US20030044458A1 - Oral dosage form comprising a therapeutic agent and an adverse-effect agent - Google Patents

Oral dosage form comprising a therapeutic agent and an adverse-effect agent Download PDF

Info

Publication number
US20030044458A1
US20030044458A1 US10/208,817 US20881702A US2003044458A1 US 20030044458 A1 US20030044458 A1 US 20030044458A1 US 20881702 A US20881702 A US 20881702A US 2003044458 A1 US2003044458 A1 US 2003044458A1
Authority
US
United States
Prior art keywords
dosage form
oral dosage
agents
composition
therapeutic agent
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US10/208,817
Inventor
Curtis Wright
Anthony Carpanzano
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Purdue Pharma LP
Original Assignee
Euro Celtique SA
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 Euro Celtique SA filed Critical Euro Celtique SA
Priority to US10/208,817 priority Critical patent/US20030044458A1/en
Priority to RU2004106620/15A priority patent/RU2004106620A/en
Priority to CA2456601A priority patent/CA2456601C/en
Priority to BR0211781-9A priority patent/BR0211781A/en
Priority to MXPA04001098A priority patent/MXPA04001098A/en
Priority to SI200230884T priority patent/SI1414459T1/en
Priority to DE60234604T priority patent/DE60234604D1/en
Priority to ES02761250T priority patent/ES2337664T3/en
Priority to EP02761250A priority patent/EP1414459B1/en
Priority to DE20220838U priority patent/DE20220838U1/en
Priority to IL16019502A priority patent/IL160195A0/en
Priority to KR1020087030854A priority patent/KR20090005247A/en
Priority to JP2003518547A priority patent/JP5143995B2/en
Priority to DK02761250.6T priority patent/DK1414459T3/en
Priority to KR1020047001854A priority patent/KR100893895B1/en
Priority to AT02761250T priority patent/ATE450259T1/en
Assigned to EURO-CELTIQUE, S.A. reassignment EURO-CELTIQUE, S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CARPANZANO, ANTHONY E., WRIGHT, IV, CURTIS
Publication of US20030044458A1 publication Critical patent/US20030044458A1/en
Priority to US10/948,575 priority patent/US7384653B2/en
Priority to HK04108654.6A priority patent/HK1067524A1/en
Assigned to PURDUE PHARMA L.P. reassignment PURDUE PHARMA L.P. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EURO-CELTIQUE S.A.
Priority to JP2008295477A priority patent/JP5485538B2/en
Priority to CY20101100149T priority patent/CY1109816T1/en
Priority to JP2013101285A priority patent/JP2013189447A/en
Priority to US13/923,362 priority patent/USRE45822E1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/30Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36Opioid-abuse
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1617Organic compounds, e.g. phospholipids, fats
    • A61K9/1623Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • This invention relates generally to an oral dosage form comprising a therapeutic agent and an adverse-effect agent.
  • opioids are excellent analgesic agents that can control severe and/or chronic pain, such as cancer pain and post-operative pain, but are also subject to abuse by drug users.
  • Opioids also known as opioid agonists, are a group of drugs that exhibit opium- or morphine-like properties. Opioids are employed primarily as moderate to strong analgesic agents, but provide other pharmacological effects as well.
  • Prior art approaches to this problem have involved combining an opioid with an opioid antagonist. When administered orally, these combinations provide the pharmacologic action of the opioid with minimal action of the antagonist. When administered parenterally, however, the antagonist can be profoundly antagonistic to the opioid.
  • Particular examples of such combinations include compositions comprising naloxone and morphine or oxymorphone (U.S. Pat. No. 3,493,657 to Lewenstein et al.); methadone and naloxone (U.S. Pat. No. 3,773,955 to Pachter et al.); methadol or acetyl methadol and naloxone (U.S. Pat. No.
  • TALWIN NX Sanofi-Winthrop
  • VALORON N a combination of tilidine and naloxone
  • TEMGESIC NX a combination of buprenorphine and naloxone
  • U.S. Pat. No. 6,228,863 to Palermo et al. discloses an oral dosage form of an opioid agonist and an opioid antagonist that reduces the abuse potential of the opioid by combining the agonist and antagonist such that at least two steps are required to separate them.
  • U.S. Pat. No. 5,935,975 to Rose et al. discloses a method for treating drug dependency by the combined administration of the drug or an agonist of the drug and an antagonist of the drug.
  • the present invention relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer.
  • the invention further relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer.
  • the invention further relates to a method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of the invention.
  • the method comprises administering to a patient in need thereof an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent; the second composition comprises an effective amount of an adverse-effect agent; an effective amount of the therapeutic agent is released in the patient's small intestine; and less than an effective amount of the adverse-effect agent is released in the patient's gastrointestinal tract.
  • the invention still further relates to a method for preparing an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer, the method comprising the step of preparing the oral dosage form as set forth herein.
  • the invention still further relates to a method for preparing an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer, the method comprising the step of preparing the oral dosage form as set forth herein.
  • FIG. 1 shows a cross-sectional view of a coated granule of a first composition useful in the oral dosage forms of the invention.
  • FIG. 2 shows a cross-sectional view of a coated granule of a second composition useful in the oral dosage forms of the invention.
  • FIG. 3 shows a cross-sectional view of a first embodiment of the invention, which is a capsule containing coated granules of a first composition and coated granules of a second composition.
  • FIG. 4 shows a cross-sectional view of a second embodiment of the invention, which is a two-layer tablet.
  • FIG. 5 shows a cross-sectional view of a third embodiment of the invention, which is a tablet containing coated granules of a first composition and coated granules of a second composition.
  • FIG. 6 shows a cross-sectional view of a fourth embodiment of the invention, which is a coated tablet containing a first composition, with granules of a coated second composition dispersed throughout the first composition.
  • FIG. 7 shows a cross-sectional view of a fifth embodiment of the invention, which is a tablet wherein a coated composition of the adverse-effect agent is further coated with the therapeutic agent and then the therapeutic agent is coated.
  • the oral dosage form of the present invention comprises a first composition and a second composition.
  • the first composition comprises a therapeutic agent
  • the second composition comprises an adverse-effect agent.
  • terapéutica agent means any drug intended to have a beneficial effect when administered to a patient.
  • the term “adverse-effect agent,” as used herein, means an agent that (A) reduces or eliminates one or more pharmacological effects of the therapeutic agent, such as a euphoric or toxic effect or (B) causes an undesired physiological reaction, such as emesis.
  • the second composition is coated with a layer that is substantially insoluble in the gastrointestinal tract.
  • the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer, which is not dissolved when orally administered to a patient.
  • both the first composition and second composition have a coating comprising at least two layers, an acid-soluble layer and a base-soluble layer, but the order of the layers in the coating on the first composition is different from that of the layers in the coating on the second composition.
  • the coating covering the first composition comprises an outer acid-soluble layer and an inner base-soluble layer, which are dissolved when orally administered to a patient.
  • the coating covering the second composition comprises an outer base-soluble layer, which gets dissolved when orally administered, and an inner acid-soluble layer, which does not get dissolved when orally administered to a patient.
  • the oral dosage form When orally administered to a patient, the oral dosage form passes through the stomach first, where its acidic environment dissolves the first composition's outer acid-soluble layer, and then passes into the small intestine, where its basic environment dissolves the first composition's inner base-soluble layer.
  • the therapeutic agent can be absorbed by the body.
  • the second composition is coated with an outer base-soluble layer, which is substantially insoluble in the stomach's acidic environment. Therefore, the second composition passes through the stomach with both the outer base-soluble layer and the inner acid-soluble layer intact.
  • the outer base-soluble layer dissolves, exposing the inner acid-soluble layer, which is substantially insoluble in the small intestine's basic environment, so that the adverse-effect agent cannot be absorbed by the body.
  • the oral dosage form of the present invention is orally administered to a patient, for example a human, as intended, only the therapeutic agent is released in the gastrointestinal tract and absorbed by the patient; the adverse-effect agent is not released and, therefore, not available for absorption into the body.
  • the therapeutic agent works as if it were administered alone without the adverse-effect agent, since only the therapeutic agent is available for absorption by the body.
  • the oral dosage form of the present invention is tampered with, e.g., chewed, crushed, ground or dissolved, particularly in a solvent with heat (e.g., greater than about 45° C. to about 50° C.), then not only the therapeutic agent but also the adverse-effect agent becomes available for absorption into the body.
  • the adverse-effect agent can then exert its effect by either reducing the effect of the therapeutic agent or eliciting an unpleasant effect in the patient.
  • the adverse-effect agent is an antagonist of the therapeutic agent, the effects of the therapeutic agent are drastically diminished or even eliminated by the effects of the adverse-effect agent.
  • the opioid antagonist becomes bioavailable, interfering with opioid-receptor binding and reducing the opioid antagonist's pharmacological effects. Accordingly, only patients who take the dosage form of the present invention as intended, i.e, orally as an intact dosage form, can experience the full pharmacological effects of the therapeutic agent.
  • the adverse-effect agent is an emetic agent and the oral dosage form is tampered with, the emetic agent induces vomiting which discourages the user from tampering with the dosage form.
  • the oral dosage form of the invention not only discourages users from tampering with it, but can also be effective to remove the therapeutic agent from subject's body. Abusing the therapeutic agent becomes less desirable when present in the oral dosage form of the present invention because, when tampered with, the adverse-effect agent exerts its undesirable effects.
  • the first composition is intended to be released slowly after it is orally administered to the subject. This prevents the burst, which some abusers seek.
  • the first composition can be formulated as a slow release formulation, for example, by further coating the first composition with a sustained-release coating that slowly dissolves so that all the therapeutic agent is not released at once.
  • the sustained-release coating is an innermost layer.
  • the first composition can be formulated as a slow release formulation by incorporating the therapeutic agent into a matrix that slowly releases the therapeutic agent over time. Therapeutic agents intended to be released slowly, when orally administered to a subject, may have side effects if released all at once, rather than slowly.
  • the coated second composition prevents tampering, which would result in immediate release of the therapeutic agent.
  • FIG. 1 shows a cross-sectional view of an embodiment of the coated first composition 10 .
  • a first composition 14 is covered with an innermost sustained-release coating 13 (optional), an inner base-soluble layer 12 , and an outer acid-soluble layer 11 .
  • FIG. 2 shows a cross-sectional view of an embodiment of the coated second composition 20 .
  • a second composition 24 is covered with an inner acid-soluble layer 23 , an outer base-soluble layer 22 and an outermost layer that is substantially insoluble in the gastrointestinal tract 21 (optional).
  • any kind of therapeutic agent can be used in the oral dosage forms of the present invention.
  • the oral dosage from is used in situations where there is a potential toxicity or overdose associated with the uncontrolled release of the drug due to tampering with the dosage form.
  • useful therapeutic agents include, but are not limited to, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile-dysfunction-improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, ⁇ -blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, levo
  • compositions include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfonate salts,
  • the therapeutic agent has potential for abuse.
  • the abuse potential of a drug is established by many factors, which may include the following: (1) the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the degree to which the drug induces euphoria similar to that produced by morphine and other opioids.
  • Opioids refers to a substance that binds, optionally stereo-specifically, to any of several subspecies of opioid receptors and produces an agonist action.
  • Opioids include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydro
  • the opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the opioid agonist is oxycodone or hydrocodone.
  • benzodiazepines refers to drugs that are derivatives of benzodiazepine and are able to depress the central nervous system.
  • Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, pharmaceutically acceptable salts thereof, and mixture thereof.
  • Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2,4,6, -trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • Stimulants refer to drugs that stimulate the central nervous system.
  • Stimulants include, but are not limited to, amphetamines, such as amphetamine, amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, pharmaceutically acceptable salts thereof and mixtures thereof.
  • therapeutic agent having potential for abuse include, but are not limited to, dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, and detropropoxyphene.
  • the therapeutic agent may also be an agent intended for delivery to the colon.
  • Therapeutic agents intended for delivery to the colon include, but are not limited to, agents that act locally in the colonic region to treat a colon diseases such as irritable bowel syndrome, irritable bowel disease, Crohns disease, constipation, post operative atony, gastrointestinal infections, and therapeutic agents that deliver antigenic material to the lymphoid tissue.
  • Agents for the treatment of colon disease include, but are not limited to 5-ASA; steroids, such as hydrocortisone and budesonide; laxatives; octreotide; cisapride; anticholinergics; opioids; calcium channel blockers; DNA for delivery to the cells of the colon; glucosamine; thromboxane A 2 synthetase inhibitors, such as Ridogrel; 5HT3-antagonists, such as ondansetron; antibodies against infectious bacteria, such as Clostridium difficile ; and antiviral agents, for example, for the prophylaxis of HIV.
  • the therapeutic agent can be an agent that is systemically active and for which absorption is improved in the colon region.
  • drugs include polar compounds such as: heparins; insulin; calcitonins; human growth hormone (HGH); growth hormone releasing hormone (GHRH); interferons; somatostatin and analogues such as octreotide and vapreotide; erythropoietin (EPO); granulocyte colony stimulating factor (GCSF); parathyroid hormone (PTH); luteinising hormone releasing hormone (LHRH) and analogues thereof; atrial natriuretic factor (ANF); vasopressin; desmopressin; calcitonin gene related peptide (CGRP); and analgesics.
  • polar compounds such as: heparins; insulin; calcitonins; human growth hormone (HGH); growth hormone releasing hormone (GHRH); interferons; somatostatin and analogues such as
  • the adverse-effect agent can be an agent that reduces or eliminates the therapeutic agent's pharmacological activities including, but not limited to: (1) the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the induction of euphoria similar to that produced by morphine and other opioids.
  • Adverse-effect agents that reduce or eliminate the pharmacological effects of the therapeutic agent include, but are not limited to, antagonists of the therapeutic agent agonist.
  • an opioid antagonist can be used as the adverse-effect agent.
  • a benzodiazepine antagonist when used as the therapeutic agent in the oral dosage form of the present invention, a benzodiazepine antagonist can be used as the adverse-effect agent.
  • a barbiturate when used as a therapeutic agent in the oral dosage form of the present invention, a barbiturate antagonist can be used as the adverse-effect agent.
  • an amphetamine when used as a therapeutic agent in the oral dosage form of the present invention, an amphetamine antagonist can be used as the adverse-effect agent.
  • the therapeutic agent is toxic when dosed above its normal therapeutic range, i.e., there is a potential for an overdose, then an antidote of the toxic therapeutic agent can be used as the adverse-effect agent.
  • compositions include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfon
  • Opioid antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, naloxone, naltrexone, nalmefene, cyclazacine, levallorphan, and mixtures thereof.
  • the opioid antagonist is naloxone or naltrexone.
  • Benzodiazepine antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, flumazenil.
