, himatropine and hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, himatropine and hydrocodone is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and himatropine and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, himatropine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, himatropine and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching himatropine and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, himatropine and hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DXV The present invention provides covalent attachment of the active agent
(hydrocodone and phenylpropanolamine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching hydrocodone and phenylpropanolamine to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising hydrocodone and phenylpropanolamine microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and hydrocodone and phenylpropanolamine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. Hydrocodone and phenylpropanolamine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting hydrocodone and phenylpropanolamine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering hydrocodone and phenylpropanolamine to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, hydrocodone and phenylpropanolamine is released from the composition by an enzyme- catalyzed release. In another preferred embodiment, hydrocodone and phenylpropanolamine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and hydrocodone and phenylpropanolamine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, hydrocodone and phenylpropanolamine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, hydrocodone and phenylpropanolamine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching hydrocodone and phenylpropanolamine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, hydrocodone and phenylpropanolamine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DXVI The present invention provides covalent attachment of the active agent
(acetaminophen and hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching acetaminophen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising acetaminophen and hydrocodone microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and acetaminophen and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. Acetaminophen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting acetaminophen and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering acetaminophen and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, acetaminophen and hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, acetaminophen and hydrocodone is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and acetaminophen and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, acetaminophen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, acetaminophen and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching acetaminophen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, acetaminophen and hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXVIIThe present invention provides covalent attachment of the active agent (chloφheniramine, hydrocodone and pseudoephedrine) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chloφheniramine, hydrocodone and pseudoephedrine to the N- terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising chloφheniramine, hydrocodone and pseudoephedrine microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and chloφheniramine, hydrocodone and pseudoephedrine covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Chloφheniramine, hydrocodone and pseudoephedrine preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C- terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting chloφheniramine, hydrocodone and pseudoephedrine from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering chloφheniramine, hydrocodone and pseudoephedrine to a patient, the patient being a human or a non- human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, chloφheniramine, hydrocodone and pseudoephedrine is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, chloφheniramine, hydrocodone and pseudoephedrine is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and chloφheniramine, hydrocodone and pseudoephedrine is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, chloφheniramine, hydrocodone and pseudoephedrine is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, chloφheniramine, hydrocodone and pseudoephedrine is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching c orpheniramine, hydrocodone and pseudoephedrine to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, chloφheniramine, hydrocodone and pseudoephedrine and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DXVIII The present invention provides covalent attachment of the active agent (guaifenesin and hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching guaifenesin and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising guaifenesin and hydrocodone microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and guaifenesin and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Guaifenesin and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide. The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting guaifenesin and hydrocodone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering guaifenesin and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, guaifenesin and hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, guaifenesin and hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and guaifenesin and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, guaifenesin and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, guaifenesin and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching guaifenesin and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and (c) polymerizing the active agent/amino acid complex N-carboxyanhydride
(NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, guaifenesin and hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXIX The present invention provides covalent attachment of the active agent (ibuprofen and hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching ibuprofen and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising ibuprofen and hydrocodone microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and ibuprofen and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Ibuprofen and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-deperident manner.
The invention also provides a method for protecting ibuprofen and hydrocodone from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering ibuprofen and hydrocodone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, ibuprofen and hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, ibuprofen and hydrocodone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and ibuprofen and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, ibuprofen and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, ibuprofen and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drag conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching ibuprofen and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, ibuprofen and hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality. It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference. DXX The present invention provides covalent attachment of the active agent
(chloφheniramine and hydrocodone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching chloφheniramine and hydrocodone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism. Alternatively, the present invention provides a pharmaceutical composition comprising chloφheniramine and hydrocodone microencapsulated by a polypeptide. The invention provides a composition comprising a polypeptide and chloφheniramine and hydrocodone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids. Chloφheniramine and hydrocodone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N-terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting chloφheniramine and hydrocodone from degradation comprising covalently attaching it to a polypeptide. The invention also provides a method for delivering chloφheniramine and hydrocodone to a patient, the patient being a human or a non-human animal, comprising
ill administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, chloφheniramine and hydrocodone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, chloφheniramine and hydrocodone is released in a time- dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and chloφheniramine and hydrocodone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, chloφheniramine and hydrocodone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, chloφheniramine and hydrocodone is released from the composition in a sustained release. In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients .
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of:
(a) attaching chloφheniramine and hydrocodone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA). In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, chloφheniramine and hydrocodone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DXXI The present invention provides covalent attachment of the active agent (naltrexone) to a polymer of peptides or amino acids. The invention is distinguished from the above-mentioned technologies by virtue of covalently attaching naltrexone to the N-terminus, the C-terminus or directly to the amino acid side chain of an oligopeptide or polypeptide, also referred to herein as a carrier peptide. In certain applications, the polypeptide will stabilize the active agent, primarily in the stomach, through conformational protection. In these applications, delivery of the active agent is controlled, in part, by the kinetics of unfolding of the carrier peptide. Upon entry into the upper intestinal tract, indigenous enzymes release the active ingredient for absoφtion by the body by selectively hydrolyzing the peptide bonds of the carrier peptide. This enzymatic action introduces a second order sustained release mechanism.
Alternatively, the present invention provides a pharmaceutical composition comprising naltrexone microencapsulated by a polypeptide.
The invention provides a composition comprising a polypeptide and naltrexone covalently attached to the polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Naltrexone preferably is covalently attached to a side chain, the N-terminus or the C-terminus of the polypeptide. In a preferred embodiment, the active agent is a carboxylic acid and is covalently attached to the N-terminus of the polypeptide. In another preferred embodiment, the active agent is an amine and is covalently attached to the C-terminus of the polypeptide. In another preferred embodiment, the active agent is an alcohol and is covalently attached to the C-terminus of the polypeptide. In yet another preferred embodiment, the active agent is an alcohol and is covalently attached to the N- terminus of the polypeptide.