  • Barbiturate antagonist which can be used as the adverse-effect agent of the present invention include, but are not limited to, amphetamines, described herein.
  • Stimulant antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, benzodiazepines, described herein.
  • the adverse-effect agent is an agent that causes an undesired physiological reaction, such as emesis.
  • This type of adverse-effect agent can be used with any kind of therapeutic agent including an opioid, a benzodiazepine, a barbiturate, and a stimulant.
  • emetic agents suitable for use as the adverse-effect agent in the present invention includes any drug that safely and effectively induces vomiting after administration including, but not limited to, ipecac and apomorphine.
  • Examples of useful coatings that are substantially insoluble in the gastrointestinal tract include, but are not limited to, coatings comprising a hydrophobic material.
  • the coating that is substantially insoluble in the gastrointestinal tract comprises a cellulose polymer.
  • the cellulose polymer is a cellulose ether, a cellulose ester, or a cellulose ester ether.
  • the cellulose polymers have a degree of substitution, D.S., on the anhydroglucose unit of from zero up to and including 3.
  • degree of substitution is meant the average number of hydroxyl groups present on the anhydroglucose unit of the cellulose polymer that are replaced by a substituting group.
  • Representative cellulose polymers include, but are not limited to, polymers selected from cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, and tricellulose alkanylates, mono, di, and tricellulose aroylates, and mono, di, and tricellulose alkenylates.
  • Exemplary cellulose polymers include cellulose acetate having an acetyl content up to about 21%; cellulose acetate having an acetyl content up to about 32 to 39.8%; cellulose acetate having a D.S. of about 1 to 2 and an acetyl content of about 21 to 35%; and cellulose acetate having a D.S.
  • the cellulose polymer is ethylcellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, or cellulose triacetate.
  • the ethylcellulose has an ethoxy content of about 44 to 55%.
  • More specific cellulose polymers include cellulose propionate having a D.S. of about 1.8 and a propyl content of about 39.2 to 45% and a hydroxyl content of about 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of about 1.8, an acetyl content of about 13 to 15%, and a butyryl content of about 34 to 39%; cellulose acetate butyrate having an acetyl content of about 2 to 29%, a butyryl content of about 17 to 53%, and a hydroxyl content of about 0.5 to 4.7%; cellulose triacylate having a D.S.
  • cellulose diacylates having a D.S. of about 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose such as cellulose acetate butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate.
  • Additional cellulose polymers useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract include, but are not limited to, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate.
  • Acrylic polymers are also useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract.
  • Acrylic polymers include, but are not limited to, acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters (e.g., the copolymer of acrylic acid lower alkyl ester and methacrylic acid lower alkyl ester) containing about 0.02 to 0.03 moles of a tri (lower alkyl) ammonium group per mole of acrylic and methacrylic monomer.
  • the acrylic resin is Eudragit RS 30 D manufactured by Rohm Tech Inc. of Fitchburg, Mass.
  • Eudragit RS 30 D is a water insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammonioethyl methacrylate chloride (TAM) in which the molar ratio of TAM to the remaining components (EA and MM) is 1:40.
  • Aqueous suspensions of acrylic resins such as EUDRAGIT RS can be used to coat the adverse-effect agent of the invention.
  • the acrylic polymer is selected from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylates, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • a cellulose polymer or an acrylic polymer is used as a coating that is substantially insoluble in the gastrointestinal tract
  • suitable plasticizers e.g., acetyl triethyl citrate and/or acetyl tributyl citrate
  • the coating that is substantially insoluble in the gastrointestinal tract may also contain additives such as coloring agents, talc, and/or magnesium stearate, which are well known in the coating art.
  • Polymers useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract also include, but not limited to, poly(lactic/glycolic acid) (“PLGA”) copolymers, polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polyesters, polydioxanone, polygluconate, polylactic-acid polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesters, and mixtures thereof.
  • PLGA poly(lactic/glycolic acid)
  • the polymer comprises a poly(lactic/glycolic acid) copolymer, a copolymer of lactic and glycolic acid, having a molecular weight of about 2,000 to about 500,000 daltons.
  • the ratio of lactic acid to glycolic acid is from about 100:0 to about 25:75, in one embodiment from about 65:35.
  • Poly(lactic/glycolic acid) may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 to Ludwig et al., the disclosure of which is expressly incorporated herein by reference thereto.
  • the coating that is substantially insoluble in the gastrointestinal tract is of sufficient thickness to prevent release of the adverse-effect agent from the second composition while it is in the gastrointestinal tract.
  • Many of the coatings that are substantially insoluble in the gastrointestinal tract are slowly biodegraded or dissolved in an aqueous environment and, after sufficient time, will eventually release the adverse-effect agent. Accordingly, the coating should be of a sufficient thickness that does not permit the adverse effect agent to be released during the time that the adverse-effect agent is present in the gastrointestinal tract. The thickness of the coating will depend on the characteristics of the coating composition being used.
  • the coating useful in the present invention comprises an acid-soluble layer.
  • the term “acid-soluble layer” refers to a layer that is substantially soluble at a pH of less than about pH 5.0, but substantially insoluble at a pH of greater than about pH 5.5.
  • the acid-soluble layer is substantially soluble at a pH of less than about pH 4.0, but substantially insoluble at a pH of greater than about pH 4.5.
  • the acid-soluble layer is substantially soluble at a pH of less than about pH 3.0, but substantially insoluble at a pH of greater than about pH 3.5.
  • the acid-soluble layer typically comprises an acid-soluble polymer.
  • the phrase “substantially soluble,” when used to describe a layer, means soluble to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is made available to the environment of the gastrointestinal tract in an effective amount.
  • the phrase “substantially insoluble,” when used to describe a layer, means that the layer does not dissolve or does so only to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is not made available to the environment of the gastrointestinal tract or is made available to the environment of the gastrointestinal tract in less than an effective amount.
  • the acid-soluble polymer has a dimethylaminoethyl ammonium functionality.
  • a polymer is commercially available as EUDRAGIT E 100 or Eudragit E PO from Rohm Pharma GmbH, Rothstat, Germany. Examples of other suitable acid-soluble polymers can be found in “Materials Used in Pharmaceutical Formulations,” edited by A. T. Florence, Society of Chemical Industries, 1984.
  • the coating of the present invention comprises a base-soluble layer.
  • base-soluble layer refers to a layer that is substantially soluble at a pH of greater than about pH 5.5, but substantially insoluble at a pH of less than about 5.0.
  • the base-soluble layer is substantially soluble at a pH of greater than about pH 6.5, but substantially insoluble at a pH of less than about 6.0.
  • the base-soluble layer is substantially soluble at a pH of greater than about pH 7.5, but substantially insoluble at a pH of less than about 7.0.
  • the base-soluble layer generally comprises a base-soluble polymer.
  • the base-soluble polymer is an anionic copolymer of methacrylic acid and methacrylates having carboxylic acid functionalities.
  • a polymer is commercially available as EUDRAGIT L 100-55, EUDRAGIT L 30D-55, EUDRAGIT L, or EUDRAGIT S 100 (commercially available from Rohm Pharma GmbH, Rothstat, Germany).
  • EUDRAGIT L 100-55 is commercially available as EUDRAGIT L 100-55, EUDRAGIT L 30D-55, EUDRAGIT L, or EUDRAGIT S 100 (commercially available from Rohm Pharma GmbH,mannstat, Germany).
  • EUDRAGIT S 100 commercially available from Rohm Pharma GmbH, Rothstat, Germany.
  • Examples of other suitable base-soluble polymers can be found in “Materials Used in Pharmaceutical Formulations,” edited by A. T. Florence, Society of Chemical Industries, 1984.
  • the therapeutic agent is released slowly over time.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the oral dosage forms of the invention.
  • Single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention.
  • the controlled release of the therapeutic agent from the first composition can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • the controlled release of the therapeutic agent can be achieved, for example by coating or admixing the therapeutic agent with a controlled-release component.
  • controlled-release component in the context of the present invention is defined herein as a compound or mixture of compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the therapeutic agent from the first composition of the oral dosage form of the invention.
  • the therapeutic agent is formulated for controlled release by coating the therapeutic agent with a sustained-release coating.
  • sustained-release coating refers to a coating made of one or more materials that allows for the slow release of the drug over time.
  • the sustained-release coating is a pH-independent layer, i.e., a coating that has a defined permeability that is not influenced by pH.
  • pH-independent layer means that the difference, at any given time, between the amount of drug released at, e.g., pH 1.6, and the amount released at any other pH, e.g., pH 7.2, when measured using a specific method, such as, for example, the USP Paddle Method at 100 rpm in 900 ml aqueous buffer, is 10% (by weight) or less.
  • any sustained-release coating known to those of ordinary skill in the art can be used in the oral dosage form of the invention.
  • Sustained-release coatings are well known in the art (See, e.g., Remingtons Pharmaceutical Sciences, 18 th ed. Mack Publishing Co., Easton, Pa., 1990, p. 1670).
  • the sustained-release coating comprises a water-insoluble material, such as a wax or a wax-like substance, fatty alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble cellulose, polymer of acrylic and/or methacrylic acid, or any other slowly digestible or dissolvable solid known in the art.
  • the coating formulations useful in the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free.
  • the film coat is applied to the first composition, for example when in the form of a tablet or a granule, to achieve a weight gain level from about 2 to about 25 percent.
  • the film coat may be lesser or greater depending upon the physical properties of the therapeutic agent included in the formulation and the desired release rate.
  • the sustained-release coating comprises a hydrophobic polymer.
  • the hydrophobic polymer comprises a water-insoluble cellulosic polymer, such as an alkylcellulose, for example ethylcellulose; an acrylic polymer; or mixtures thereof.
  • the sustained-release coating comprises an acrylic polymer.
  • Any acrylic polymer that is pharmaceutically acceptable can be used.
  • the acrylic polymer can be an acrylate or methacrylate, formed from one or more of acrylic acid, methacrylic acid, acrylic acid esters, and methacrylic acid esters.
  • These polymers can be cationic, anionic, or non-ionic, so that it is possible to obtain polymers that are soluble in, or resistant to dissolution, over a wide range of pH values.
  • Some acrylic polymers useful for the purposes of the present invention are those that are marketed under the trade name EUDRAGIT (commercially available from Rohm Pharma GmbH, Rothstat, Germany).
  • acrylic polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate polymers, methyl methacrylate copolymers, ethoxyethyl methacrylates polymers, cyanoethyl methacrylate polymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the acrylic polymer can comprise one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers are well known in the art, and are fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • polymers suitable for use in the invention include, but are not limited to, hydroxyalkylcelluloses; poly(lactic/glycolic acid) (“PLGA”); polylactide; polyglycolide; polyanhydrides; polyorthoesters; polycaprolactone; polyphosphazenes; polysaccharides; proteinaceous polymers; polyesters; polydioxanone; polygluconate; polylactic-acid polyethylene oxide copolymers; poly(hydroxybutyrate) polyphosphoesters; or mixtures thereof.
  • PLGA poly(lactic/glycolic acid)
  • polylactide polyglycolide
  • polyanhydrides polyorthoesters
  • polycaprolactone polyphosphazenes
  • polysaccharides proteinaceous polymers
  • polyesters polydioxanone
  • polygluconate polylactic-acid polyethylene oxide copolymers
  • poly(hydroxybutyrate) polyphosphoesters or mixtures thereof.
  • ethylcellulose has a relatively high glass-transition temperature (“Tg”) and does not form flexible films under normal coating conditions, it is often necessary to plasticize the ethylcellulose before using it as a coating material.
  • Tg glass-transition temperature
  • the suitability of a plasticizer may relate to its affinity or solvating power for the polymer and its effectiveness for interfering with polymer-polymer attachments. Such activity imparts a desired flexibility to the polymer by relieving molecular rigidity.
  • An important parameter in determining the suitability of a plasticizer for a polymer is related to the Tg of the polymer.
  • the Tg is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer. Below the Tg, polymer chain mobility is severely restricted.
  • the polymer will behave as a glass at room temperature, being hard, non-pliable, and rather brittle: properties that are restrictive for a film coating since the coated dosage form may be subjected to a certain amount of external stress.
  • Incorporation of suitable plasticizers into the polymer matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and, thus, better able to resist mechanical stress.
  • Other aspects of suitable plasticizers include their ability to act as a good “swelling agent,” especially for ethylcellulose, and to improve the solubility profile of the coating in water.
  • plasticizers for ethylcellulose include dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate, although other plasticizers (such as acetylated monoglycerides, phthalate esters and castor oil) can be used.
  • triethyl citrate is a plasticizer for the aqueous dispersions of ethyl cellulose.
  • plasticizers for the acrylic polymers useful in the present invention include, but are not limited to, citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and 1,2-propylene glycol.
  • Other plasticizers suitable for enhancing the elasticity of the films formed from acrylic films, such as EUDRAGIT RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • the plasticizer is typically added to a solution of the polymer in an aqueous or non-aqueous solvent that is used to coat the first composition.
  • the amount of plasticizer included in a coating solution is based on the concentration of the coating.
  • the amount of plasticizer included in a coating solution of ethylcellulose is from about 1 to about 50 percent by weight of the ethylcellulose.
  • the amount of plasticizer included in a coating solution of an aqueous dispersion of acrylic polymer is about 20%.
  • the necessary concentration of the plasticizer for a particular coating solution and method of application can be readily determined by one of ordinary skill in the art without undue experimentation.
  • a commercially available aqueous dispersion of ethylcellulose suitable for use in the invention is AQUACOAT (commercially available from FMC Corp., Philadelphia, Pa., U.S.A.).
  • AQUACOAT is prepared by dissolving ethylcellulose in a water-immiscible organic solvent and then emulsifying the organic solvent in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. Plasticizer is not incorporated in the pseudolatex during the manufacturing phase; therefore, prior to using the pseudolatex as a coating, it is necessary to intimately mix the AQUACOAT with a suitable plasticizer.
  • SURELEASE commercially available from Colorcon, Inc., West Point, Pa., U.S.A.
  • the acrylic coating comprises an acrylic resin lacquer used in the form of an aqueous dispersion, such as EUDRAGIT.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma GmbH, Stammstat, Germany under the tradenames EUDRAGIT RL 30 D and EUDRAGIT RS 30 D. These materials are copolymers of acrylic and methacrylic esters having a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL 30 D and 1:40 in EUDRAGIT RS 30 D. The mean molecular weight of these materials is about 150,000.
  • EUDRAGIT RL/RS mixtures are substantially insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids.
  • the EUDRAGIT RL/RS dispersions useful in the present invention can be mixed together in any desired ratio in order to ultimately obtain a controlled-release formulation having a desirable dissolution profile.
  • Desirable controlled-release formulations can be obtained, for instance, from a coating derived from 100% EUDRAGIT RL; 50% EUDRAGIT RL, 50% EUDRAGIT RS; and 10% EUDRAGIT RL, 90% Eudragit RS (each commercially available from Rohm Pharma GmbH,mannstat, Germany).
  • the sustained-release coating can also comprise a mixture of a hydrophobic material and a hydrophilic material.
  • the ratio of hydrophobic material to hydrophilic material is determined by, among other factors, the required release rate of the therapeutic agent and the solubility characteristics of the materials selected.
  • Hydrophilic materials include, but are not limited to, polyvinylpyrrolidone and water soluble celluloses, such as hydroxypropylmethyl cellulose. Examples of combinations of hydrophobic material and hydrophilic material useful for the sustained-release coating include, but are not limited, to a combination of shellac and polyvinylpyrrolidone and a combination of ethyl cellulose and hydroxypropylmethyl cellulose.
  • the therapeutic agent can be dispersed in a controlled-release matrix.
  • controlled-release matrix means a matrix that slowly releases the therapeutic agent over time. Any controlled-release matrix can be used in the oral dosage form of the invention.
  • Certain controlled-release matrices are known for oral formulations (See, e.g., Remingtons Pharmaceutical Sciences, 1 8 th ed. Mack Publishing Co., Easton, Pa., 1990, p. 1684-1685). Other examples of useful controlled-release matrices are described iri U.S. Pat. Nos.
  • the controlled-release matrix can be a fusible hydrophobic material, optionally combined with a hydrophilic material.
  • the hydrophobic fusible material can be, for example, a hydrophobic polymer or a natural or synthetic wax or oil, such as hydrogenated vegetable oil or hydrogenated castor oil, which in one embodiment has a melting point of from about 35 to 100° C., and in another embodiment from about 45 to 90° C.
  • the hydrophilic material can be a hydrophilic polymer; a water soluble fusible material, such as polyethylene glycol; or a water soluble particulate material, such as dicalcium phosphate or lactose.
  • the therapeutic agent dispersed in a controlled-release matrix can be prepared by formulating, e.g., using dry or wet granulation or by blending, the therapeutic agent with a component other than the fusible component.
  • Suitable non-fusible materials for inclusion in a controlled release matrix include, but are not limited to:
  • hydrophilic or hydrophobic polymers such as gums, cellulose ethers, protein-derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, and cellulose acetate phthalate.
  • cellulose ethers for example substituted cellulose ethers such as alkylcelluloses (e.g., ethylcellulose), C 1 -C 6 hydroxyalkylcelluloses (e.g., hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic resins (e.g., methacrylates such as methacrylic acid copolymers) are used in one embodiment.
  • the controlled-release matrix can conveniently contain between 1% and 80% (by weight) of the hydrophobic and/or hydrophilic polymer.
  • digestible, long chain (C 1 -C 50 , in one embodiment C 8 -C 40 ) substituted or unsubstituted hydrocarbons such as fatty acids; hydrogenated vegetable oils; fatty alcohols, such as lauryl, myristyl, stearyl, cetyl or, in one embodiment cetostearyl alcohol; glyceryl esters of fatty acids, for example, glyceryl monostearate; mineral oils; and waxes, such as beeswax, glycowax, castor wax, and camauba wax.
  • Hydrocarbons having a melting point of between about 25° C. and 90° C. are used in one embodiment.
  • fatty (aliphatic) alcohols are useful in one embodiment.
  • the controlled-release matrix may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • the controlled-release matrix may contain up to 60% (by weight) of at least one polyalkylene glycol.
  • a suitable controlled-release matrix for use in the oral dosage form of the invention comprises one or more cellulose ethers or acrylic resins, one or more C 12 -C 36 , in one embodiment C 12 -C 22 , aliphatic alcohols, and/or one or more hydrogenated vegetable oils.
  • a particular suitable matrix comprises one or more alkylcelluloses, one or more C 12 -C 36 , in one embodiment C 12 -C 22 , aliphatic alcohols, and optionally one or more polyalkylene glycols.
  • the matrix contains between about 0.5% and 60%, and in another embodiment, between 1% and 50% (by weight) of the cellulose ether.
  • the acrylic resin is for example a methacrylate such as methacrylic acid copolymer USNF Type A (EUDRAGIT L), Type B (EUDRAGIT S,), Type C (EUDRAGIT L 100-55), EUDRAGIT NE 30 D, EUDRAGIT E, EUDRAGIT RL, or EUDRAGIT RS (commercially available from Rohm Pharma GmbH,mannstat, Germany).
  • the matrix contains between about 0.5% and 60% by weight, and in another embodiment between 1% and 50% by weight of the acrylic resin.
  • the matrix in one embodiment contains between about 1% and 40%, in another embodiment between about 2% and 36% (by weight) of the aliphatic alcohol.
  • the combined weight of the aliphatic alcohol and the polyalkylene glycol in one embodiment constitutes between about 2% and 40%, in another embodiment between about 2 and 36% (by weight) of the matrix.
  • the polyalkylene glycol may be, for example, polypropylene glycol or, in one embodiment, polyethylene glycol.
  • the number average molecular weight of the at least one polyalkylene glycol is in one embodiment between 200 and 15,000, and in another embodiment between 400 and 12,000.
  • the controlled-release matrix containing the therapeutic agent can readily be prepared by dispersing the therapeutic agent in the components of the matrix using conventional pharmaceutical techniques including, but not limited to, melt granulation, wet granulation, dry blending, dry granulation, and co-precipitation.
  • the controlled-release formulations slowly release the therapeutic agent when ingested and exposed to gastric and/or intestinal fluids.
  • the first and second compositions are solids, such as, but not limited to, granules, fine granules, pills, beads, capsules, tablets, or powders. Methods for preparing these solids are well known in the art.
  • compositions can additionally comprise any conventional pharmaceutically acceptable excipient such as a binding agent (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolate); or wetting agent (e.g., sodium lauryl sulphate).
  • a binding agent e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • filler e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricant e.g., magnesium stearate, talc or silica
  • disintegrant e.g., potato starch or sodium starch glycolate
  • wetting agent
  • the first and/or second composition comprises a hydrophobic material to provide the composition with a sustained-release property.
  • a hydrophobic material examples include wet granulation, melt extrusion, and tableting by compression.
  • the solid compositions are coated with layers by applying one or more coating mixtures.
  • Coating mixtures are prepared by any conventional means, for example, by dissolving the above-mentioned polymers and optionally plasticizers in a suitable solvent or mixture of solvents, for example water, methanol, ethanol, isopropanol, acetone, ethylacetate, ethylene chloride, or mixtures thereof.
  • suitable solvent or mixture of solvents for example water, methanol, ethanol, isopropanol, acetone, ethylacetate, ethylene chloride, or mixtures thereof.
  • plasticizers include, but are not limited to, citric acid esters, such as triethyl citrate and tributyl citrate; dibutyl phthalate; 1,2-propylene glycol; polyethylene glycols; castor oil; and triacetin.
  • the coating mixture is an aqueous dispersion
  • a small amount of talc, glyceral monostearate, or colloidal silicon dixide may be added to reduce the tendency of the aqueous dispersion to stick during processing.
  • the coating mixture can also contain additives such as coloring agents and/or magnesium stearate, which are well known in the coating art.
  • the coating solution can be applied to the solid composition by any means available to those of ordinary skill in the art such as, for example, spraying or dipping.
  • Conventional coating apparatuses well known to those of ordinary skill in the art, can be used to coat the solid composition (See, e.g., Remingtons Pharmaceutical Sciences, 18 th ed. Mack Publishing Co., Easton, Pa., 1990).
  • Conventional coating apparatuses include, but are not limited to, coating-granulating apparatuses of the centrifugal fluidized type, pan-coating apparatuses, and fluidized-bed granulating coating apparatuses.
  • a Wuster fluidized-bed system can be used in which an air jet, injected from underneath, fluidizes the coated material and effects drying while the polymer coating is sprayed on.
  • the first coating solution is applied and then allowed to dry before the second coating solution is applied.
  • the coating solutions are applied to provide a dosage form that has a dissolution profile substantially unaffected by exposure to accelerated-storage conditions.
  • accelerated-storage conditions means storage conditions of elevated temperature and/or elevated relative humidity to which the oral dosage form is subjected for the purpose of obtaining regulatory approval, e.g., the FDA for approval in the U.S., and an expiration date.
  • regulatory approval e.g., the FDA for approval in the U.S.
  • an expiration date e.g., a generally accepted test employed in FDA guidelines relates to the storage of a drug product (i.e., in its container and package) at 40° C. and 75% Relative Humidity (RH).
  • RH Relative Humidity
  • the amount of the therapeutic agent per dosage unit is that which is an effective amount for its particular indication and is independent of the amount of the adverse-effect agent.
  • the therapeutic agent is an opioid agonist
  • the amount of the opioid agonist in the oral dosage form of the present invention is generally from about 75 ng to about 1000 mg, in one embodiment from about 75 ng to about 750 mg.
  • One of ordinary skill in the art can readily determine, without undue experimentation, the amount of therapeutic agent needed for a particular indication.
  • the amount of the adverse-effect agent in the oral dosage form of the present invention is such that the adverse-effect agent can give the intended adverse effect.
  • the amount of the adverse-effect agent in the oral dosage form is at least sufficient to reduce or eliminate the effects of the therapeutic agent when both agents are released.
  • the phrase “to reduce or eliminate the effects of the therapeutic agent,” as used herein, means that the effects of the therapeutic agent that attract potential abusers are eliminated or become lessened.
  • an adverse-effect agent can reduce the euphoric effect of a therapeutic agent.
  • the amount of the opioid antagonist, present in a oral dosage form of the present invention can be from about 10 ng to 275 mg.
  • the amount of the adverse-effect agent in the oral dosage form is at least sufficient to cause such effect upon release.
  • the amount of the adverse-effect agent present in the oral dosage form should not be harmful to humans even if fully released.
  • One of ordinary skill in the art can readily determine, without undue experimentation, the amount of adverse-effect agent needed to elicit the intended adverse-effect without being harmful.
  • the ratio of the therapeutic agent to the adverse-effect agent in the oral dosage form is about 1:1 to about 50:1 by weight, in one embodiment about 1:1 to about 20:1 by weight. In certain other embodiments, the ratio is about 1:1 to about 10:1 by weight.
  • the therapeutic agent includes oxycodone or hydrocodone and is present in the amount of about 15-45 mg, and the adverse-effect agent includes naltrexone and is present in about 0.5-5 mg.
  • the first composition has a sustained-release coating
  • the therapeutic agent is an opioid agonist
  • the adverse-effect agent is an opioid antagonist
  • the sustained-release oral dosage forms can include analgesic doses from about 5 mg to about 80 mg of hydrocodone per dosage unit.
  • the opioid agonist is hydromorphone
  • it may be included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride per dosage unit.
  • the opioid agonist is morphine
  • the oral dosage forms of the present invention include from about 2.5 mg to about 800 mg morphine per dosage unit.
  • the opioid agonist is oxycodone and the oral dosage forms include from about 2.5 mg to about 800 mg oxycodone, in another embodiment from about 20 mg to about 30 mg oxycodone per dosage unit.
  • Controlled-release oxycodone formulations are known in the art.
  • the opioid agonist can be tramadol in an amount from about 25 mg to 800 mg tramadol per dosage unit.
  • the dosage form can contain more than one opioid agonist.
  • the first composition and the second composition are coated as explained in section 5.4, supra to provide the first coated composition and the second coated composition.
  • the first composition comprising a therapeutic agent
  • the second composition comprising an adverse-effect agent
  • the first composition and the second composition are then combined to provide a unit dosage of the oral composition of the invention.
  • the first composition and the second composition are similar in their size, shape and color so that they cannot be readily distinguished from each other.
  • the first composition and the second composition can each be powders, granules, or beads that are combined and incorporated into a capsule or tablet using methods well known to those of ordinary skill in the art.
  • the capsule may be hard or soft, for example, gelatin.
  • the capsule can also contain pharmaceutically acceptable excipients.
  • FIG. 3 shows a cross-sectional view of a capsule 30 , which has a first part 33 and a second part 34 and contains powders, granules, or beads of a first composition 31 and powders or granules of a second composition 32 .
  • FIG. 5 shows a cross-sectional view of a dosage form according to the invention in the form of a tablet 50 .
  • the first composition is in the form of powders or granules 51 and the coated second composition is in the form of powders, granules, or beads 52 .
  • the first composition and the coated second composition are mixed with a pharmaceutically acceptable matrix 53 and compressed into a tablet.
  • the capsule or tablet contains the first composition without the outer acid-soluble layer and without the inner base-soluble layer and the second composition coated with an outer base-soluble layer and an inner acid-soluble layer.
  • FIG. 6 Depicts another embodiment of the oral dosage form of the invention in the form of a tablet comprising a core that is a mixture of an uncoated first composition 64 and a second composition coated with a base-soluble outer layer and an acid soluble inner layer 65 .
  • the core is then coated with an inner base-soluble layer 62 , and an outer acid-soluble layer 61 , and an optional innermost sustained release coating 63 .
  • the second composition can be coated with a layer that is substantially insoluble in the gastrointestinal tract.
  • Another embodiment of the oral dosage form of the invention is a two-layer tablet 40 as shown in FIG. 4.
  • a solid nucleus of the first composition 45 is covered with an innermost sustained-release coating 43 (optional), an inner base-soluble layer 42 , and an outer acid-soluble layer 41 .
  • a solid nucleus of the second composition 44 is covered with an inner acid-soluble layer 46 , an outer base-soluble layer 47 , and an outermost layer that is substantially insoluble in the gastrointestinal tract 48 (optional).
  • the two coated nuclei are then compressed into a two-layer tablet 40 using conventional tableting equipment and standard techniques to provide a two-layered tablet.
  • the compressed two-layer tablet can then optionally be coated with an additional coating to provide a tablet of uniform appearance.
  • the additional coating is a coating that dissolves in the stomach after the tablet is swallowed.
  • the first composition is uncoated, i.e., is not covered with the outer acid-soluble layer or the inner base-soluble layer, but the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer.
  • FIG. 7 Yet another embodiment of the oral dosage 70 is shown in FIG. 7.
  • a solid nucleus of the second composition 77 is coated with an innermost acid-soluble layer 76 and an outer base-soluble layer 75 .
  • the second composition is further coated with a layer of the first composition 74 , an optional innermost pH-independent layer 73 , an inner base-soluble layer 72 , and an outer acid-soluble layer 71 .
  • the oral dosage 70 may be a tablet or a granule.
  • EUDRAGIT RS 30 D is plasticized by mixing with triacetin. The dispersion is then combined with the oxycodone HCl or naltrexene HCl, spray dried lactose, and providone using a fluid-bed granulator. The resulting mixture is granulated. If necessary the granules are dried. The granules are then screened with a sieve to provide granules of an appropriate size.
  • An acid-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT E 100 in 200 ml of ethanol to provide a clear solution, and 4 g of the plasticizer triethyl citrate is added to the solution.
  • a base-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT L in 200 ml of ethanol to provide a clear solution.
  • the oxycodone HCl granules are spray coated with the base-soluble coating solution and dried. After drying, the resulting oxycodone HCl granules coated with the base-soluble coating are then spray coated with the acid-soluble coating solution and the resulting granules dried.
  • naltrexone HCl granules are spray coated with the acid-soluble coating solution and dried. After drying, the resulting naltrexone HCl granules coated with the acid-soluble coating are then spray coated with the base-soluble coating solution and the resulting granules dried.
  • coated oxycodone HCl granules and the coated naltrexone HCl granules are mixed together to provide a mixture, and a gelatin capsule is filled with the mixture.
  • Stearyl alcohol is melted, and the melted stearyl alcohol (25.00 mg per unit) is mixed with the coated granules obtained in Example 1 to wax them.
  • the waxed granules are cooled in a fluid bed dryer and then blended with talc (2.50 mg per unit) and magnesium stearate (1.25 mg per unit) to provide a blend.
  • the resulting blend is compressed into a tablet using a tablet press.