The composition of the invention can also include one or more of a microencapsulating agent, an adjuvant and a pharmaceutically acceptable excipient. The microencapsulating agent can be selected from polyethylene glycol (PEG), an amino acid, a sugar and a salt. When an adjuvant is included in the composition, the adjuvant preferably activates an intestinal transporter.
Preferably, the composition of the invention is in the form of an ingestable tablet, an intravenous preparation or an oral suspension. The active agent can be conformationally protected by folding of the polypeptide about the active agent. In another embodiment, the polypeptide is capable of releasing the active agent from the composition in a pH-dependent manner.
The invention also provides a method for protecting naltrexone from degradation comprising covalently attaching it to a polypeptide.
The invention also provides a method for delivering naltrexone to a patient, the patient being a human or a non-human animal, comprising administering to the patient a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. In a preferred embodiment, naltrexone is released from the composition by an enzyme-catalyzed release. In another preferred embodiment, naltrexone is released in a time-dependent manner based on the pharmacokinetics of the enzyme-catalyzed release. In another preferred embodiment, the composition further comprises a microencapsulating agent and naltrexone is released from the composition by dissolution of the microencapsulating agent. In another preferred embodiment, naltrexone is released from the composition by a pH-dependent unfolding of the polypeptide. In another preferred embodiment, naltrexone is released from the composition in a sustained release.
In yet another preferred embodiment, the composition further comprises an adjuvant covalently attached to the polypeptide and release of the adjuvant from the composition is controlled by the polypeptide. The adjuvant can be microencapsulated into a carrier peptide-drug conjugate for biphasic release of active ingredients.
The invention also provides a method for preparing a composition comprising a polypeptide and an active agent covalently attached to the polypeptide. The method comprises the steps of: (a) attaching naltrexone to a side chain of an amino acid to form an active agent/amino acid complex;
(b) forming an active agent/amino acid complex N-carboxyanhydride (NCA) from the active agent/amino acid complex; and
(c) polymerizing the active agent/amino acid complex N-carboxyanhydride (NCA).
In a preferred embodiment, steps (a) and (b) are repeated prior to step (c) with a second active agent. When steps (a) and (b) are repeated prior to step (c) with a second agent, naltrexone and a second active agent can be copolymerized in step (c). In another preferred embodiment, the amino acid is glutamic acid and the active agent is released from the glutamic acid as a dimer upon a hydrolysis of the polypeptide and wherein the active agent is released from the glutamic acid by coincident intramolecular transamination. In another preferred embodiment, the glutamic acid is replaced by an amino acid selected from the group consisting of aspartic acid, arginine, asparagine, cysteine, lysine, threonine, and serine, and wherein the active agent is attached to the side chain of the amino acid to form an amide, a thioester, an ester, an ether, a urethane, a carbonate, an anhydride or a carbamate. In yet another preferred embodiment, the glutamic acid is replaced by a synthetic amino acid with a pendant group comprising an amine, an alcohol, a sulfhydryl, an amide, a urea, or an acid functionality.
It is to be understood that both the foregoing general description and the following detailed description are exemplary, but are not restrictive, of the invention. The general applications of this invention to other active pharmaceutical agents is described in U.S. Patent Application Serial Number 09/642,820, filed August 22, 2000, incoφorated herein by reference.
DETAILED DESCRIPTION OF THE INVENTION
Proteins, oligopeptides and polypeptides are polymers of amino acids that have primary, secondary and tertiary structures. The secondary structure of the protein is the local conformation of the polypeptide chain and consists of helices, pleated sheets and turns. The protein's amino acid sequence and the structural constraints on the conformations of the chain determine the spatial arrangement of the molecule. The folding of the secondary structure and the spatial arrangement of the side chains constitute the tertiary structure.
Proteins fold because of the dynamics associated between neighboring atoms on the protein and solvent molecules. The thermodynamics of protein folding and unfolding are defined by the free energy of a particular condition of the protein that relies on a particular model. The process of protein folding involves, amongst other things, amino acid residues packing into a hydrophobic core. The amino acid side chains inside the protein core occupy the same volume as they do in amino acid crystals. The folded protein interior is therefore more like a crystalline solid than an oil drop and so the best model for determining forces contributing to protein stability is the solid reference state.
The major forces contributing to the thermodynamics of protein folding are Van der Waals interactions, hydrogen bonds, electrostatic interactions, configurational entropy and the hydrophobic effect. Considering protein stability, the hydrophobic effect refers to the energetic consequences of removing apolar groups from the protein interior and exposing them to water. Comparing the energy of amino acid hydrolysis with protein unfolding in the solid reference state, the hydrophobic effect is the dominant force. Hydrogen bonds are established during the protein fold process and intramolecular bonds are formed at the expense of hydrogen bonds with water. Water molecules are "pushed out" of the packed, hydrophobic protein core. All of these forces combine and contribute to the overall stability of the folded protein where the degree to which ideal packing occurs determines the degree of relative stability of the protein. The result of maximum packing is to produce a center of residues or hydrophobic core that has maximum shielding from solvent.
Since it is likely that lipophilic drugs would reside in the hydrophobic core of a peptide, it would require energy to unfold the peptide before the drug can be released. The unfolding process requires overcoming the hydrophobic effect by hydrating the amino acids or achieving the melting temperature of the protein. The heat of hydration is a destabilization of a protein.
Detailed 501 Page 1 Typically, the folded state of a protein is favored by only 5-15 kcal/mole over the unfolded state. Nonetheless, protein unfolding at neutral pH and at room temperature requires chemical reagents. In fact, partial unfolding of a protein is often observed prior to the onset of irreversible chemical or conformation processes. Moreover, protein conformation generally controls the rate and extent of deleterious chemical reactions.
Conformational protection of active agents by proteins depends on the stability of the protein's folded state and the thermodynamics associated with the agent's decomposition. Conditions necessary for the agent's decomposition should be different than for protein unfolding.