Abstract

The present invention provides an oral dosage form comprising a first composition and a second composition. The first composition comprises an effective amount of a therapeutic agent and the second composition comprises an effective amount of an adverse-effect agent. The adverse-effect agent is covered with a coating that is substantially insoluble in the gastrointestinal tract. In one embodiment, the adverse-effect agent is coated with an outer base-soluble layer and an inner acid-soluble layer. The therapeutic agent can be uncoated or can be coated with a coating having an outer acid-soluble layer and an inner base-soluble layer. The dosage form discourages administration of the therapeutic agent by other than oral administration.

Description

  • This application claims the benefit of U.S. Provisional Application No. 60/309,791, filed Aug. 6, 2001, the disclosure of which is incorporated by reference herein in its entirety.[0001]
  • 1. FIELD OF THE INVENTION
  • This invention relates generally to an oral dosage form comprising a therapeutic agent and an adverse-effect agent. [0002]
  • 2. BACKGROUND OF THE INVENTION [0003]
  • Many therapeutic agents are highly effective for improving quality of life but, because of their abuse potential, may attract drug abusers. For example, opioids are excellent analgesic agents that can control severe and/or chronic pain, such as cancer pain and post-operative pain, but are also subject to abuse by drug users. [0004]
  • Opioids, also known as opioid agonists, are a group of drugs that exhibit opium- or morphine-like properties. Opioids are employed primarily as moderate to strong analgesic agents, but provide other pharmacological effects as well. [0005]
  • There have been previous attempts in the art to control the potential for abuse of opioid analgesics. For example, sustained release forms enable an active ingredient to work over many hours, and such slow release tends to deter illicit use of opioids because abusers tend to prefer the quick euphoric rush, also known as the “burst,” provided by immediate release opioids. Drug abusers, however, can defeat the controlled release design by crushing or dissolving the original drug form, for example a tablet, giving them access to snortable and/or injectable opioids that provide the burst. Accordingly, there is an important need for more effective methods of deterring opioid abuse while still keeping orally administered opioids available to patients who have a legitimate need for them. [0006]
  • Prior art approaches to this problem have involved combining an opioid with an opioid antagonist. When administered orally, these combinations provide the pharmacologic action of the opioid with minimal action of the antagonist. When administered parenterally, however, the antagonist can be profoundly antagonistic to the opioid. Particular examples of such combinations include compositions comprising naloxone and morphine or oxymorphone (U.S. Pat. No. 3,493,657 to Lewenstein et al.); methadone and naloxone (U.S. Pat. No. 3,773,955 to Pachter et al.); methadol or acetyl methadol and naloxone (U.S. Pat. No. 3,966,940 to Pachter et al.); oxycodone and naloxone (U.S. Pat. No. 4,457,933 to Gordon et al.); and buprenorphine and naloxone (U.S. Pat. No. 4,582,835 to Lewis et al.). Also, the combination of pentazocine hydrochloride and naloxone has been marketed in the United States as TALWIN NX (Sanofi-Winthrop); VALORON N, a combination of tilidine and naloxone, has been available in Germany for the management of severe pain since 1978; and TEMGESIC NX, a combination of buprenorphine and naloxone, has been available in New Zealand since 1991. [0007]
  • U.S. Pat. No. 6,228,863 to Palermo et al. discloses an oral dosage form of an opioid agonist and an opioid antagonist that reduces the abuse potential of the opioid by combining the agonist and antagonist such that at least two steps are required to separate them. [0008]
  • U.S. Pat. No. 5,935,975 to Rose et al. discloses a method for treating drug dependency by the combined administration of the drug or an agonist of the drug and an antagonist of the drug. [0009]
  • There remains, however, a clear need in the art for more advanced oral dosage forms that are effective for preventing abuse and useful for delivering a therapeutic agent. [0010]
  • 3. SUMMARY OF THE INVENTION
  • The present invention relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer. [0011]
  • The invention further relates to an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer. [0012]
  • The invention further relates to a method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of the invention. In one embodiment the method comprises administering to a patient in need thereof an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent; the second composition comprises an effective amount of an adverse-effect agent; an effective amount of the therapeutic agent is released in the patient's small intestine; and less than an effective amount of the adverse-effect agent is released in the patient's gastrointestinal tract. [0013]
  • The invention still further relates to a method for preparing an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and the second composition comprises an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer, the method comprising the step of preparing the oral dosage form as set forth herein. [0014]
  • The invention still further relates to a method for preparing an oral dosage form comprising a first composition and a second composition, wherein the first composition comprises a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer, the method comprising the step of preparing the oral dosage form as set forth herein.[0015]
  • 4. BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 shows a cross-sectional view of a coated granule of a first composition useful in the oral dosage forms of the invention. [0016]
  • FIG. 2 shows a cross-sectional view of a coated granule of a second composition useful in the oral dosage forms of the invention. [0017]
  • FIG. 3 shows a cross-sectional view of a first embodiment of the invention, which is a capsule containing coated granules of a first composition and coated granules of a second composition. [0018]
  • FIG. 4 shows a cross-sectional view of a second embodiment of the invention, which is a two-layer tablet. [0019]
  • FIG. 5 shows a cross-sectional view of a third embodiment of the invention, which is a tablet containing coated granules of a first composition and coated granules of a second composition. [0020]
  • FIG. 6 shows a cross-sectional view of a fourth embodiment of the invention, which is a coated tablet containing a first composition, with granules of a coated second composition dispersed throughout the first composition. [0021]
  • FIG. 7 shows a cross-sectional view of a fifth embodiment of the invention, which is a tablet wherein a coated composition of the adverse-effect agent is further coated with the therapeutic agent and then the therapeutic agent is coated. [0022]
  • 5. DETAILED DESCRIPTION OF THE INVENTION
  • The oral dosage form of the present invention comprises a first composition and a second composition. The first composition comprises a therapeutic agent, and the second composition comprises an adverse-effect agent. [0023]
  • The term “therapeutic agent,” as used herein, means any drug intended to have a beneficial effect when administered to a patient. [0024]
  • The term “adverse-effect agent,” as used herein, means an agent that (A) reduces or eliminates one or more pharmacological effects of the therapeutic agent, such as a euphoric or toxic effect or (B) causes an undesired physiological reaction, such as emesis. In a first embodiment of the oral dosage form of the invention, the second composition is coated with a layer that is substantially insoluble in the gastrointestinal tract. Thus, when the oral dosage form of the present invention is orally administered to a patient as intended, only the therapeutic agent is released in the gastrointestinal tract of the patient, and the adverse-effect agent is not released. If the oral dosage form is tampered with so that the coating on the second composition is damaged, however, then not only the therapeutic agent but also the adverse-effect agent are released upon administration. [0025]
  • In a second embodiment the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer, which is not dissolved when orally administered to a patient. [0026]
  • In a third embodiment of the oral dosage form of the invention, both the first composition and second composition have a coating comprising at least two layers, an acid-soluble layer and a base-soluble layer, but the order of the layers in the coating on the first composition is different from that of the layers in the coating on the second composition. The coating covering the first composition comprises an outer acid-soluble layer and an inner base-soluble layer, which are dissolved when orally administered to a patient. On the other hand, the coating covering the second composition comprises an outer base-soluble layer, which gets dissolved when orally administered, and an inner acid-soluble layer, which does not get dissolved when orally administered to a patient. [0027]
  • When orally administered to a patient, the oral dosage form passes through the stomach first, where its acidic environment dissolves the first composition's outer acid-soluble layer, and then passes into the small intestine, where its basic environment dissolves the first composition's inner base-soluble layer. Here, the therapeutic agent can be absorbed by the body. In contrast, the second composition is coated with an outer base-soluble layer, which is substantially insoluble in the stomach's acidic environment. Therefore, the second composition passes through the stomach with both the outer base-soluble layer and the inner acid-soluble layer intact. When the second composition enters the small intestine, the outer base-soluble layer dissolves, exposing the inner acid-soluble layer, which is substantially insoluble in the small intestine's basic environment, so that the adverse-effect agent cannot be absorbed by the body. Thus, when the oral dosage form of the present invention is orally administered to a patient, for example a human, as intended, only the therapeutic agent is released in the gastrointestinal tract and absorbed by the patient; the adverse-effect agent is not released and, therefore, not available for absorption into the body. Here, the therapeutic agent works as if it were administered alone without the adverse-effect agent, since only the therapeutic agent is available for absorption by the body. [0028]
  • However, if the oral dosage form of the present invention is tampered with, e.g., chewed, crushed, ground or dissolved, particularly in a solvent with heat (e.g., greater than about 45° C. to about 50° C.), then not only the therapeutic agent but also the adverse-effect agent becomes available for absorption into the body. The adverse-effect agent can then exert its effect by either reducing the effect of the therapeutic agent or eliciting an unpleasant effect in the patient. Thus, where the adverse-effect agent is an antagonist of the therapeutic agent, the effects of the therapeutic agent are drastically diminished or even eliminated by the effects of the adverse-effect agent. For example, where the therapeutic agent is an opioid agonist and the adverse-effect agent is an opioid antagonist, and the oral dosage form is tampered with, the opioid antagonist becomes bioavailable, interfering with opioid-receptor binding and reducing the opioid antagonist's pharmacological effects. Accordingly, only patients who take the dosage form of the present invention as intended, i.e, orally as an intact dosage form, can experience the full pharmacological effects of the therapeutic agent. Where the adverse-effect agent is an emetic agent and the oral dosage form is tampered with, the emetic agent induces vomiting which discourages the user from tampering with the dosage form. Moreover, where the adverse-effect agent causes vomiting the oral dosage form of the invention not only discourages users from tampering with it, but can also be effective to remove the therapeutic agent from subject's body. Abusing the therapeutic agent becomes less desirable when present in the oral dosage form of the present invention because, when tampered with, the adverse-effect agent exerts its undesirable effects. [0029]
  • In one embodiment of the present invention, the first composition is intended to be released slowly after it is orally administered to the subject. This prevents the burst, which some abusers seek. The first composition can be formulated as a slow release formulation, for example, by further coating the first composition with a sustained-release coating that slowly dissolves so that all the therapeutic agent is not released at once. In the embodiments where the first composition is coated with an outer acid-soluble layer and an inner base-soluble layer, the sustained-release coating is an innermost layer. In another embodiment the first composition can be formulated as a slow release formulation by incorporating the therapeutic agent into a matrix that slowly releases the therapeutic agent over time. Therapeutic agents intended to be released slowly, when orally administered to a subject, may have side effects if released all at once, rather than slowly. The coated second composition prevents tampering, which would result in immediate release of the therapeutic agent. [0030]
  • FIG. 1 shows a cross-sectional view of an embodiment of the coated [0031] first composition 10. A first composition 14 is covered with an innermost sustained-release coating 13 (optional), an inner base-soluble layer 12, and an outer acid-soluble layer 11.
  • FIG. 2 shows a cross-sectional view of an embodiment of the coated [0032] second composition 20. A second composition 24 is covered with an inner acid-soluble layer 23, an outer base-soluble layer 22 and an outermost layer that is substantially insoluble in the gastrointestinal tract 21 (optional).
  • 5.1 Therapeutic Agent
  • Any kind of therapeutic agent can be used in the oral dosage forms of the present invention. In one embodiment the oral dosage from is used in situations where there is a potential toxicity or overdose associated with the uncontrolled release of the drug due to tampering with the dosage form. Examples of useful therapeutic agents include, but are not limited to, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile-dysfunction-improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, and non-essential fatty acids. The first composition can comprise more than one therapeutic agent. [0033]
  • The phrase “therapeutic agent” is also meant to encompass all pharmaceutically acceptable salts of the therapeutic agent. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, and the like; and amino acid salts, such as arginate salts, asparginate salts, glutamate salts, and the like. [0034]
  • In another embodiment the therapeutic agent has potential for abuse. The abuse potential of a drug is established by many factors, which may include the following: (1) the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the degree to which the drug induces euphoria similar to that produced by morphine and other opioids. The term “a therapeutic agent having abuse potential,” as used herein, refers to a therapeutic agent having at least one of the above-identified factors. Examples of therapeutic agents having abuse potential include, but are not limited to, opioids, benzodiazepines, barbiturates, and stimulants, such as methylphenidate and amphetamines. [0035]
  • The term “opioid” refers to a substance that binds, optionally stereo-specifically, to any of several subspecies of opioid receptors and produces an agonist action. Opioids include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, PANTOPON, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof. [0036]
  • In certain embodiments, the opioid agonist is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof. In one embodiment the opioid agonist is oxycodone or hydrocodone. [0037]
  • The term “benzodiazepines” refers to drugs that are derivatives of benzodiazepine and are able to depress the central nervous system. Benzodiazepines include, but are not limited to, alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate, pharmaceutically acceptable salts thereof, and mixture thereof. [0038]
  • Barbiturates refer to sedative-hypnotic drugs derived from barbituric acid (2,4,6, -trioxohexahydropyrimidine). Barbiturates include, but are not limited to, amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixtures thereof. [0039]
  • Stimulants refer to drugs that stimulate the central nervous system. Stimulants include, but are not limited to, amphetamines, such as amphetamine, amphetamine, dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, pharmaceutically acceptable salts thereof and mixtures thereof. [0040]
  • Other examples of therapeutic agent having potential for abuse include, but are not limited to, dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, and detropropoxyphene. [0041]
  • The therapeutic agent may also be an agent intended for delivery to the colon. Therapeutic agents intended for delivery to the colon include, but are not limited to, agents that act locally in the colonic region to treat a colon diseases such as irritable bowel syndrome, irritable bowel disease, Crohns disease, constipation, post operative atony, gastrointestinal infections, and therapeutic agents that deliver antigenic material to the lymphoid tissue. Agents for the treatment of colon disease, include, but are not limited to 5-ASA; steroids, such as hydrocortisone and budesonide; laxatives; octreotide; cisapride; anticholinergics; opioids; calcium channel blockers; DNA for delivery to the cells of the colon; glucosamine; thromboxane A[0042] 2 synthetase inhibitors, such as Ridogrel; 5HT3-antagonists, such as ondansetron; antibodies against infectious bacteria, such as Clostridium difficile; and antiviral agents, for example, for the prophylaxis of HIV.
  • Alternatively, the therapeutic agent can be an agent that is systemically active and for which absorption is improved in the colon region. Such drugs include polar compounds such as: heparins; insulin; calcitonins; human growth hormone (HGH); growth hormone releasing hormone (GHRH); interferons; somatostatin and analogues such as octreotide and vapreotide; erythropoietin (EPO); granulocyte colony stimulating factor (GCSF); parathyroid hormone (PTH); luteinising hormone releasing hormone (LHRH) and analogues thereof; atrial natriuretic factor (ANF); vasopressin; desmopressin; calcitonin gene related peptide (CGRP); and analgesics. [0043]
  • 5.2 Adverse-Effect Agent
  • The adverse-effect agent can be an agent that reduces or eliminates the therapeutic agent's pharmacological activities including, but not limited to: (1) the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; (2) the ability to suppress withdrawal symptoms caused by withdrawal from the drug; and (3) the induction of euphoria similar to that produced by morphine and other opioids. Adverse-effect agents that reduce or eliminate the pharmacological effects of the therapeutic agent include, but are not limited to, antagonists of the therapeutic agent agonist. When an opioid agonist is used as the therapeutic agent in the oral dosage form of the present invention, an opioid antagonist can be used as the adverse-effect agent. Likewise, when a benzodiazepine is used as the therapeutic agent in the oral dosage form of the present invention, a benzodiazepine antagonist can be used as the adverse-effect agent. When a barbiturate is used as a therapeutic agent in the oral dosage form of the present invention, a barbiturate antagonist can be used as the adverse-effect agent. When an amphetamine is used as a therapeutic agent in the oral dosage form of the present invention, an amphetamine antagonist can be used as the adverse-effect agent. When the therapeutic agent is toxic when dosed above its normal therapeutic range, i.e., there is a potential for an overdose, then an antidote of the toxic therapeutic agent can be used as the adverse-effect agent. [0044]
  • The phrase “adverse-effect agent” is also meant to encompass all pharmaceutically acceptable salts of the adverse-effect agent. Pharmaceutically acceptable salts include, but are not limited to, metal salts, such as sodium salts, potassium salts, and lithium salts; alkaline earth metals, such as calcium salts, magnesium salts, and the like; organic amine salts, such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N′-dibenzylethylenediamine salts, and the like; inorganic acid salts such as hydrochloride salts, hydrobromide salts, sulfate salts, phosphate salts, and the like; organic acid salts such as formate salts, acetate salts, trifluoroacetate salts, maleate salts, tartrate salts, and the like; sulfonate salts such as methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts, and the like; and amino acid salts, such as arginate salts, asparginate salts, glutamate salts, and the like. [0045]
  • Opioid antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, naloxone, naltrexone, nalmefene, cyclazacine, levallorphan, and mixtures thereof. In certain embodiments, the opioid antagonist is naloxone or naltrexone. [0046]