Selection of the amino acids will depend on the physical properties desired. For instance, if increase in bulk or lipophilicity is desired, then the carrier polypeptide will be enriched in the amino acids in the table provided below. Polar amino acids, on the other hand, can be selected to increase the hydrophilicity of the polypeptide.
Ionizing amino acids can be selected for pH controlled peptide unfolding. Aspartic acid, glutamic acid and tyrosine carry a neutral charge in the stomach, but will ionize upon entry into the intestine. Conversely, basic amino acids, such as histidine, lysine and arginine, ionize in the stomach and are neutral in an alkaline environment.
Other factors such as π-π interactions between aromatic residues, kinking of the peptide chain by addition of proline, disulfide crosslinking and hydrogen bonding can all be used to select the optimum amino acid sequence for a given application. Ordering of the linear sequence can influence how these interactions can be maximized and is important in directing the secondary and tertiary structures of the polypeptide.
Furthermore, amino acids with reactive side chains (e.g., glutamic acid, lysine, aspartic acid, serine, threonine and cysteine) can be incoφorated for attaching multiple active agents or adjuvants to the same carrier peptide. This is particularly useful if a synergistic effect between two or more active agents is desired.
As stated above, variable molecular weights of the carrier compound can have profound effects on the active agent release kinetics. As a result, low molecular weight active agent delivery systems are preferred. An advantage of this invention is that chain length and molecular- weight of the polypeptide can be optimized depending on the level of conformational protection desired. This property can be optimized in concert with the kinetics of the first order release
Detailed 501 Page 2 mechanism. Thus, another advantage of this invention is that prolonged release time can be imparted by increasing the molecular weight of the carrier polypeptide. Another, significant advantage of the invention is that the kinetics of active agent release is primarily controlled by the enzymatic hydrolysis of the key bond between the carrier peptide and the active agent. Dextran is the only polysaccharide known that has been explored as a macromolecular carrier for the covalent binding of drug for colon specific drag delivery. Generally, it was only possible to load up to 1/10 of the total drag-dextran conjugate weight with drug. As stated earlier, polysaccharides are digested mainly in the colon and drug absoφtion is mainly limited to the colon. As compared to dextran, this invention has two major advantages. First, peptides are hydrolyzed by any one of several atninopeptidases found in the intestinal lumen or associated with the brush-border membrane and so active agent release and subsequent absoφtion can occur in the jejunum or the ileum. Second, the molecular weight of the carrier molecule can be controlled and, thus, active agent loading can also be controlled.
As a practical example, the following table lists the molecular weights of lipophilic amino acids (less one water molecule) and selected analgesics and vitamins.
TABLE
Amino acid MM Active agent MW
Glycine 57 Acetaminophen 151
Alanine 71 Vitamin B6 (Pyroxidine) 169
Valine 99 Vitamin C (Ascorbic acid) 176
Leucine 113 Aspirin 180
Isoleucine 113 Ibuprofen 206
Phenylalanine 147 Retinoic acid 300
Tyrosine 163 Vitamin B2 (Riboflavin) 376
Vitamin D2 397
Vitamin E (Tocopherol) 431
Lipophilic amino acids are preferred because conformational protection through the stomach is important for the selected active agents, which were selected based on ease of covalent attachment to an oligopeptide. Eighteen was subtracted from the amino acid's molecular weight
Detailed 501 Page 3 so that their condensation into a polypeptide is considered. For example, a decamer of glycine (MW=588) linked to aspirin would have a total molecular weight of 750 and aspirin would represent 24% of the total weight of the active agent delivery composition or over two times the maximum drag loading for dextran. This is only for an N- or C- terminus application, for those active agents attached to pendant groups of decaglutamic acid, for instance, a drug with a molecular weight of 180 could conceivably have a loading of 58%, although this may not be entirely practical.
The alcohol, amine or carboxylic acid group of an active agent may be covalently attached to the N-terminus, the C-terminus or the side chain of the oligopeptide or polypeptide. The location of attachment depends somewhat on the functional group selection. For instance, if the active drag is a carboxylic acid (e.g., aspirin) then the N-terminus of the oligopeptide is the preferred point of attachment. If the active agent is an amine (e.g., ampicillin), then the C- terminus is the preferred point of attachment in order to achieve a stable peptide linked active agent. In both, the C- and N-terminus examples, the peptide is, in essence, extended by one monomeric unit forming a new peptide bond. If the active agent is an alcohol, then either the C- terminus or the N-terminus is the preferred point of attachment in order to achieve a stable composition. As in the example above where the alcohol, norethindrone, was covalently attached to poly(hydroxypropylglutamine), an alcohol can be converted into an alkylchloroformate with phosgene. This invention, then, pertains to the reaction of this key intermediate with the N-terminus of the peptide carrier. The active ingredient can be released from the peptide carrier by intestinal peptidases.
The alcohol can be selectively bound to the gamma carboxylate of glutamic acid and then this conjugate covalently attached to the C-terminus of the peptide carrier. Because the glutamic acid-drug conjugate can be considered a dimer, this product adds two monomeric units to the C- terminus of the peptide carrier where the glutamic acid moiety serves as a spacer between the peptide and the drug as shown in Fig. 4. Intestinal enzymatic hydrolysis of the key peptide bond releases the glutamic acid-drag moiety from the peptide carrier. The newly formed free amine of the glutamic acid residue will then undergo an intramolecular transamination reaction, thereby, releasing the active agent with coincident formation of pyroglutamic acid as shown in Fig. 5. Alternatively, the glutamic acid-drag dimer can be converted into the gamma ester of glutamic acid N-carboxyanhydride. This intermediate can then be polymerized, as described above, using
Detailed 501 Page 4 any suitable initiator as shown in Fig. 4. The product of this polymerization is polyglutamic acid with active ingredients attached to multiple pendant groups. Hence, maximum drag loading of the carrier peptide can be achieved. In addition, other amino acid-NCA's can be copolymerized with the gamma ester glutamic acid NCA to impart specific properties to the drug delivery system.
The invention also provides a method of imparting the same mechanism of action for other polypeptides containing functional side chains. Examples include, but are not limited to, polylysine, polyasparagine, polyarginine, polyserine, polycysteine, polytyrosine, polythreonine and polyglutamine. The mechanism can translate to these polypeptides through a spacer or linker on the pendant group, which is terminated, preferably, by the glutamic acid-drug dimer. This carrier peptide-drug conjugate is distinguished from the prior art by virtue of the fact that the primary release of the drag moiety relies on peptidases and not on esterases. Alternatively, the active agent can be attached directly to the pendant group where some other indigenous enzymes in the alimentary tract can affect release.
The active agent can be covalently attached to the N-terminus, the C-terminus or the side chain of the polypeptide using known techniques. Examples of linking organic compounds to the N-terminus type of a peptide include, but are not limited to, the attachment of naphthylacetic acid to LH-RH, coumarinic acid to opioid peptides and l,3-dialkyl-3-acyltriazenes to tetragastrin and pentagastrin. As another example, there are known techniques for forming peptide linked biotin and peptide linked acridine.
The polypeptide carrier can be prepared using conventional techniques. A preferred technique is copolymerization of mixtures of amino acid N-carboxyanhydrides. Alternatively, if a specific sequence is desired, a solid state automated peptide synthesizer can be used. The addition of stabilizers to the composition has the potential of stabilizing the polypeptide further. Stabilizers such as sugar, amino acids, polyethylene glycol (PEG) and salts have been shown to prevent protein unfolding. In another embodiment of the invention, a pre-frst order release of the active agent is imparted by microencapsulating the carrier polypeptide-active agent conjugate in a polysaccharide, amino acid complex, PEG or salts.
There is evidence that hydrophilic compounds are absorbed through the intestinal epithelia efficiently via specialized transporters. The entire membrane transport system is intrinsically asymmetric and responds asymmetrically to cofactors. Thus, one can expect that
Detailed 501 Page 5 excitation of the membrane transport system will involve some sort of specialized adjuvant resulting in localized delivery of active agents. There are seven known intestinal transport systems classified according to the physical properties of the transported substrate. They include the amino acid, oligopeptide, glucose, monocarboxic acid, phosphate, bile acid and the P- glycoprotein transport systems and each has its own associated mechanism of transport. The mechanisms can depend on hydrogen ions, sodium ions, binding sites or other cofactors. The invention also allows targeting the mechanisms for intestinal epithelial transport systems to facilitate absoφtion of active agents.
In another embodiment of the invention, the composition includes one or more adjuvants to enhance the bioavailability of the active agent. Addition of an adjuvant is particularly preferred when using an otherwise poorly absorbed active agent. Suitable adjuvants, for example, include: papain, which is a potent enzyme for releasing the catalytic domain of aminopeptidase-N into the lumen; glycorecognizers, which activate enzymes in the BBM; and bile acids, which have been attached to peptides to enhance absoφtion of the peptides. Compositions of the invention are, in essence, the formation of amides from acids and amines and can be prepared by the following examples.
Acid/N-terminus conjugation
An acid bioactive agent can be dissolved in DMF under nitrogen and cooled to 0°C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine peptide carrier. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, the product precipitated out in ether and purified using gel permeation chromatography (GPC) or dialysis.
Amine/C-terminus conjugation
The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0°C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the amine bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, and the product precipitated out in ether and purified using GPC or dialysis.
Detailed 501 Page 6 AIcohoI/N-Terminus Conjugation
In the following example the combination of the alcohol with triphosgene produces a chloroformate, which when reacted with the N-teπninus of the peptide produces a carbamate. Pursuant to this, an alcohol bioactive agent can be treated with triphosgene in dry DMF under nitrogen. The suitably protected peptide carrier is then added slowly and the solution stirred at room temperature for several hours. The product is then precipitated out in ether. The crude product is suitably deprotected and purified using GPC.
Other solvents, activating agents, cocatalysts and bases can be used. Examples of other solvents include dimefhylsulfoxide, ethers such as tetrahydrofuran or chlorinated solvents such as chloroform. Examples of other activating agents include dicyclohexylcarbodiimide or thionyl chloride. An example of another cocatalyst is N-hydroxysuccinimide. Examples of bases include pyrrolidinopyridine, dimethylaminopyridine, triethylamine or tributylamine.
Preparation of γ- Alkyl Glutamate
There have been over 30 different γ-alkyl glutamates prepared any one of which may be suitable for the drug alcohol of choice. For example, a suspension of glutamic acid, the alcohol and concentrated hydrochloric acid can be prepared and heated for several hours. The γ-alkyl glutamate product can be precipitated out in acetone, filtered, dried and recrystallized from hot water.
γ-Alkyl Glutamate/C-Terminus Conjugation
The peptide carrier can be dissolved in DMF under nitrogen and cooled to 0°C. The solution can then be treated with diisopropylcarbodiimide and hydroxybenzotriazole followed by the γ-alkyl glutamate bioactive agent. The reaction can then be stirred for several hours at room temperature, the urea by-product filtered off, and the product precipitated out in ether and purified using GPC or dialysis.
Preparation of γ- Alkyl Glutamate-NCA γ- Alkyl glutamate can be suspended in dry THF where triphosgene is added and the mixture refluxed under a nitrogen atmosphere until the mixture becomes homogenous. The solution can
Detailed 501 Page 7 be poured into heptane to precipitate the NCA product, which is filtered, dried and recrystallized from a suitable solvent.
Preparation of Poly[γ-Alkyl Glutamate] γ- Alkyl glutamate-NCA can be dissolved in dry DMF where a catalytic amount of a primary amine can be added to the solution until it becomes viscous (typically overnight). The product can be isolated from the solution by pouring it into water and filtering. The product can be purified using GPC or dialysis.