  • Benzodiazepine antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, flumazenil. [0047]
  • Barbiturate antagonist which can be used as the adverse-effect agent of the present invention include, but are not limited to, amphetamines, described herein. [0048]
  • Stimulant antagonists that can be used as the adverse-effect agent of the present invention include, but are not limited to, benzodiazepines, described herein. [0049]
  • In another embodiment of the present invention, the adverse-effect agent is an agent that causes an undesired physiological reaction, such as emesis. This type of adverse-effect agent can be used with any kind of therapeutic agent including an opioid, a benzodiazepine, a barbiturate, and a stimulant. Examples of emetic agents suitable for use as the adverse-effect agent in the present invention includes any drug that safely and effectively induces vomiting after administration including, but not limited to, ipecac and apomorphine. [0050]
  • 5.4 Coatings 5.4.1. Coatings Insoluble in the Gastrointestinal Tract
  • Examples of useful coatings that are substantially insoluble in the gastrointestinal tract include, but are not limited to, coatings comprising a hydrophobic material. In one embodiment the coating that is substantially insoluble in the gastrointestinal tract comprises a cellulose polymer. In certain embodiments, the cellulose polymer is a cellulose ether, a cellulose ester, or a cellulose ester ether. In one embodiment, the cellulose polymers have a degree of substitution, D.S., on the anhydroglucose unit of from zero up to and including 3. By “degree of substitution” is meant the average number of hydroxyl groups present on the anhydroglucose unit of the cellulose polymer that are replaced by a substituting group. Representative cellulose polymers include, but are not limited to, polymers selected from cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono, di, and tricellulose alkanylates, mono, di, and tricellulose aroylates, and mono, di, and tricellulose alkenylates. Exemplary cellulose polymers include cellulose acetate having an acetyl content up to about 21%; cellulose acetate having an acetyl content up to about 32 to 39.8%; cellulose acetate having a D.S. of about 1 to 2 and an acetyl content of about 21 to 35%; and cellulose acetate having a D.S. of about 2 to 3 and an acetyl content of about 35 to 44.8%. In one embodiment, the cellulose polymer is ethylcellulose, cellulose acetate, cellulose propionate (low, medium, or high molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, or cellulose triacetate. In one embodiment, the ethylcellulose has an ethoxy content of about 44 to 55%. [0051]
  • More specific cellulose polymers include cellulose propionate having a D.S. of about 1.8 and a propyl content of about 39.2 to 45% and a hydroxyl content of about 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of about 1.8, an acetyl content of about 13 to 15%, and a butyryl content of about 34 to 39%; cellulose acetate butyrate having an acetyl content of about 2 to 29%, a butyryl content of about 17 to 53%, and a hydroxyl content of about 0.5 to 4.7%; cellulose triacylate having a D.S. of about 2.9 to 3 such as cellulose triacetate, cellulose trivalerate, cellulose trilaurate, cellulose tripatmitate, cellulose trisuccinate, and cellulose trioctanoate; cellulose diacylates having a D.S. of about 2.2 to 2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose dipentanoate, and coesters of cellulose such as cellulose acetate butyrate, cellulose acetate octanoate butyrate, and cellulose acetate propionate. [0052]
  • Additional cellulose polymers useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract include, but are not limited to, acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate. [0053]
  • Acrylic polymers are also useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract. Acrylic polymers include, but are not limited to, acrylic resins comprising copolymers synthesized from acrylic and methacrylic acid esters (e.g., the copolymer of acrylic acid lower alkyl ester and methacrylic acid lower alkyl ester) containing about 0.02 to 0.03 moles of a tri (lower alkyl) ammonium group per mole of acrylic and methacrylic monomer. In one embodiment, the acrylic resin is Eudragit RS 30 D manufactured by Rohm Tech Inc. of Fitchburg, Mass. Eudragit RS 30 D is a water insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammonioethyl methacrylate chloride (TAM) in which the molar ratio of TAM to the remaining components (EA and MM) is 1:40. Aqueous suspensions of acrylic resins such as EUDRAGIT RS can be used to coat the adverse-effect agent of the invention. [0054]
  • In certain embodiments of the invention, the acrylic polymer is selected from acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylates, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. [0055]
  • When a cellulose polymer or an acrylic polymer is used as a coating that is substantially insoluble in the gastrointestinal tract, suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyl tributyl citrate, may also be admixed with the polymer. The coating that is substantially insoluble in the gastrointestinal tract may also contain additives such as coloring agents, talc, and/or magnesium stearate, which are well known in the coating art. [0056]
  • Polymers useful for coating the second composition with a coating that is substantially insoluble in the gastrointestinal tract also include, but not limited to, poly(lactic/glycolic acid) (“PLGA”) copolymers, polylactides, polyglycolides, polyanhydrides, polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, polyesters, polydioxanone, polygluconate, polylactic-acid polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesters, and mixtures thereof. [0057]
  • In certain embodiments, the polymer comprises a poly(lactic/glycolic acid) copolymer, a copolymer of lactic and glycolic acid, having a molecular weight of about 2,000 to about 500,000 daltons. The ratio of lactic acid to glycolic acid is from about 100:0 to about 25:75, in one embodiment from about 65:35. Poly(lactic/glycolic acid) may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 to Ludwig et al., the disclosure of which is expressly incorporated herein by reference thereto. [0058]
  • The coating that is substantially insoluble in the gastrointestinal tract is of sufficient thickness to prevent release of the adverse-effect agent from the second composition while it is in the gastrointestinal tract. Many of the coatings that are substantially insoluble in the gastrointestinal tract are slowly biodegraded or dissolved in an aqueous environment and, after sufficient time, will eventually release the adverse-effect agent. Accordingly, the coating should be of a sufficient thickness that does not permit the adverse effect agent to be released during the time that the adverse-effect agent is present in the gastrointestinal tract. The thickness of the coating will depend on the characteristics of the coating composition being used. [0059]
  • 5.4.2 Acid-Soluble Layer
  • In various embodiments, the coating useful in the present invention comprises an acid-soluble layer. The term “acid-soluble layer” refers to a layer that is substantially soluble at a pH of less than about pH 5.0, but substantially insoluble at a pH of greater than about pH 5.5. In one embodiment, the acid-soluble layer is substantially soluble at a pH of less than about pH 4.0, but substantially insoluble at a pH of greater than about pH 4.5. In another embodiment, the acid-soluble layer is substantially soluble at a pH of less than about pH 3.0, but substantially insoluble at a pH of greater than about pH 3.5. The acid-soluble layer typically comprises an acid-soluble polymer. [0060]
  • As used herein, the phrase “substantially soluble,” when used to describe a layer, means soluble to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is made available to the environment of the gastrointestinal tract in an effective amount. [0061]
  • As used herein, the phrase “substantially insoluble,” when used to describe a layer, means that the layer does not dissolve or does so only to a degree that a portion of that which the layer covers, for example, an acid-soluble layer, a base-soluble layer, a first composition, or a second composition, is not made available to the environment of the gastrointestinal tract or is made available to the environment of the gastrointestinal tract in less than an effective amount. [0062]
  • In one embodiment, the acid-soluble polymer has a dimethylaminoethyl ammonium functionality. Such a polymer is commercially available as EUDRAGIT E 100 or Eudragit E PO from Rohm Pharma GmbH, Weiterstat, Germany. Examples of other suitable acid-soluble polymers can be found in “Materials Used in Pharmaceutical Formulations,” edited by A. T. Florence, Society of Chemical Industries, 1984. [0063]
  • 5.4.3 Base-Soluble Layer
  • In various embodiments, the coating of the present invention comprises a base-soluble layer. The term “base-soluble layer” refers to a layer that is substantially soluble at a pH of greater than about pH 5.5, but substantially insoluble at a pH of less than about 5.0. In one embodiment, the base-soluble layer is substantially soluble at a pH of greater than about pH 6.5, but substantially insoluble at a pH of less than about 6.0. In another embodiment, the base-soluble layer is substantially soluble at a pH of greater than about pH 7.5, but substantially insoluble at a pH of less than about 7.0. The base-soluble layer generally comprises a base-soluble polymer. In one embodiment, the base-soluble polymer is an anionic copolymer of methacrylic acid and methacrylates having carboxylic acid functionalities. Such a polymer is commercially available as EUDRAGIT L 100-55, EUDRAGIT L 30D-55, EUDRAGIT L, or EUDRAGIT S 100 (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). Examples of other suitable base-soluble polymers can be found in “Materials Used in Pharmaceutical Formulations,” edited by A. T. Florence, Society of Chemical Industries, 1984. [0064]
  • 5.4.4 Slow-Release Formulations
  • In one embodiment, the therapeutic agent is released slowly over time. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the oral dosage forms of the invention. Single unit dosage forms suitable for oral administration, such as tablets, capsules, gelcaps, caplets, and the like, that are adapted for controlled-release are encompassed by the present invention. [0065]
  • The controlled release of the therapeutic agent from the first composition can be stimulated by various inducers, for example pH, temperature, enzymes, water, or other physiological conditions or compounds. The controlled release of the therapeutic agent can be achieved, for example by coating or admixing the therapeutic agent with a controlled-release component. The term “controlled-release component” in the context of the present invention is defined herein as a compound or mixture of compounds, including polymers, polymer matrices, gels, permeable membranes, liposomes, microspheres, or the like, or a combination thereof, that facilitates the controlled-release of the therapeutic agent from the first composition of the oral dosage form of the invention. [0066]
  • As discussed above, in one embodiment of the invention the therapeutic agent is formulated for controlled release by coating the therapeutic agent with a sustained-release coating. The term “sustained-release coating” refers to a coating made of one or more materials that allows for the slow release of the drug over time. In one embodiment, the sustained-release coating is a pH-independent layer, i.e., a coating that has a defined permeability that is not influenced by pH. The term “pH-independent layer” means that the difference, at any given time, between the amount of drug released at, e.g., pH 1.6, and the amount released at any other pH, e.g., pH 7.2, when measured using a specific method, such as, for example, the USP Paddle Method at 100 rpm in 900 ml aqueous buffer, is 10% (by weight) or less. [0067]
  • Any sustained-release coating known to those of ordinary skill in the art can be used in the oral dosage form of the invention. Sustained-release coatings are well known in the art (See, e.g., Remingtons Pharmaceutical Sciences, 18[0068] th ed. Mack Publishing Co., Easton, Pa., 1990, p. 1670). Typically, the sustained-release coating comprises a water-insoluble material, such as a wax or a wax-like substance, fatty alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble cellulose, polymer of acrylic and/or methacrylic acid, or any other slowly digestible or dissolvable solid known in the art. The coating formulations useful in the present invention should be capable of producing a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free. Generally, the film coat is applied to the first composition, for example when in the form of a tablet or a granule, to achieve a weight gain level from about 2 to about 25 percent. However, the film coat may be lesser or greater depending upon the physical properties of the therapeutic agent included in the formulation and the desired release rate.
  • In one embodiment, the sustained-release coating comprises a hydrophobic polymer. In another embodiment, the hydrophobic polymer comprises a water-insoluble cellulosic polymer, such as an alkylcellulose, for example ethylcellulose; an acrylic polymer; or mixtures thereof. [0069]
  • In another embodiment, the sustained-release coating comprises an acrylic polymer. Any acrylic polymer that is pharmaceutically acceptable can be used. For example, the acrylic polymer can be an acrylate or methacrylate, formed from one or more of acrylic acid, methacrylic acid, acrylic acid esters, and methacrylic acid esters. These polymers can be cationic, anionic, or non-ionic, so that it is possible to obtain polymers that are soluble in, or resistant to dissolution, over a wide range of pH values. Some acrylic polymers useful for the purposes of the present invention are those that are marketed under the trade name EUDRAGIT (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). Examples of suitable acrylic polymers include, but are not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate polymers, methyl methacrylate copolymers, ethoxyethyl methacrylates polymers, cyanoethyl methacrylate polymers, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. [0070]
  • The acrylic polymer can comprise one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. In order to obtain a desirable dissolution profile for a given therapeutic agent, it might be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties. For example, it is known that by changing the molar ratio of the quaternary ammonium groups to neutral (meth)acrylic esters, the permeability properties of the resultant coating can be modified. One of ordinary skill in the art will readily know how to combine monomers to provide a copolymer that releases the therapeutic agent at the desired release rate. Copolymers of acrylate and methacrylate having a quaternary ammonium group functionality are commercially available as EUDRAGIT RS and EUDRAGIT RL from Rohm Pharma GmbH, Weiterstat, Germany. [0071]
  • Other polymers suitable for use in the invention include, but are not limited to, hydroxyalkylcelluloses; poly(lactic/glycolic acid) (“PLGA”); polylactide; polyglycolide; polyanhydrides; polyorthoesters; polycaprolactone; polyphosphazenes; polysaccharides; proteinaceous polymers; polyesters; polydioxanone; polygluconate; polylactic-acid polyethylene oxide copolymers; poly(hydroxybutyrate) polyphosphoesters; or mixtures thereof. [0072]
  • The inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer can further improve the physical properties of the film. For example, because ethylcellulose has a relatively high glass-transition temperature (“Tg”) and does not form flexible films under normal coating conditions, it is often necessary to plasticize the ethylcellulose before using it as a coating material. [0073]
  • The suitability of a plasticizer may relate to its affinity or solvating power for the polymer and its effectiveness for interfering with polymer-polymer attachments. Such activity imparts a desired flexibility to the polymer by relieving molecular rigidity. An important parameter in determining the suitability of a plasticizer for a polymer is related to the Tg of the polymer. The Tg is related to the temperature or temperature range where there is a fundamental change in the physical properties of the polymer. This change does not reflect a change in state, but rather a change in the macromolecular mobility of the polymer. Below the Tg, polymer chain mobility is severely restricted. Thus, for a given polymer, if the Tg is above room temperature, the polymer will behave as a glass at room temperature, being hard, non-pliable, and rather brittle: properties that are restrictive for a film coating since the coated dosage form may be subjected to a certain amount of external stress. Incorporation of suitable plasticizers into the polymer matrix effectively reduces the Tg, so that under ambient conditions the films are softer, more pliable and often stronger, and, thus, better able to resist mechanical stress. Other aspects of suitable plasticizers include their ability to act as a good “swelling agent,” especially for ethylcellulose, and to improve the solubility profile of the coating in water. [0074]
  • Examples of suitable plasticizers for ethylcellulose include dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl citrate, although other plasticizers (such as acetylated monoglycerides, phthalate esters and castor oil) can be used. In one embodiment, triethyl citrate is a plasticizer for the aqueous dispersions of ethyl cellulose. [0075]
  • Examples of suitable plasticizers for the acrylic polymers useful in the present invention include, but are not limited to, citric acid esters such as triethyl citrate, tributyl citrate, dibutyl phthalate, and 1,2-propylene glycol. Other plasticizers suitable for enhancing the elasticity of the films formed from acrylic films, such as EUDRAGIT RL/RS lacquer solutions, include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. The plasticizer is typically added to a solution of the polymer in an aqueous or non-aqueous solvent that is used to coat the first composition. [0076]
  • Generally, the amount of plasticizer included in a coating solution is based on the concentration of the coating. In one embodiment, the amount of plasticizer included in a coating solution of ethylcellulose is from about 1 to about 50 percent by weight of the ethylcellulose. In another embodiment, the amount of plasticizer included in a coating solution of an aqueous dispersion of acrylic polymer is about 20%. The necessary concentration of the plasticizer for a particular coating solution and method of application can be readily determined by one of ordinary skill in the art without undue experimentation. [0077]
  • A commercially available aqueous dispersion of ethylcellulose suitable for use in the invention is AQUACOAT (commercially available from FMC Corp., Philadelphia, Pa., U.S.A.). AQUACOAT is prepared by dissolving ethylcellulose in a water-immiscible organic solvent and then emulsifying the organic solvent in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. Plasticizer is not incorporated in the pseudolatex during the manufacturing phase; therefore, prior to using the pseudolatex as a coating, it is necessary to intimately mix the AQUACOAT with a suitable plasticizer. [0078]
  • Another commercially available aqueous dispersion of ethylcellulose suitable for use in the invention is SURELEASE (commercially available from Colorcon, Inc., West Point, Pa., U.S.A.). [0079]
  • In one embodiment, the acrylic coating comprises an acrylic resin lacquer used in the form of an aqueous dispersion, such as EUDRAGIT. In further embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma GmbH, Weiterstat, Germany under the tradenames EUDRAGIT RL 30 D and [0080] EUDRAGIT RS 30 D. These materials are copolymers of acrylic and methacrylic esters having a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL 30 D and 1:40 in EUDRAGIT RS 30 D. The mean molecular weight of these materials is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. EUDRAGIT RL/RS mixtures are substantially insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. The EUDRAGIT RL/RS dispersions useful in the present invention can be mixed together in any desired ratio in order to ultimately obtain a controlled-release formulation having a desirable dissolution profile. Desirable controlled-release formulations can be obtained, for instance, from a coating derived from 100% EUDRAGIT RL; 50% EUDRAGIT RL, 50% EUDRAGIT RS; and 10% EUDRAGIT RL, 90% Eudragit RS (each commercially available from Rohm Pharma GmbH, Weiterstat, Germany).
  • The sustained-release coating can also comprise a mixture of a hydrophobic material and a hydrophilic material. The ratio of hydrophobic material to hydrophilic material is determined by, among other factors, the required release rate of the therapeutic agent and the solubility characteristics of the materials selected. Hydrophilic materials include, but are not limited to, polyvinylpyrrolidone and water soluble celluloses, such as hydroxypropylmethyl cellulose. Examples of combinations of hydrophobic material and hydrophilic material useful for the sustained-release coating include, but are not limited, to a combination of shellac and polyvinylpyrrolidone and a combination of ethyl cellulose and hydroxypropylmethyl cellulose. [0081]