Although illustrated and described above with reference to specific embodiments, the invention is nevertheless not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the spirit of the invention.
I The present invention provides several benefits for active agent delivery. First, the invention can stabilize ethylmoφhine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ethylmoφhine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises ethylmoφhine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, ethylmoφhine is covalently attached to the polypeptide via a ketal bond.
Preferably, the resultant peptide-ethylmoφhine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
Detailed 501 Page 8 1. A pharmaceutical composition comprising: a polypeptide; and ethylmoφhine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein ethylmoφhine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
Detailed 501 Page 9 14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein ethylmoφhine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing ethylmoφhine from said composition in a pH-dependent manner.
19. A method for protecting ethylmoφhine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of ethylmoφhine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ethylmoφhine to said polypeptide.
21. A method for delivering ethylmoφhine to a patient comprising administering to said patient a composition comprising: a polypeptide; and ethylmoφhine covalently attached to said polypeptide.
22. The method of claim 21 wherein ethylmoφhine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein ethylmoφhine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
Detailed 501 Page 10 25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
jU The present invention provides several benefits for active agent delivery. First, the invention can stabilize diacetylmoφhine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of diacetylmoφhine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises diacetylmoφhine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, diacetylmoφhine is covalently attached to the polypeptide via a ketal bond.
Preferably, the resultant peptide-diacetylmoφhine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and diacetylmoφhine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
Detailed 501 Page l l 5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein diacetylmoφhine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein diacetylmoφhine is conformationally protected by folding of said polypeptide about said active agent.
Detailed 501 Page 12 18. The composition of claim 1 wherein said polypeptide is capable of releasing diacetylmoφhine from said composition in a pH-dependent manner.
19. A method for protecting diacetylmoφhine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of diacetylmoφhine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching diacetylmoφhine to said polypeptide.
21. A method for delivering diacetylmoφhine to a patient comprising administering to said patient a composition comprising: a polypeptide; and diacetylmoφhine covalently attached to said polypeptide.
22. The method of claim 21 wherein diacetylmoφhine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein diacetylmoφhine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
|ϊϊ The present invention provides several benefits for active agent delivery. First, the invention can stabilize hydromoφhone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of hydromoφhone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
Detailed 501 Page 13 The composition of the invention comprises hydromoφhone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, hydromoφhone is covalently attached to the polypeptide via the hydroxyl group.
Preferably, the resultant peptide-hydromoφhone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and hydromoφhone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 14 8. The composition of claim 1 wherein hydromoφhone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein hydromoφhone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing hydromoφhone from said composition in a pH-dependent manner.
19. A method for protecting hydromoφhone from degradation comprising covalently attaching said active agent to a polypeptide.
Detailed 501 Page 15 20. A method for controlling release of hydromoφhone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching hydromoφhone to said polypeptide.
21. A method for delivering hydromoφhone to a patient comprising administering to said patient a composition comprising: a polypeptide; and hydromoφhone covalently attached to said polypeptide.
22. The method of claim 21 wherein hydromoφhone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein hydromoφhone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
JV The present invention provides several benefits for active agent delivery. First, the invention can stabilize hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 16 In the present invention, hydrocodone is covalently attached to the polypeptide via a ketal bond.
Preferably, the resultant peptide-hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
Detailed 501 Page 17 12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching hydrocodone to said polypeptide.
21. A method for delivering hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein hydrocodone is released from said composition by an enzyme-catalyzed release.
Detailed 501 Page 18 23. The method of claim 21 wherein hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
jNj The present invention provides several benefits for active agent delivery. First, the invention can stabilize oxymoφhone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of oxymoφhone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises oxymoφhone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, oxymoφhone is covalently attached to the polypeptide via hydroxyl group.
Preferably, the resultant peptide-oxymoφhone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and oxymoφhone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
Detailed 501 Page 19 3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein oxymoφhone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
Detailed 501 Page 20 16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein oxymoφhone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing oxymoφhone from said composition in a pH-dependent manner.
19. A method for protecting oxymoφhone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of oxymoφhone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching oxymoφhone to said polypeptide.
21. A method for delivering oxymoφhone to a patient comprising administering to said patient a composition comprising: a polypeptide; and oxymoφhone covalently attached to said polypeptide.
22. The method of claim 21 wherein oxymoφhone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein oxymoφhone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
Nϊ The present invention provides several benefits for active agent delivery. First, the invention can stabilize dihydrocodeine and prevent its digestion in the stomach. In addition, the
Detailed 501 Page 21 pharmacologic effect can be prolonged by delayed release of dihydrocodeine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises dihydrocodeine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, dihydrocodeine is covalently attached to the polypeptide via a ketal bond.
Preferably, the resultant peptide-dihydrocodeine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and dihydrocodeine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
Detailed 501 Page 22 7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein dihydrocodeine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
1 . The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein dihydrocodeine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing dihydrocodeine from said composition in a pH-dependent manner.
19. A method for protecting dihydrocodeine from degradation comprising covalently attaching said active agent to a polypeptide.
Detailed 501 Page 23 20. A method for controlling release of dihydrocodeine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching dihydrocodeine to said polypeptide.
21. A method for delivering dihydrocodeine to a patient comprising administering to said patient a composition comprising: a polypeptide; and dihydrocodeine covalently attached to said polypeptide.
22. The method of claim 21 wherein dihydrocodeine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein dihydrocodeine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
NIΪ The present invention provides several benefits for active agent delivery. First, the invention can stabilize dihydromoφhine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of dihydromoφhine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises dihydromoφhine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 24 In the present invention, dihydromoφhine is covalently attached to the polypeptide via the hydroxyl group.
Preferably, the resultant peptide-dihydromoφhine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and dihydromoφhine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein dihydromoφhine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The- composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
Detailed 501 Page 25 12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein dihydromoφhine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing dihydromoφhine from said composition in a pH-dependent manner.
19. A method for protecting dihydromoφhine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of dihydromoφhine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching dihydromoφhine to said polypeptide.
21. A method for delivering dihydromoφhine to a patient comprising administering to said patient a composition comprising: a polypeptide; and dihydromoφhine covalently attached to said.polypeptide.
22. The method of claim 21 wherein dihydromoφhine is released from said composition by an enzyme-catalyzed release.
Detailed 501 Page 26 23. The method of claim 21 wherein dihydromoφhine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
j ffi The present invention provides several benefits for active agent delivery. First, the invention can stabilize methyldihydromoφhinone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of methyldihydromoφhinone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises methyldihydromoφhinone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, methyldihydromoφhinone is covalently attached to the polypeptide via the hydroxyl group.
Preferably, the resultant peptide-methyldihydromoφhinone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and methyldihydromoφhinone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
Detailed 501 Page 27 3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein methyldihydromoφhinone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
Detailed 501 Page 28 16. The composition of claim 1 wherein said composition is in the fonn of an oral suspension.
17. The composition of claim 1 wherein methyldihydromoφhinone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing methyldihydromoφhinone from said composition in a pH-dependent manner.
19. A method for protecting methyldihydromoφhinone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of methyldihydromoφhinone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching methyldihydromoφhinone to said polypeptide.
21. A method for delivering methyldihydromoφhinone to a patient comprising administering to said patient a composition comprising: a polypeptide; and methyldihydromoφhinone covalently attached to said polypeptide.
22. The method of claim 21 wherein methyldihydromoφhinone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein methyldihydromoφhinone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
X The present invention provides several benefits for active agent delivery. First, the invention can stabilize codeine and promethazine and prevent its digestion in the stomach. In
Detailed 501 Page 29 addition, the pharmacologic effect can be prolonged by delayed release of codeine and promethazine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises codeine and promethazine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-codeine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 30 8. The composition of claim 1 wherein codeine and promethazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein codeine and promethazine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing codeine and promethazine from said composition in a pH-dependent manner.
19. A method for protecting codeine and promethazine from degradation comprising covalently attaching said active agent to a polypeptide.
Detailed 501 Page 31 20. A method for controlling release of codeine and promethazine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching codeine and promethazine to said polypeptide.
21. A method for delivering codeine and promethazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and promethazine covalently attached to said polypeptide.
22. The method of claim 21 wherein codeine and promethazine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein codeine and promethazine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
X, The present invention provides several benefits for active agent delivery. First, the invention can stabilize codeine, phenyleplirine and promethazine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of codeine, phenylephrine and promethazine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises codeine, phenylephrine and promethazine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 32 Preferably, the resultant peptide-codeine, phenylephrine and promethazine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and codeine, phenylephrine and promethazine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein codeine, phenylephrine and promethazine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
Detailed 501 Page 33 12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein codeine, phenylephrine and promethazine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing codeine, phenylephrine and promethazine from said composition in a pH-dependent manner.
19. A method for protecting codeine, phenylephrine and promethazine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of codeine, phenylephrine and promethazine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching codeine, phenylephrine and promethazine to said polypeptide.
21. A method for delivering codeine, phenylephrine and promethazine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine, phenylephrine and promethazine covalently attached to said polypeptide.
22. The method of claim 21 wherein codeine, phenylephrine and promethazine is released from said composition by an enzyme-catalyzed release.
Detailed 501 Page 34 23. The method of claim 21 wherein codeine, phenylephrine and promethazine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
jX The present invention provides several benefits for active agent delivery. First, the invention can stabilize codeine and guaifenesin and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of codeine and guaifenesin. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises codeine and guaifenesin covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-codeine and guaifenesin conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and codeine and guaifenesin covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide..
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
Detailed 501 Page 35 4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein codeine and guaifenesin is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
Detailed 501 Page 36 17. The composition of claim 1 wherein codeine and guaifenesin is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing codeine and guaifenesin from said composition in a pH-dependent manner.
19. A method for protecting codeine and guaifenesin from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of codeine and guaifenesin from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching codeine and guaifenesin to said polypeptide.
21. A method for delivering codeine and guaifenesin to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine and guaifenesin covalently attached to said polypeptide.
22. The method of claim 21 wherein codeine and guaifenesin is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein codeine and guaifenesin is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
jXfl The present invention provides several benefits for active agent delivery. First, the invention can stabilize codeine, guaifenesin and pseudoephidrine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of codeine, guaifenesin and pseudoephidrine. Furthermore, active agents can be combined to produce
Detailed 501 Page 37 synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises codeine, guaifenesin and pseudoephidrine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-codeine, guaifenesin and pseudoephidrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 38 8. The composition of claim 1 wherein codeine, guaifenesin and pseudoephidrine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein codeine, guaifenesin and pseudoephidrine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing codeine, guaifenesin and pseudoephidrine from said composition in a pH-dependent manner.
19. A method for protecting codeine, guaifenesin and pseudoephidrine from degradation comprising covalently attaching said active agent to a polypeptide.
Detailed 501 Page 39 20. A method for controlling release of codeine, guaifenesin and pseudoephidrine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching codeine, guaifenesin and pseudoephidrine to said polypeptide.
21. A method for delivering codeine, guaifenesin and pseudoephidrine to a patient comprising administering to said patient a composition comprising: a polypeptide; and codeine, guaifenesin and pseudoephidrine covalently attached to said polypeptide.