  • Alternatively, the therapeutic agent can be dispersed in a controlled-release matrix. The phrase “controlled-release matrix,” as used herein means a matrix that slowly releases the therapeutic agent over time. Any controlled-release matrix can be used in the oral dosage form of the invention. Certain controlled-release matrices are known for oral formulations (See, e.g., Remingtons Pharmaceutical Sciences, 1[0082] 8th ed. Mack Publishing Co., Easton, Pa., 1990, p. 1684-1685). Other examples of useful controlled-release matrices are described iri U.S. Pat. Nos. 6,143,328 to Heafield et al.; 6,063,405 to Drizen et al.; 5,462,747 to Radebaugh et al.; 5,451,409 to Rencher et al.; 5,334,392 to Cuine et al.; and 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 5,356,467, and 5,472,712, each to Oshlack et al., the contents of which are expressly incorporated herein by reference thereto. Particularly useful controlled-release matrices for opioids are described in U.S. Pat. No. 6,143,328 to Heafield et al. and 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351, 5,356,467, and 5,472,712, each to Oshlack et al.
  • The controlled-release matrix can be a fusible hydrophobic material, optionally combined with a hydrophilic material. The hydrophobic fusible material can be, for example, a hydrophobic polymer or a natural or synthetic wax or oil, such as hydrogenated vegetable oil or hydrogenated castor oil, which in one embodiment has a melting point of from about 35 to 100° C., and in another embodiment from about 45 to 90° C. The hydrophilic material can be a hydrophilic polymer; a water soluble fusible material, such as polyethylene glycol; or a water soluble particulate material, such as dicalcium phosphate or lactose. [0083]
  • The therapeutic agent dispersed in a controlled-release matrix can be prepared by formulating, e.g., using dry or wet granulation or by blending, the therapeutic agent with a component other than the fusible component. Suitable non-fusible materials for inclusion in a controlled release matrix include, but are not limited to: [0084]
  • (a) hydrophilic or hydrophobic polymers, such as gums, cellulose ethers, protein-derived materials, nylon, acrylic resins, polylactic acid, polyvinylchloride, starches, polyvinylpyrrolidones, and cellulose acetate phthalate. Of these polymers, cellulose ethers, for example substituted cellulose ethers such as alkylcelluloses (e.g., ethylcellulose), C[0085] 1-C6 hydroxyalkylcelluloses (e.g., hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic resins (e.g., methacrylates such as methacrylic acid copolymers) are used in one embodiment. The controlled-release matrix can conveniently contain between 1% and 80% (by weight) of the hydrophobic and/or hydrophilic polymer.
  • (b) digestible, long chain (C[0086] 1-C50, in one embodiment C8-C40) substituted or unsubstituted hydrocarbons, such as fatty acids; hydrogenated vegetable oils; fatty alcohols, such as lauryl, myristyl, stearyl, cetyl or, in one embodiment cetostearyl alcohol; glyceryl esters of fatty acids, for example, glyceryl monostearate; mineral oils; and waxes, such as beeswax, glycowax, castor wax, and camauba wax. Hydrocarbons having a melting point of between about 25° C. and 90° C. are used in one embodiment. Of these long chain hydrocarbon materials, fatty (aliphatic) alcohols are useful in one embodiment. The controlled-release matrix may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
  • (c) Polyalkylene glycols. The controlled-release matrix may contain up to 60% (by weight) of at least one polyalkylene glycol. [0087]
  • A suitable controlled-release matrix for use in the oral dosage form of the invention comprises one or more cellulose ethers or acrylic resins, one or more C[0088] 12-C36, in one embodiment C12-C22, aliphatic alcohols, and/or one or more hydrogenated vegetable oils. A particular suitable matrix comprises one or more alkylcelluloses, one or more C12-C36, in one embodiment C12-C22, aliphatic alcohols, and optionally one or more polyalkylene glycols. In another embodiment the matrix contains between about 0.5% and 60%, and in another embodiment, between 1% and 50% (by weight) of the cellulose ether.
  • The acrylic resin is for example a methacrylate such as methacrylic acid copolymer USNF Type A (EUDRAGIT L), Type B (EUDRAGIT S,), Type C (EUDRAGIT L 100-55), EUDRAGIT NE 30 D, EUDRAGIT E, EUDRAGIT RL, or EUDRAGIT RS (commercially available from Rohm Pharma GmbH, Weiterstat, Germany). In one embodiment the matrix contains between about 0.5% and 60% by weight, and in another embodiment between 1% and 50% by weight of the acrylic resin. [0089]
  • In the absence of polyalkylene glycol, the matrix in one embodiment contains between about 1% and 40%, in another embodiment between about 2% and 36% (by weight) of the aliphatic alcohol. When polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol in one embodiment constitutes between about 2% and 40%, in another embodiment between about 2 and 36% (by weight) of the matrix. [0090]
  • The polyalkylene glycol may be, for example, polypropylene glycol or, in one embodiment, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is in one embodiment between 200 and 15,000, and in another embodiment between 400 and 12,000. [0091]
  • The controlled-release matrix containing the therapeutic agent can readily be prepared by dispersing the therapeutic agent in the components of the matrix using conventional pharmaceutical techniques including, but not limited to, melt granulation, wet granulation, dry blending, dry granulation, and co-precipitation. [0092]
  • The controlled-release formulations slowly release the therapeutic agent when ingested and exposed to gastric and/or intestinal fluids. [0093]
  • 5.4.5 Coating Process
  • In one embodiment the first and second compositions are solids, such as, but not limited to, granules, fine granules, pills, beads, capsules, tablets, or powders. Methods for preparing these solids are well known in the art. The compositions can additionally comprise any conventional pharmaceutically acceptable excipient such as a binding agent (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricant (e.g., magnesium stearate, talc or silica); disintegrant (e.g., potato starch or sodium starch glycolate); or wetting agent (e.g., sodium lauryl sulphate). Such compositions, if desired, can also contain a minor amount of an emulsifying agent or a pH-buffering agent. In one embodiment, the first and/or second composition comprises a hydrophobic material to provide the composition with a sustained-release property. Examples of useful hydrophobic material are disclosed in section 5.4.4, supra. Solid compositions can be prepared by using conventional methods known in the art, for example, wet granulation, melt extrusion, and tableting by compression. [0094]
  • The solid compositions are coated with layers by applying one or more coating mixtures. Coating mixtures are prepared by any conventional means, for example, by dissolving the above-mentioned polymers and optionally plasticizers in a suitable solvent or mixture of solvents, for example water, methanol, ethanol, isopropanol, acetone, ethylacetate, ethylene chloride, or mixtures thereof. Examples of plasticizers include, but are not limited to, citric acid esters, such as triethyl citrate and tributyl citrate; dibutyl phthalate; 1,2-propylene glycol; polyethylene glycols; castor oil; and triacetin. If the coating mixture is an aqueous dispersion, a small amount of talc, glyceral monostearate, or colloidal silicon dixide may be added to reduce the tendency of the aqueous dispersion to stick during processing. The coating mixture can also contain additives such as coloring agents and/or magnesium stearate, which are well known in the coating art. [0095]
  • The coating solution can be applied to the solid composition by any means available to those of ordinary skill in the art such as, for example, spraying or dipping. Conventional coating apparatuses, well known to those of ordinary skill in the art, can be used to coat the solid composition (See, e.g., Remingtons Pharmaceutical Sciences, 18[0096] th ed. Mack Publishing Co., Easton, Pa., 1990). Conventional coating apparatuses include, but are not limited to, coating-granulating apparatuses of the centrifugal fluidized type, pan-coating apparatuses, and fluidized-bed granulating coating apparatuses. For example, a Wuster fluidized-bed system can be used in which an air jet, injected from underneath, fluidizes the coated material and effects drying while the polymer coating is sprayed on. When the solid composition is coated with more than one coating, the first coating solution is applied and then allowed to dry before the second coating solution is applied. In one embodiment, the coating solutions are applied to provide a dosage form that has a dissolution profile substantially unaffected by exposure to accelerated-storage conditions.
  • The phrase “accelerated-storage conditions,” as used herein, means storage conditions of elevated temperature and/or elevated relative humidity to which the oral dosage form is subjected for the purpose of obtaining regulatory approval, e.g., the FDA for approval in the U.S., and an expiration date. For example, a generally accepted test employed in FDA guidelines relates to the storage of a drug product (i.e., in its container and package) at 40° C. and 75% Relative Humidity (RH). The length of time that the drug product can be stored under these conditions without chemically degrading and with its dissolution and physical characteristics remaining unchanged, is used to determine the expiration date of the drug product. For example, storage for three months without chemical degradation and without change in dissolution or appearance can result in the drug product being accorded a two year expiration date. Other generally accepted accelerated tests include those where the drug product is subjected to storage at 37° C. and 80% relative humidity for one month or longer, in one embodiment three months. [0097]
  • 5.5 Oral Dosage Form 5.5.1 Amount per Dosage Unit
  • In the oral dosage form of the present invention, the amount of the therapeutic agent per dosage unit is that which is an effective amount for its particular indication and is independent of the amount of the adverse-effect agent. For example, if the therapeutic agent is an opioid agonist, the amount of the opioid agonist in the oral dosage form of the present invention is generally from about 75 ng to about 1000 mg, in one embodiment from about 75 ng to about 750 mg. One of ordinary skill in the art can readily determine, without undue experimentation, the amount of therapeutic agent needed for a particular indication. [0098]
  • The amount of the adverse-effect agent in the oral dosage form of the present invention is such that the adverse-effect agent can give the intended adverse effect. When the adverse-effect agent is intended to reduce or eliminate the pharmacological effects of the therapeutic agent, the amount of the adverse-effect agent in the oral dosage form is at least sufficient to reduce or eliminate the effects of the therapeutic agent when both agents are released. [0099]
  • In the present invention, the phrase “to reduce or eliminate the effects of the therapeutic agent,” as used herein, means that the effects of the therapeutic agent that attract potential abusers are eliminated or become lessened. For example, an adverse-effect agent can reduce the euphoric effect of a therapeutic agent. [0100]
  • When the adverse-effect agent is an opioid antgonist, the amount of the opioid antagonist, present in a oral dosage form of the present invention, can be from about 10 ng to 275 mg. The opioid antagonists cyclazocine and naltrexone, when administered orally, retain much of their efficacy with a long duration of action, approaching 24 hours, Accordingly, amounts of less than 100 mg of these opioid antagonists are typically used in the oral formulations of the invention. [0101]
  • When the adverse-effect agent is intended to cause an undesired physiological reaction, such as a emesis, the amount of the adverse-effect agent in the oral dosage form is at least sufficient to cause such effect upon release. [0102]
  • For safety reasons, the amount of the adverse-effect agent present in the oral dosage form should not be harmful to humans even if fully released. One of ordinary skill in the art can readily determine, without undue experimentation, the amount of adverse-effect agent needed to elicit the intended adverse-effect without being harmful. [0103]
  • In certain embodiments of the present invention, the ratio of the therapeutic agent to the adverse-effect agent in the oral dosage form is about 1:1 to about 50:1 by weight, in one embodiment about 1:1 to about 20:1 by weight. In certain other embodiments, the ratio is about 1:1 to about 10:1 by weight. In another embodiment of the invention, the therapeutic agent includes oxycodone or hydrocodone and is present in the amount of about 15-45 mg, and the adverse-effect agent includes naltrexone and is present in about 0.5-5 mg. [0104]
  • In another embodiment the first composition has a sustained-release coating, the therapeutic agent is an opioid agonist and the adverse-effect agent is an opioid antagonist. In embodiments in which the opioid agonist is hydrocodone, the sustained-release oral dosage forms can include analgesic doses from about 5 mg to about 80 mg of hydrocodone per dosage unit. In oral dosage forms where the opioid agonist is hydromorphone, it may be included in an amount from about 2 mg to about 64 mg hydromorphone hydrochloride per dosage unit. In another embodiment, the opioid agonist is morphine, and the oral dosage forms of the present invention include from about 2.5 mg to about 800 mg morphine per dosage unit. In yet another embodiment, the opioid agonist is oxycodone and the oral dosage forms include from about 2.5 mg to about 800 mg oxycodone, in another embodiment from about 20 mg to about 30 mg oxycodone per dosage unit. Controlled-release oxycodone formulations are known in the art. The opioid agonist can be tramadol in an amount from about 25 mg to 800 mg tramadol per dosage unit. The dosage form can contain more than one opioid agonist. [0105]
  • 5.5.2 Embodiments of the Oral Dosage Form
  • In one embodiment, the first composition and the second composition are coated as explained in section 5.4, supra to provide the first coated composition and the second coated composition. As discussed above, the first composition, comprising a therapeutic agent, is coated with an outer acid-soluble layer, an inner base-soluble layer and, optionally, an innermost sustained release coating; and the second composition, comprising an adverse-effect agent, is coated with an inner acid-soluble layer, an outer base-soluble layer, and, optionally, a layer substantially insoluble in the gastrointestinal tract. The first composition and the second composition are then combined to provide a unit dosage of the oral composition of the invention. In one embodiment, the first composition and the second composition are similar in their size, shape and color so that they cannot be readily distinguished from each other. For example, the first composition and the second composition can each be powders, granules, or beads that are combined and incorporated into a capsule or tablet using methods well known to those of ordinary skill in the art. The capsule may be hard or soft, for example, gelatin. The capsule can also contain pharmaceutically acceptable excipients. [0106]
  • FIG. 3 shows a cross-sectional view of a [0107] capsule 30, which has a first part 33 and a second part 34 and contains powders, granules, or beads of a first composition 31 and powders or granules of a second composition 32.
  • FIG. 5 shows a cross-sectional view of a dosage form according to the invention in the form of a [0108] tablet 50. The first composition is in the form of powders or granules 51 and the coated second composition is in the form of powders, granules, or beads 52. The first composition and the coated second composition are mixed with a pharmaceutically acceptable matrix 53 and compressed into a tablet.
  • In another embodiment the capsule or tablet contains the first composition without the outer acid-soluble layer and without the inner base-soluble layer and the second composition coated with an outer base-soluble layer and an inner acid-soluble layer. [0109]
  • FIG. 6. Depicts another embodiment of the oral dosage form of the invention in the form of a tablet comprising a core that is a mixture of an uncoated [0110] first composition 64 and a second composition coated with a base-soluble outer layer and an acid soluble inner layer 65. The core is then coated with an inner base-soluble layer 62, and an outer acid-soluble layer 61, and an optional innermost sustained release coating 63. Alternatively, the second composition can be coated with a layer that is substantially insoluble in the gastrointestinal tract.
  • Another embodiment of the oral dosage form of the invention is a two-[0111] layer tablet 40 as shown in FIG. 4. A solid nucleus of the first composition 45 is covered with an innermost sustained-release coating 43 (optional), an inner base-soluble layer 42, and an outer acid-soluble layer 41. A solid nucleus of the second composition 44 is covered with an inner acid-soluble layer 46, an outer base-soluble layer 47, and an outermost layer that is substantially insoluble in the gastrointestinal tract 48 (optional). The two coated nuclei are then compressed into a two-layer tablet 40 using conventional tableting equipment and standard techniques to provide a two-layered tablet. The compressed two-layer tablet can then optionally be coated with an additional coating to provide a tablet of uniform appearance. In one embodiment, the additional coating is a coating that dissolves in the stomach after the tablet is swallowed.
  • In another embodiment of the two-layer tablet, the first composition is uncoated, i.e., is not covered with the outer acid-soluble layer or the inner base-soluble layer, but the second composition is coated with an outer base-soluble layer and an inner acid-soluble layer. [0112]
  • Yet another embodiment of the [0113] oral dosage 70 is shown in FIG. 7. A solid nucleus of the second composition 77 is coated with an innermost acid-soluble layer 76 and an outer base-soluble layer 75. Then, the second composition is further coated with a layer of the first composition 74, an optional innermost pH-independent layer 73, an inner base-soluble layer 72, and an outer acid-soluble layer 71. The oral dosage 70 may be a tablet or a granule.
  • 6. EXAMPLES
  • The following prophetic examples are set forth to assist in understanding the invention and should not, of course, be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein. [0114]
  • Example 1 Capsule
  • (1) Preparation of Oxycodone Granules and Naltrexone HCl Granules [0115]
    Ingredient Amount/unit (mg)
    Oxycodone HCl or 20.00
    Naltrexone HCl 5.00
    Spray Dried Lactose 59.25
    Providone 5.00
    Eudragit RS 30D (dry wt.) 10.00
    Triacetin 2.00
    Total 131.00
  • EUDRAGIT RS 30 D is plasticized by mixing with triacetin. The dispersion is then combined with the oxycodone HCl or naltrexene HCl, spray dried lactose, and providone using a fluid-bed granulator. The resulting mixture is granulated. If necessary the granules are dried. The granules are then screened with a sieve to provide granules of an appropriate size. [0116]
  • (2) Coating [0117]
  • An acid-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT E 100 in 200 ml of ethanol to provide a clear solution, and 4 g of the plasticizer triethyl citrate is added to the solution. [0118]
  • A base-soluble coating solution is prepared by dispersing 15.0 g EUDRAGIT L in 200 ml of ethanol to provide a clear solution. [0119]
  • The oxycodone HCl granules are spray coated with the base-soluble coating solution and dried. After drying, the resulting oxycodone HCl granules coated with the base-soluble coating are then spray coated with the acid-soluble coating solution and the resulting granules dried. [0120]
  • The naltrexone HCl granules are spray coated with the acid-soluble coating solution and dried. After drying, the resulting naltrexone HCl granules coated with the acid-soluble coating are then spray coated with the base-soluble coating solution and the resulting granules dried. [0121]
  • (3) Encapsulating [0122]
  • The coated oxycodone HCl granules and the coated naltrexone HCl granules are mixed together to provide a mixture, and a gelatin capsule is filled with the mixture. [0123]
  • Example 2 Tablet
  • Stearyl alcohol is melted, and the melted stearyl alcohol (25.00 mg per unit) is mixed with the coated granules obtained in Example 1 to wax them. The waxed granules are cooled in a fluid bed dryer and then blended with talc (2.50 mg per unit) and magnesium stearate (1.25 mg per unit) to provide a blend. The resulting blend is compressed into a tablet using a tablet press. [0124]
  • The present invention is not to be limited in scope by the specific embodiments disclosed in the examples which are intended as illustrations of a few aspects of the invention and any embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims. [0125]
  • A number of references have been cited, the entire disclosures of which are incorporated herein by reference. [0126]