22. The method of claim 21 wherein codeine, guaifenesin and pseudoephidrine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein codeine, guaifenesin and pseudoephidrine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
Kltϊ The present invention provides several benefits for active agent delivery. First, the invention can stabilize aspirin, carisoprodol, and codeine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of aspirin, carisoprodol, and codeine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises aspirin, carisoprodol, and codeine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 40 Preferably, the resultant peptide-aspirin, carisoprodol, and codeine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and aspirin, carisoprodol, and codeine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein aspirin, carisoprodol, and codeine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
Detailed 501 Page 41 12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein aspirin, carisoprodol, and codeine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing aspirin, carisoprodol, and codeine from said composition in a pH-dependent manner.
19. A method for protecting aspirin, carisoprodol, and codeine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of aspirin, carisoprodol, and codeine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching aspirin, carisoprodol, and codeine to said polypeptide.
21. A method for delivering aspirin, carisoprodol, and codeine to a patient comprising administering to said patient a composition comprising: a polypeptide; and aspirin, carisoprodol, and codeine, covalently attached to said polypeptide.
22. The method of claim 21 wherein aspirin, carisoprodol, and codeine is released from said composition by an enzyme-catalyzed release.
Detailed 501 Page 42 23. The method of claim 21 wherein aspirin, carisoprodol, and codeine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
XfVj The present invention provides several benefits for active agent delivery. First, the invention can stabilize himatropine and hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of himatropine and hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises himatropine and hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-himatropine and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and himatropine and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
Detailed 501 Page 43 4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein himatropine and hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
Detailed 501 Page 44 17. The composition of claim 1 wherein himatropine and hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing himatropine and hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting himatropine and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of himatropine and hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching himatropine and hydrocodone to said polypeptide.
21. A method for delivering himatropine and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and himatropine and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein himatropine and hydrocodone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein himatropine and hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
XVj The present invention provides several benefits for active agent delivery. First, the invention can stabilize hydrocodone and phenylpropanolamine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of hydrocodone and phenylpropanolamine. Furthermore, active agents can be combined to produce
Detailed 501 Page 45 synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises hydrocodone and phenylpropanolamine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-hydrocodone and phenylpropanolamine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and hydrocodone and phenylpropanolamine covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 46 8. The composition of claim 1 wherein hydrocodone and phenylpropanolamine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein hydrocodone and phenylpropanolamine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing hydrocodone and phenylpropanolamine from said composition in a pH-dependent manner.
19. A method for protecting hydrocodone and phenylpropanolamine from degradation comprising covalently attaching said active agent to a polypeptide.
Detailed 501 Page 47 20. A method for controlling release of hydrocodone and phenylpropanolamine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching hydrocodone and phenylpropanolamine to said polypeptide.
21. A method for delivering hydrocodone and phenylpropanolamine to a patient comprising administering to said patient a composition comprising: a polypeptide; and hydrocodone and phenylpropanolamine covalently attached to said polypeptide.
22. The method of claim 21 wherein hydrocodone and phenylpropanolamine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein hydrocodone and phenylpropanolamine is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
{XVΪ The present invention provides several benefits for active agent delivery. First, the invention can stabilize acetaminophen and hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of acetaminophen and hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises acetaminophen and hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Detailed 501 Page 48 Preferably, the resultant peptide-acetaminophen and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and acetaminophen and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein acetaminophen and hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
Detailed 501 Page 49 12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein acetaminophen and hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing acetaminophen and hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting acetaminophen and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of acetaminophen and hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching acetaminophen and hydrocodone to said polypeptide.
21. A method for delivering acetaminophen and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and acetaminophen and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein acetaminophen and hydrocodone is released from said composition by an enzyme-catalyzed release.
Detailed 501 Page 50 23. The method of claim 21 wherein acetaminophen and hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
! $Tj The present invention provides several benefits for active agent delivery. First, the invention can stabilize chloφheniramine, hydrocodone and pseudoephedrine and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of chloφheniramine, hydrocodone and pseudoephedrine. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises chloφheniramine, hydrocodone and pseudoephedrine covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-chloφheniramine, hydrocodone and pseudoephedrine conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and chloφheniramine, hydrocodone and pseudoephedrine covalently attached to said polypeptide.
Detailed 501 Page 51 2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein chloφheniramine, hydrocodone and pseudoephedrine is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
Detailed 501 Page 52 15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein chloφheniramine, hydrocodone and pseudoephedrine is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing chloφheniramine, hydrocodone and pseudoephedrine from said composition in a pH-dependent manner.
19. A method for protecting chloφheniramine, hydrocodone and pseudoephedrine from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of chloφheniramine, hydrocodone and pseudoephedrine from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching chloφheniramine, hydrocodone and pseudoephedrine to said polypeptide.
21. A method for delivering chloφheniramine, hydrocodone and pseudoephedrine to a patient comprising administering to said patient a composition comprising: a polypeptide; and chloφheniramine, hydrocodone and pseudoephedrine covalently attached to said polypeptide.
22. The method of claim 21 wherein chloφheniramine, hydrocodone and pseudoephedrine is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein chloφheniramine, hydrocodone and pseudoephedrine is released from said composition by a pH-dependent unfolding of said polypeptide.
Detailed 501 Page 53 24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
JKNlf The present invention provides several benefits for active agent delivery. First, the invention can stabilize guaifenesin and hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of guaifenesin and hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises guaifenesin and hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-guaifenesin and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and guaifenesin and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
Detailed 501 Page 54 5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein guaifenesin and hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein guaifenesin and hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
Detailed 501 Page 55 18. The composition of claim 1 wherein said polypeptide is capable of releasing guaifenesin and hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting guaifenesin and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of guaifenesin and hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching guaifenesin and hydrocodone to said polypeptide.
21. A method for delivering guaifenesin and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and guaifenesin and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein guaifenesin and hydrocodone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein guaifenesin and hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
XΪX The present invention provides several benefits for active agent delivery. First, the invention can stabilize ibuprofen and hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of ibuprofen and hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
Detailed 501 Page 56 The composition of the invention comprises ibuprofen and hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-ibuprofen and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and ibuprofen and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein ibuprofen and hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
Detailed 501 Page 57 10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein ibuprofen and hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing ibuprofen and hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting ibuprofen and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of ibuprofen and hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching ibuprofen and hydrocodone to said polypeptide.
21. A method for delivering ibuprofen and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and
Detailed 501 Page 58 ibuprofen and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein ibuprofen and hydrocodone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein ibuprofen and hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
The present invention provides several benefits for active agent delivery. First, the invention can stabilize chloφheniramine and hydrocodone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of chloφheniramine and hydrocodone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises chloφheniramine and hydrocodone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
Preferably, the resultant peptide-chloφheniramine and hydrocodone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and
Detailed 501 Page 59 chloφheniramine and hydrocodone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein chloφheniramine and hydrocodone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
Detailed 501 Page 60 15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein chloφheniramine and hydrocodone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing chloφheniramine and hydrocodone from said composition in a pH-dependent manner.
19. A method for protecting chloφheniramine and hydrocodone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of chloφheniramine and hydrocodone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching chloφheniramine and hydrocodone to said polypeptide.
21. A method for delivering chloφheniramine and hydrocodone to a patient comprising administering to said patient a composition comprising: a polypeptide; and chloφheniramine and hydrocodone covalently attached to said polypeptide.
22. The method of claim 21 wherein chloφheniramine and hydrocodone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein chloφheniramine and hydrocodone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
Detailed 501 Page 61 XXI The present invention provides several benefits for active agent delivery. First, the invention can stabilize naltrexone and prevent its digestion in the stomach. In addition, the pharmacologic effect can be prolonged by delayed release of naltrexone. Furthermore, active agents can be combined to produce synergistic effects. Also, absoφtion of the active agent in the intestinal tract can be enhanced. The invention also allows targeted delivery of active agents to specifics sites of action.
The composition of the invention comprises naltrexone covalently attached to a polypeptide. Preferably, the polypeptide is (i) an oligopeptide, (ii) a homopolymer of one of the twenty naturally occurring amino acids, (iii) a heteropolymer of two or more naturally occurring amino acids, (iv) a homopolymer of a synthetic amino acid, (v) a heteropolymer of two or more synthetic amino acids or (vi) a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
In the present invention, naltrexone is covalently attached to the polypeptide via a ketal bond.
Preferably, the resultant peptide-naltrexone conjugate is formulated into a tablet using suitable excipients and can either be wet granulated or dry compressed.
1. A pharmaceutical composition comprising: a polypeptide; and naltrexone covalently attached to said polypeptide.
2. The composition of claim 1 wherein said polypeptide is an oligopeptide.
3. The composition of claim 1 wherein said polypeptide is a homopolymer of a naturally occurring amino acid.
4. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more naturally occurring amino acids.
5. The composition of claim 1 wherein said polypeptide is a homopolymer of a synthetic amino acid.
Detailed 501 Page 62 6. The composition of claim 1 wherein said polypeptide is a heteropolymer of two or more synthetic amino acids.
7. The composition of claim 1 wherein said polypeptide is a heteropolymer of one or more naturally occurring amino acids and one or more synthetic amino acids.
8. The composition of claim 1 wherein naltrexone is covalently attached to a side chain, the N-terminus or the C-terminus of said polypeptide.
9. The composition of claim 1 further comprising a microencapsulating agent.
10. The composition of claim 9 wherein said microencapsulating agent is selected from the group consisting of polyethylene glycol (PEG), an amino acid, a sugar and a salt.
11. The composition of claim 1 further comprising an adjuvant.
12. The composition of claim 11 wherein said adjuvant activates an intestinal transporter.
13. The composition of claim 1 further comprising a pharmaceutically acceptable excipient.
14. The composition of claim 1 wherein said composition is in the form of an ingestable tablet.
15. The composition of claim 1 wherein said composition is in the form of an intravenous preparation.
16. The composition of claim 1 wherein said composition is in the form of an oral suspension.
17. The composition of claim 1 wherein naltrexone is conformationally protected by folding of said polypeptide about said active agent.
18. The composition of claim 1 wherein said polypeptide is capable of releasing naltrexone from said composition in a pH-dependent manner.
Detailed 501 Page 63 _ 19. A method for protecting naltrexone from degradation comprising covalently attaching said active agent to a polypeptide.
20. A method for controlling release of naltrexone from a composition wherein said composition comprises a polypeptide, said method comprising covalently attaching naltrexone to said polypeptide.
21. A method for delivering naltrexone to a patient comprising administering to said patient a composition comprising: a polypeptide; and naltrexone covalently attached to said polypeptide.
22. The method of claim 21 wherein naltrexone is released from said composition by an enzyme-catalyzed release.
23. The method of claim 21 wherein naltrexone is released from said composition by a pH-dependent unfolding of said polypeptide.
24. The method of claim 21 wherein said active agent is released from said composition in a sustained release.
25. The method of claim 21 wherein said composition further comprises an adjuvant covalently attached to said polypeptide and wherein release of said adjuvant from said composition is controlled by said polypeptide.
Detailed 501 Page 64

Claims

What is claimed is:
1. A pharmaceutical composition comprising: a polypeptide; and an active agent attached to said polypeptide.
PCT/US2001/043115 2000-08-22 2001-11-16 A novel pharmaceutical compound and methods of making and using same WO2002051432A1 (en)

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US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
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EP1490090A2 (en) * 2002-02-22 2004-12-29 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
EP1490090A4 (en) * 2002-02-22 2006-09-20 New River Pharmaceuticals Inc Active agent delivery systems and methods for protecting and administering active agents
EP2266590A3 (en) * 2002-02-22 2011-04-20 Shire LLC Active agent delivery sytems and methods for protecting and administering active agents
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US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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