Claims (79)

What is claimed is:
1. An oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent and the second composition comprises an effective amount of an adverse-effect agent, wherein the second composition is coated with an inner acid-soluble layer and an outer base-soluble layer.
2. The oral dosage form of claim 1, wherein the first composition and the second composition are in the form of powders, granules, or beads contained within a capsule.
3. The oral dosage form of claim 1, wherein the first composition and the second composition are in the form of granules or a powder dispersed in a pharmaceutically acceptable matrix.
4. The oral dosage form of claim 1 in the form of a two-layer tablet having a first layer comprising the first composition and a second layer comprising the second composition.
5. The oral dosage form of claim 4, wherein the two-layer tablet is further coated with a coating that dissolves in the stomach.
6. The oral dosage form of claim 1, wherein the adverse-effect agent is an antagonist of the therapeutic agent.
7. The oral dosage form of claim 1, wherein the adverse-effect agent is an emetic.
8. The oral dosage form of claim 1, wherein the acid-soluble layer is soluble at a pH value of less than about 5.0 and substantially insoluble at a pH value of greater than about 5.5.
9. The oral dosage form of claim 1, wherein the base-soluble layer is soluble at a pH value of greater than about 5.5 but substantially insoluble at a pH value of less than about 5.0.
10. The oral dosage form of claim 1, wherein the acid-soluble layer comprises a cationic polymer with dimethylaminoethyl ammonium functionalities.
11. The oral dosage form of claim 1, wherein the base-soluble layer comprises an anionic polymer of methacrylic acid or a methacrylate with carboxylic acid functionalities.
12. The oral dosage form of claim 1, wherein the first composition is a controlled-release dosage form.
13. The oral dosage form of claim 12, wherein the first composition is coated with a sustained-release coating.
14. The oral dosage form of claim 13, wherein the sustained-release coating is selected from the group consisting of a wax, fatty alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble cellulose, polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and methacrylic acid, and mixtures thereof.
15. The oral dosage form of claim 12, wherein the first composition is dispersed in a controlled-release matrix.
16. The oral dosage form of claim 1, wherein the therapeutic agent is selected from a group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
17. The oral dosage form of claim 1, wherein the therapeutic agent is an agent having a potential for abuse.
18. The oral dosage form of claim 17, wherein the therapeutic agent is an opioid, benzodiazepine, barbiturate, or a stimulant.
19. The oral dosage form of claim 18, wherein the therapeutic agent is an opioid and the adverse-effect agent is an opioid antagonist.
20. The oral dosage form of claim 19, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
21. The oral dosage form of claim 20, wherein the opioid is selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof.
22. The oral dosage form of claim 21, wherein the opioid is oxycodone or hydrocodone.
23. The oral dosage form of claim 19, wherein the adverse-effect agent is selected from the group consisting of naloxone, naltrexone, nalmefene, cyclazacine, and levallorphan.
24. The oral dosage form of claim 23, wherein the adverse-effect agent is naloxone or naltrexone.
25. The oral dosage form of claim 18, wherein the therapeutic agent is a benzodiazepine and the adverse-effect agent is a benzodiazepine antagonist.
26. The oral dosage form of claim 25, wherein the benzodiazepine is selected from the group consisting of alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepan, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmaceutically acceptable salts thereof, and mixtures thereof .
27. The oral dosage form of claim 25, wherein the benzodiazepine antagonist is flumazenil.
28. The oral dosage form of claim 18, wherein the therapeutic agent is a barbiturate and the adverse-effect agent is a barbiturate antagonist.
29. The oral dosage form of claim 28, wherein the barbiturate is selected from the group consisting of amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixtures thereof.
30. The oral dosage form of claim 28, wherein the barbiturate antagonist is a stimulant.
31. The oral dosage form of claim 18, wherein the therapeutic agent is a stimulant and the adverse-effect agent is an a stimulant antagonist.
32. The oral dosage form of claim 31, wherein the stimulant is selected from the group consisting of amphetamine, amphetamine and dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, a pharmaceutically acceptable salt thereof, and mixtures thereof.
33. The oral dosage form of claim 31, wherein the stimulant antagonist is a benzodiazepine.
34. The oral dosage form of claim 17, wherein the therapeutic agent is selected from a group consisting of dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, detropropoxyphene, pharmaceutically acceptable salts thereof, and mixtures thereof.
35. The oral dosage form of claim 1, wherein the therapeutic agent is selected from the group consisting of 5-ASA, steroids, laxatives, octreotide, cisapride, anticholinergics, calcium channel blockers, DNA for delivery to the cells of the colon, glucosamine, thromboxane A2 synthetase inhibitor, 5HT3-antagonists, antibodies against infectious bacteria, antiviral agents, heparins, insulin, calcitonins, human growth hormone, growth hormone releasing hormon, interferons, somatostatin and analogues thereof, erythropoietin, granulocyte colony stimulating factor, parathyroid hormone, luteinising hormone releasing hormone and analogues thereof, atrial natriuretic factor, vasopressin, desmopressin, calcitonin gene related peptide, and analgesics.
36. The oral dosage form of claim 1, wherein the ratio of therapeutic agent to adverse-effect agent is from about 1:1 to 50:1.
37. An oral dosage form comprising a first composition and a second composition, wherein the first composition comprises an effective amount of a therapeutic agent and is coated with an inner base-soluble layer and an outer acid-soluble layer and the second composition comprises an effective amount of an adverse-effect agent and is coated with an inner acid-soluble layer and an outer base-soluble layer.
38. The oral dosage form of claim 37, wherein the first composition and the second composition are in the form of powders, granules, or beads contained within a capsule.
39. The oral dosage form of claim 37, wherein the first composition and the second composition are in the form of granules or a powder dispersed in a pharmaceutically acceptable matrix.
40. The oral dosage form of claim 37 in the form of a two-layer tablet having a first layer comprising the first composition and a second layer comprising the second composition.
41. The oral dosage form of claim 40, wherein the two-layer tablet is further coated with a coating that dissolves in the stomach.
42. The oral dosage form of claim 37 in the form of a tablet comprising a core coated with an inner-base soluble layer and an outer acid soluble layer, wherein the core comprises the second composition coated with an inner acid-soluble layer and an outer base-soluble layer dispersed within the therapeutic agent.
43. The oral dosage form of claim 37 in the form of a tablet comprising a core of the second composition coated with an inner acid-soluble layer, an outer base-soluble layer, a coating of the first composition, an inner-base-soluble layer, and an outer acid-soluble layer.
44. The oral dosage form of claim 37, wherein the adverse-effect agent is an antagonist of the therapeutic agent.
45. The oral dosage form of claim 37, wherein the adverse-effect agent is laxative.
46. The oral dosage form of claim 37, wherein each acid-soluble layer is soluble at a pH value of less than about 5.0 and substantially insoluble at a pH value of greater than about 5.5.
47. The oral dosage form of claim 37, wherein each base-soluble layer is soluble at a pH value of greater than about 5.5 but substantially insoluble at a pH value of less than about 5.0.
48. The oral dosage form of claim 37, wherein each acid-soluble layer comprises a cationic polymer with dimethylaminoethyl ammonium functionalities.
49. The oral dosage form of claim 37, wherein each base-soluble layer comprises an anionic polymer of methacrylic acid or a methacrylate with carboxylic acid functionalities.
50. The oral dosage form of claim 37, wherein the first composition is a controlled-release dosage form.
51. The oral dosage form of claim 50, wherein the first composition is coated with an inner-most sustained-release coating.
52. The oral dosage form of claim 51, wherein the sustained-release coating is selected from the group consisting of a wax, fatty alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble cellulose, polymers of acrylic acid, polymers of methacrylic acid, copolymers of acrylic acid and methacrylic acid, and mixtures thereof.
53. The oral dosage form of claim 50, wherein the first composition is dispersed in a controlled-release matrix.
54. The oral dosage form of claim 37, wherein the therapeutic agent is selected from a group consisting of analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents, erectile dysfunction improvement agents, immunosuppressants, anti-protozoal agents, anti-thyroid agents, anxiolytic agents, sedatives, hypnotics, neuroleptics, β-Blockers, cardiac ionotropic agents, corticosteroids, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine receptor antagonists, keratolytics, lipid regulating agents, anti-anginal agents, cox-2-inhibitors, leukotriene inhibitors, macrolides, muscle relaxants, nutritional agents, opioid analgesics, protease inhibitors, sex hormones, stimulants, muscle relaxants, anti-osteoporosis agents, anti-obesity agents, cognition enhancers, anti-urinary incontinence agents, nutritional oils, anti-benign prostate hypertrophy agents, essential fatty acids, non-essential fatty acids, and mixtures thereof.
55. The oral dosage form of claim 37, wherein the therapeutic agent is an agent having a potential for abuse.
56. The oral dosage form of claim 55, wherein the therapeutic agent is an opioid, benzodiazepine, barbiturate, or a stimulant.
57. The oral dosage form of claim 56, wherein the therapeutic agent is an opioid and the adverse-effect agent is an opioid antagonist.
58. The oral dosage form of claim 57, wherein the opioid is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroetorphine, fentanyl, hydrocodone, hydromorphone, hydromorphodone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, paregoric, pentazocine, phenadoxone, phendimetrazine, phendimetrazone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, propylhexedrine, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof.
59. The oral dosage form of claim 58, wherein the opioid selected from the group consisting of hydrocodone, morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine, methadone, oxymorphone, buprenorphine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, etorphine, dihydroetorphine, butorphanol, levorphanol, pharmaceutically acceptable salts thereof, and mixtures thereof.
60. The oral dosage form of claim 59, wherein the opioid is oxycodone or hydrocodone.
61. The oral dosage form of claim 57, wherein the adverse-effect agent is selected from the group consisting of naloxone, naltrexone, nalmefene, cyclazacine, and levallorphan.
62. The oral dosage form of claim 57, wherein the adverse-effect agent is naloxone or naltrexone.
63. The oral dosage form of claim 56, wherein the therapeutic agent is a benzodiazepine and the adverse-effect agent is a benzodiazepine antagonist.
64. The oral dosage form of claim 63, wherein the benzodiazepine is selected from the group consisting of alprazolam, bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepan, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, triazolam, pharmaceutically acceptable salts thereof, and mixtures thereof.
65. The oral dosage form of claim 63, wherein the benzodiazepine antagonist is flumazenil.
66. The oral dosage form of claim 56, wherein the therapeutic agent is a barbiturate and the adverse-effect agent is a barbiturate antagonist.
67. The oral dosage form of claim 66, wherein the barbiturate is selected from the group consisting of amobarbital, aprobarbotal, butabarbital, butalbital, methohexital, mephobarbital, metharbital, pentobarbital, phenobarbital, secobarbital, pharmaceutically acceptable salts thereof, and mixture thereof.
68. The oral dosage form of claim 56, wherein the barbiturate antagonist is a stimulant.
69. The oral dosage form of claim 5, wherein the therapeutic agent is a stimulant and the adverse-effect agent is a stimulant antagonist.
70. The oral dosage form of claim 69, wherein the amphetamine is selected from the group consisting of amphetamine, amphetamine and dextroamphetamine resin complex, dextroamphetamine, methamphetamine, methylphenidate, a pharmaceutically acceptable salt thereof, and mixtures thereof.
71. The oral dosage form of claim 69, wherein the stimulant antagonist is a benzodiazepine.
72. The oral dosage form of claim 56, wherein the therapeutic agent is selected from a group consisting of dronabinol, glutethimide, methylphenidate, nabilone, anabolic steroids, methylprylon, ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline, levomethadyl, benzphetamine, chlorphentermine, diethylpropion, phentermine, mebutamate, chlortermine, phenylacetone, dronabinol, nabilone, benphetamine, chloral hydrate, ethclorovynol, paraldehyde, midazolam, detropropoxyphene, pharmaceutically acceptable salts thereof, and mixtures thereof.
73. The oral dosage form of claim 37, wherein the therapeutic agent is selected from the group consisting of 5-ASA, steroids, laxatives, octreotide, cisapride, anticholinergics, calcium channel blockers, DNA for delivery to the cells of the colon, glucosamine, thromboxane A2 synthetase inhibitor, 5HT3-antagonists, antibodies against infectious bacteria, antiviral agents, heparins, insulin, calcitonins, human growth hormone, growth hormone releasing hormon, interferons, somatostatin and analogues thereof, erythropoietin, granulocyte colony stimulating factor, parathyroid hormone, luteinising hormone releasing hormone and analogues thereof, atrial natriuretic factor, vasopressin, desmopressin, calcitonin gene related peptide, and analgesics.
74. The oral dosage form of claim 37, wherein the ratio of therapeutic agent to adverse-effect agent is from about 1:1 to 50:1.
75. A method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of claim 1.
76. A method for treating or preventing pain, comprising administering to a patient in need thereof the oral dosage form of claim 37.
77. A method for treating or preventing pain, comprising administering to a patient in need thereof an oral dosage form comprising a first composition and a second composition, wherein:
the first composition comprises an effective amount of a therapeutic agent;
the second composition comprises an effective amount of an adverse-effect agent;
effective amount of the therapeutic agent is released in the patient's small intestine; and
less than an effective amount of the adverse-effect agent is released in the patient's gastrointestinal tract.
78. A method for preparing the oral dosage form of claim 1, comprising the step of preparing the oral dosage form as set forth herein.
79. A method for preparing the oral dosage form of claim 37, comprising the step of preparing the oral dosage form as set forth herein.
US10/208,817 2001-08-06 2002-08-01 Oral dosage form comprising a therapeutic agent and an adverse-effect agent Abandoned US20030044458A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
US10/208,817 US20030044458A1 (en) 2001-08-06 2002-08-01 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
KR1020087030854A KR20090005247A (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
KR1020047001854A KR100893895B1 (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
DK02761250.6T DK1414459T3 (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and a damaging agent
MXPA04001098A MXPA04001098A (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent.
CA2456601A CA2456601C (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
DE60234604T DE60234604D1 (en) 2001-08-06 2002-08-05 ORAL DOSAGE FORM CONTAINS A THERAPEUTIC AGENT AND AN ACTIVE ACTIVE SUBSTANCE
ES02761250T ES2337664T3 (en) 2001-08-06 2002-08-05 ORAL DOSAGE FORM INCLUDING A THERAPEUTIC AGENT AND AN ADVERSE EFFECT AGENT.
AT02761250T ATE450259T1 (en) 2001-08-06 2002-08-05 ORAL DOSAGE FORM CONTAINING A THERAPEUTIC ACTIVE INGREDIENT AND AN COUNTERACTIVE ACTIVE INGREDIENT
DE20220838U DE20220838U1 (en) 2001-08-06 2002-08-05 Oral dosage form containing a therapeutic agent and a counteracting agent
IL16019502A IL160195A0 (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
RU2004106620/15A RU2004106620A (en) 2001-08-06 2002-08-05 MEDICAL FORM CONTAINING A THERAPEUTIC MEDICINE AND A SIDE EFFECT
JP2003518547A JP5143995B2 (en) 2001-08-06 2002-08-05 Oral preparations containing therapeutic and adverse agents
BR0211781-9A BR0211781A (en) 2001-08-06 2002-08-05 Oral dosage form, and methods for treating or preventing pain, and for preparing oral dosage form
SI200230884T SI1414459T1 (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
EP02761250A EP1414459B1 (en) 2001-08-06 2002-08-05 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US10/948,575 US7384653B2 (en) 2001-08-06 2004-09-23 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
HK04108654.6A HK1067524A1 (en) 2001-08-06 2004-11-03 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
JP2008295477A JP5485538B2 (en) 2001-08-06 2008-11-19 Oral preparations containing therapeutic and adverse agents
CY20101100149T CY1109816T1 (en) 2001-08-06 2010-02-12 BY ORAL DOSAGE FORM THAT INCLUDES A THERAPEUTIC FACTOR AND AN ANTI-EFFECTIVE FACTOR
JP2013101285A JP2013189447A (en) 2001-08-06 2013-05-13 Oral dosage form comprising therapeutic agent and adverse-effect agent
US13/923,362 USRE45822E1 (en) 2001-08-06 2013-10-28 Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30979101P 2001-08-06 2001-08-06
US10/208,817 US20030044458A1 (en) 2001-08-06 2002-08-01 Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/948,575 Continuation US7384653B2 (en) 2001-08-06 2004-09-23 Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Publications (1)

Publication Number Publication Date
US20030044458A1 true US20030044458A1 (en) 2003-03-06

Family

ID=23199688

Family Applications (3)

Application Number Title Priority Date Filing Date
US10/208,817 Abandoned US20030044458A1 (en) 2001-08-06 2002-08-01 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US10/948,575 Ceased US7384653B2 (en) 2001-08-06 2004-09-23 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US13/923,362 Active 2026-03-18 USRE45822E1 (en) 2001-08-06 2013-10-28 Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10/948,575 Ceased US7384653B2 (en) 2001-08-06 2004-09-23 Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US13/923,362 Active 2026-03-18 USRE45822E1 (en) 2001-08-06 2013-10-28 Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Country Status (19)

Country Link
US (3) US20030044458A1 (en)
EP (1) EP1414459B1 (en)
JP (3) JP5143995B2 (en)
KR (2) KR20090005247A (en)
AT (1) ATE450259T1 (en)
AU (1) AU2008202531A1 (en)
BR (1) BR0211781A (en)
CA (1) CA2456601C (en)
CY (1) CY1109816T1 (en)
DE (1) DE20220838U1 (en)
DK (1) DK1414459T3 (en)
ES (1) ES2337664T3 (en)
HK (1) HK1067524A1 (en)
HU (1) HUP0401066A2 (en)
MX (1) MXPA04001098A (en)
PT (1) PT1414459E (en)
RU (1) RU2004106620A (en)
SI (1) SI1414459T1 (en)
WO (1) WO2003013538A1 (en)

Cited By (89)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030091635A1 (en) * 2001-09-26 2003-05-15 Baichwal Anand R. Opioid formulations having reduced potential for abuse
US20030129230A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
WO2004026283A1 (en) 2002-09-20 2004-04-01 Alpharma, Inc. Sequestering subunit and related compositions and metohds
US20040202717A1 (en) * 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
US20050031546A1 (en) * 2003-08-06 2005-02-10 Johannes Bartholomaus Abuse-proffed dosage form
US20050186139A1 (en) * 2002-10-25 2005-08-25 Gruenenthal Gmbh Abuse-proofed dosage form
US20050214223A1 (en) * 2002-10-25 2005-09-29 Gruenenthal Gmbh Abuse-safeguarded dosage form
US20050236741A1 (en) * 2004-04-22 2005-10-27 Elisabeth Arkenau Process for the production of an abuse-proofed solid dosage form
US20050245483A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Matrix for sustained, invariant and independent release of active compounds
US20050271594A1 (en) * 2004-06-04 2005-12-08 Groenewoud Pieter J Abuse resistent pharmaceutical composition
US20060002859A1 (en) * 2004-07-01 2006-01-05 Elisabeth Arkenau Process for production of an abuse-proofed solid dosage form
US20060002860A1 (en) * 2004-07-01 2006-01-05 Johannes Bartholomaus Abuse-proofed oral dosage form
US20060039864A1 (en) * 2004-07-01 2006-02-23 Johannes Bartholomaus Abuse-proofed oral dosage form
EP1660048A1 (en) * 2003-08-12 2006-05-31 Endo Pharmaceuticals Inc. Method for deterring abuse of opioids by combination with non-release formulation of emetic
US20060188447A1 (en) * 2005-02-04 2006-08-24 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20070020339A1 (en) * 2005-07-20 2007-01-25 Pharmorx Inc. Compositions and methods for controlling abuse of medications
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20070098794A1 (en) * 2001-07-06 2007-05-03 Haui-Hung Kao Oxymorphone controlled release formulations
US20070134328A1 (en) * 2001-07-06 2007-06-14 Endo Pharmaceuticals, Inc. Oxymorphone controlled release formulations
US20070183979A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20070185147A1 (en) * 2004-06-08 2007-08-09 Euro-Celtique S.A. Opioids for the treatment of the restless leg syndrome
US20070183980A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
US20070259045A1 (en) * 2005-01-28 2007-11-08 Euro-Celtique S.A. Alcohol Resistant Dosage Forms
EP1861072A2 (en) * 2005-03-14 2007-12-05 Massachusetts Institute Of Technology Nanocells for diagnosis and treatment of diseases and disorders
US20070298103A1 (en) * 2004-02-12 2007-12-27 Euro-Celtique S.A. Particulates
WO2008024490A2 (en) * 2006-08-24 2008-02-28 Theraquest Biosciences, Inc. Oral pharmaceutical formulations of abuse deterrent cannabinoids and method of use
US20080069871A1 (en) * 2006-07-21 2008-03-20 Vaughn Jason M Hydrophobic abuse deterrent delivery system
US20080102113A1 (en) * 2005-06-13 2008-05-01 Paul Rosenberg Emetic embedded capsule
US20090004267A1 (en) * 2007-03-07 2009-01-01 Gruenenthal Gmbh Dosage Form with Impeded Abuse
US20090029170A1 (en) * 2004-02-12 2009-01-29 Geoffrey Gerard Hayes Extrusion
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
US20090175937A1 (en) * 2007-12-17 2009-07-09 Labopharm, Inc. Misuse Preventative, Controlled Release Formulation
US20090202634A1 (en) * 2008-01-25 2009-08-13 Grunenthal Gmbh Pharmaceutical dosage form
US20100196427A1 (en) * 2009-01-30 2010-08-05 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
US20100222312A1 (en) * 2009-01-26 2010-09-02 Nitec Pharma Ag Delayed-release glucocorticoid treatment of asthma
US20100239662A1 (en) * 2008-12-16 2010-09-23 Miloud Rahmouni Misuse preventative, controlled release formulation
US20110082214A1 (en) * 2008-05-09 2011-04-07 Gruenthal Gmbh Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US20110172259A1 (en) * 2005-02-28 2011-07-14 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
US20110177133A1 (en) * 2008-07-07 2011-07-21 Michael Hopp Use of opioid antagonists for treating urinary retention
US20110187017A1 (en) * 2010-02-03 2011-08-04 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US20110237615A1 (en) * 2008-12-12 2011-09-29 Paladin Labs Inc. Narcotic Drug Formulations with Decreased Abuse Potential
US20110305658A1 (en) * 2008-12-11 2011-12-15 L'oreal S.A. Lengthening mascara composition
US20120022020A1 (en) * 2007-11-14 2012-01-26 Laboratorios Farmaceuticos Rovi S.A. Pharmaceutical forms for the release of active compounds
US20120178771A1 (en) * 2008-03-08 2012-07-12 Najib Babul Oral Pharmaceutical Compositions of Buprenorphine and Method of Use
EP2526932A1 (en) 2006-06-19 2012-11-28 Alpharma Pharmaceuticals, LLC Pharmaceutical composition
US20130190341A1 (en) * 2004-06-04 2013-07-25 Camurus Ab High bioavailability opioid formulations
US8518925B2 (en) 2004-06-08 2013-08-27 Euro-Celtique S.A. Opioids for the treatment of the chronic obstructive pulmonary disease (COPD)
US8673355B2 (en) 1997-12-22 2014-03-18 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US8822487B2 (en) 1997-12-22 2014-09-02 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
US8969369B2 (en) 2001-05-11 2015-03-03 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US8999393B1 (en) * 2013-01-09 2015-04-07 Edgemont Pharmaceuticals Llc Sustained release formulations of lorazepam
US9101625B2 (en) 2006-08-30 2015-08-11 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9271940B2 (en) 2009-03-10 2016-03-01 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US20170348305A1 (en) * 2008-01-09 2017-12-07 Locl Pharma, Inc. Pharmaceutical compositions
US9849125B1 (en) 2015-11-03 2017-12-26 Banner Lifie Sciences LLC Anti-overingestion dosage forms
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9937164B2 (en) 2012-07-26 2018-04-10 Camurus Ab Opioid formulations
US10016368B2 (en) 2009-07-08 2018-07-10 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10071089B2 (en) 2013-07-23 2018-09-11 Euro-Celtique S.A. Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US10258235B2 (en) 2005-02-28 2019-04-16 Purdue Pharma L.P. Method and device for the assessment of bowel function
AU2017258853B2 (en) * 2016-11-08 2019-05-16 Alpex Pharma Sa Extended release tablet comprising a weight-loss drug
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10758532B2 (en) 2018-12-11 2020-09-01 Satsuma Pharmaceuticals, Inc. Compositions, devices, and methods for treating or preventing headaches
US10772840B2 (en) 2016-03-04 2020-09-15 Charleston Laboratories, Inc. Sumatriptan promethazine pharmaceutical compositions
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
CN114401746A (en) * 2019-08-12 2022-04-26 耶路撒冷希伯来大学伊森姆研究发展有限公司 Pharmaceutical compositions and composites comprising combinations of opiate antagonists and methods of use thereof

Families Citing this family (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2359812C (en) 2000-11-20 2004-02-10 The Procter & Gamble Company Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures
CN1592609A (en) * 2001-05-11 2005-03-09 恩德制药公司 Abuse-resistant opioid dosage form
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US20030068375A1 (en) 2001-08-06 2003-04-10 Curtis Wright Pharmaceutical formulation containing gelling agent
MXPA04009968A (en) 2002-04-09 2004-12-13 Flamel Tech Sa Oral suspension of active principle microcapsules.
WO2003090717A1 (en) * 2002-04-23 2003-11-06 Nanotherapeutics, Inc Process of forming and modifying particles and compositions produced thereby
DE10250087A1 (en) * 2002-10-25 2004-05-06 Grünenthal GmbH Dosage form protected against abuse
US7524515B2 (en) * 2003-01-10 2009-04-28 Mutual Pharmaceuticals, Inc. Pharmaceutical safety dosage forms
EP1615625A4 (en) * 2003-04-21 2010-12-15 Euro Celtique Sa Tamper resistant dosage form comprising co-extruded, adverse agent particles and process of making same
US8778382B2 (en) * 2003-04-30 2014-07-15 Purdue Pharma L.P. Tamper resistant transdermal dosage form
US8790689B2 (en) * 2003-04-30 2014-07-29 Purdue Pharma L.P. Tamper resistant transdermal dosage form
KR20120080241A (en) 2003-06-20 2012-07-16 뉴트리니아 리미티드 Bioactive compounds protection method and compositions containing the same
US8802139B2 (en) 2003-06-26 2014-08-12 Intellipharmaceutics Corp. Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient
US20070191815A1 (en) 2004-09-13 2007-08-16 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery
US7201920B2 (en) 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
EP1703916A2 (en) * 2004-01-13 2006-09-27 Vasogenix Pharmaceuticals, Inc. Methods for treating acute myocardial infarction by calcitonin gene related peptide and compositions containing the same
EP1703895A2 (en) 2004-01-13 2006-09-27 Vasogenix Pharmaceuticals, Inc. Controlled release cgrp delivery composition for cardiovascular and renal indications
DE602005012244D1 (en) 2004-03-30 2009-02-26 Euro Celtique Sa MANIPULATION SAFE DOSING FORM WITH AN ADSORBEN AND AN ADVERSE MEDIUM
EP3326617A1 (en) 2004-06-12 2018-05-30 Collegium Pharmaceutical, Inc. Abuse-deterrent drug formulations
US10624858B2 (en) 2004-08-23 2020-04-21 Intellipharmaceutics Corp Controlled release composition using transition coating, and method of preparing same
US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
EP1809259B1 (en) * 2004-10-15 2014-12-03 Supernus Pharmaceuticals, Inc. Less abusable pharmaceutical preparations
TWI436991B (en) 2004-11-22 2014-05-11 Euro Celtique Sa Methods for purifying trans-(-)-△9-tetrahydrocannabinol and trans-(+)-△9-tetrahydrocannabinol
US20060177380A1 (en) * 2004-11-24 2006-08-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20070231268A1 (en) * 2004-11-24 2007-10-04 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20060110327A1 (en) * 2004-11-24 2006-05-25 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
US20080152595A1 (en) * 2004-11-24 2008-06-26 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of orally administered pharmaceutical products
EP1817032A2 (en) * 2004-11-29 2007-08-15 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP1863490A2 (en) * 2005-03-28 2007-12-12 Vertex Pharmaceuticals Incorporated Muscarinic modulators
CA2612044C (en) * 2005-06-13 2016-02-02 Paul Rosenberg Emetic embedded capsule
WO2006133733A1 (en) * 2005-06-13 2006-12-21 Flamel Technologies Oral dosage form comprising an antimisuse system
DE502005006082D1 (en) * 2005-09-26 2009-01-08 Faber Castell Ag Cosmetic liquid for coloring the nails and the skin
FR2892937B1 (en) * 2005-11-10 2013-04-05 Flamel Tech Sa MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US9522188B2 (en) 2005-12-13 2016-12-20 Biodelivery Sciences International, Inc. Abuse resistant transmucosal drug delivery device
US10064828B1 (en) 2005-12-23 2018-09-04 Intellipharmaceutics Corp. Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems
EP1810678A1 (en) 2006-01-19 2007-07-25 Holger Lars Hermann Use of morphine and naloxone for drug substitution
CN104825397A (en) 2006-04-03 2015-08-12 伊萨·奥迪迪 Controlled release delivery device comprising an organosol coat
US10960077B2 (en) 2006-05-12 2021-03-30 Intellipharmaceutics Corp. Abuse and alcohol resistant drug composition
RS54764B1 (en) 2006-07-21 2016-10-31 Biodelivery Sciences Int Inc Transmucosal delivery devices with enhanced uptake
KR101445757B1 (en) * 2006-08-04 2014-10-02 에씨팜 Granule and orally disintegrating tablet comprising oxycodone
US8187636B2 (en) 2006-09-25 2012-05-29 Atlantic Pharmaceuticals, Inc. Dosage forms for tamper prone therapeutic agents
WO2009032246A2 (en) 2007-09-03 2009-03-12 Nanotherapeutics, Inc. Particulate compositions for delivery of poorly soluble drugs
EP2042176A1 (en) * 2007-09-26 2009-04-01 Euro-Celtique S.A. Use of a combination of an opioid agonist and an opioid antagonist for the treatment of Crohn's disease
US8623418B2 (en) 2007-12-17 2014-01-07 Alpharma Pharmaceuticals Llc Pharmaceutical composition
JP2011516412A (en) * 2008-03-05 2011-05-26 ビカス セラピューティクス,エルエルシー Compositions and methods for the treatment of cancer and mucositis
WO2010044842A1 (en) * 2008-10-16 2010-04-22 University Of Tennessee Research Foundation Tamper resistant oral dosage forms containing an embolizing agent
US20110311631A1 (en) * 2009-03-18 2011-12-22 Evonik Röhm Gmbh Controlled release pharmaceutical composition with resistance against the influence of ethanol employing a coating comprising a polymer mixture and excipients
WO2011020030A2 (en) * 2009-08-13 2011-02-17 The General Hospital Corporation Methods and compositions to prevent addiction
EP3064064A1 (en) 2009-09-30 2016-09-07 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
IT1398930B1 (en) * 2010-03-24 2013-03-28 Molteni & C PHARMACEUTICAL FORMULATIONS BISTRATO CONTAINING OPPOSING AGONISTS AND ANTAGONISTS.
GB2479213B (en) * 2010-04-01 2013-07-10 Theravida Inc Pharmaceutical formulations for the treatment of overactive bladder
CN104873455B (en) 2010-12-22 2023-09-12 普渡制药公司 Coated Tamper Resistant Controlled Release Dosage Forms
US9233073B2 (en) 2010-12-23 2016-01-12 Purdue Pharma L.P. Tamper resistant solid oral dosage forms
RU2013139247A (en) 2011-02-23 2015-03-27 Церулеус Лтд. FLUMAZENIL COMPLEXES CONTAINING THEIR COMPOSITIONS AND THEIR APPLICATIONS
JP6068447B2 (en) 2011-05-10 2017-01-25 セラヴィダ,インコーポレイテッド Combination of solifenacin and salivary stimulant for the treatment of overactive bladder
EP2729148A4 (en) * 2011-07-06 2015-04-22 Parkinson S Inst Compositions and methods for treatment of symptoms in parkinson's disease patients
SG2014009401A (en) 2011-09-19 2014-05-29 Orexo Ab New abuse-resistant pharmaceutical composition for the treatment of opioid dependence
US9901539B2 (en) 2011-12-21 2018-02-27 Biodelivery Sciences International, Inc. Transmucosal drug delivery devices for use in chronic pain relief
US9763928B2 (en) * 2012-02-10 2017-09-19 Niconovum Usa, Inc. Multi-layer nicotine-containing pharmaceutical composition
WO2013128276A2 (en) * 2012-03-02 2013-09-06 Rhodes Pharmaceuticals L.P. Tamper resistant immediate release formulations
EA201491875A1 (en) 2012-04-17 2015-04-30 Пурдью Фарма Л.П. SYSTEMS AND METHODS OF TREATMENT OF OPIOID-INDUCED PHARMACEUTICAL PHARMACODYNAMIC RESPONSE
CA2888278A1 (en) * 2012-10-15 2014-04-24 Isa Odidi Oral drug delivery formulations
MX366159B (en) 2012-11-30 2019-07-01 Acura Pharmaceuticals Inc Self-regulated release of active pharmaceutical ingredient.
CA2899455C (en) 2013-01-30 2021-06-08 Pharmorx Therapeutics, Inc. Treatments for depression and other diseases with a low dose agent
EA201500742A1 (en) 2013-02-05 2015-12-30 Пердью Фарма Л.П. PHARMACEUTICAL COMPOSITIONS PROTECTED FROM NON-GOAL USE
US10751287B2 (en) 2013-03-15 2020-08-25 Purdue Pharma L.P. Tamper resistant pharmaceutical formulations
JP6539274B2 (en) 2013-08-12 2019-07-03 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド Extruded immediate release abuse deterrent pills
US9763912B2 (en) 2013-10-30 2017-09-19 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Compositions, methods of use, and methods of treatment
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
WO2015145459A1 (en) 2014-03-26 2015-10-01 Sun Pharma Advanced Research Company Ltd. Abuse deterrent immediate release coated reservoir solid dosage form
ES2809458T3 (en) 2014-07-17 2021-03-04 Pharmaceutical Manufacturing Res Services Inc Liquid filled, abuse deterrent and immediate release dosage form
US9849124B2 (en) 2014-10-17 2017-12-26 Purdue Pharma L.P. Systems and methods for treating an opioid-induced adverse pharmacodynamic response
AU2015336065A1 (en) 2014-10-20 2017-05-04 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2016123406A1 (en) 2015-01-28 2016-08-04 Chrono Therapeutics Inc. Drug delivery methods and systems
CA2977814A1 (en) 2015-03-12 2016-09-15 Chrono Therapeutics Inc. Craving input and support system
US11103581B2 (en) 2015-08-31 2021-08-31 Acura Pharmaceuticals, Inc. Methods and compositions for self-regulated release of active pharmaceutical ingredient
US9889120B2 (en) 2016-01-14 2018-02-13 Vicus Therapeutics, Llc Combination drug therapies for cancer and methods of making and using them
CA3011683C (en) 2016-01-20 2023-09-26 Theravida, Inc. Methods and compositions for treating hyperhidrosis
HUE062950T2 (en) 2016-03-24 2023-12-28 Elgan Pharma Ltd Use of insulin for promoting gastric emptying
US10292977B2 (en) 2016-04-11 2019-05-21 Neurocea, LLC Compositions and methods for treatment related to fall and fall frequency in neurodegenerative diseases
US10143687B2 (en) 2016-04-11 2018-12-04 Neurocea, LLC Compositions and methods for treatment related to fall and fall frequency in neurodegenerative diseases
WO2017222575A1 (en) 2016-06-23 2017-12-28 Collegium Pharmaceutical, Inc. Process of making more stable abuse-deterrent oral formulations
JP2020503950A (en) 2017-01-06 2020-02-06 クロノ セラピューティクス インコーポレイテッドChrono Therapeutics Inc. Device and method for transdermal drug delivery
WO2019173062A1 (en) * 2018-03-07 2019-09-12 Trucapsol, Llc Reduced permeability microcapsules
US11344502B1 (en) 2018-03-29 2022-05-31 Trucapsol Llc Vitamin delivery particle
WO2019232077A1 (en) 2018-05-29 2019-12-05 Chrono Therapeutics Inc. Drug delivery methods and systems
US11794161B1 (en) 2018-11-21 2023-10-24 Trucapsol, Llc Reduced permeability microcapsules
US11571674B1 (en) 2019-03-28 2023-02-07 Trucapsol Llc Environmentally biodegradable microcapsules
US11542392B1 (en) 2019-04-18 2023-01-03 Trucapsol Llc Multifunctional particle additive for enhancement of toughness and degradation in biodegradable polymers
US11465117B2 (en) 2020-01-30 2022-10-11 Trucapsol Llc Environmentally biodegradable microcapsules
US11878280B2 (en) 2022-04-19 2024-01-23 Trucapsol Llc Microcapsules comprising natural materials
US11904288B1 (en) 2023-02-13 2024-02-20 Trucapsol Llc Environmentally biodegradable microcapsules

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3493657A (en) * 1961-03-14 1970-02-03 Mozes Juda Lewenstein Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4582835A (en) * 1983-12-06 1986-04-15 Reckitt & Colman Products Limited Analgesic compositions
US4738973A (en) * 1985-09-11 1988-04-19 National Research Development Corporation Pharmaceutical compositions and medical uses of dioxopiperidine derivatives
US4798725A (en) * 1986-06-16 1989-01-17 Norwich Eaton Pharmaceuticals, Inc. Sustained release capsule
US5866164A (en) * 1996-03-12 1999-02-02 Alza Corporation Composition and dosage form comprising opioid antagonist
US5935975A (en) * 1986-03-17 1999-08-10 Robert J. Schaap Agonist-antagonist combination to reduce the use of nicotine and other drugs
US6228863B1 (en) * 1997-12-22 2001-05-08 Euro-Celtique S.A. Method of preventing abuse of opioid dosage forms
US6228398B1 (en) * 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
US6368629B1 (en) * 1994-04-22 2002-04-09 Yamanouchi Pharmaceutical Company Ltd. Colon-specific drug release system
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form

Family Cites Families (183)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2770569A (en) 1952-08-01 1956-11-13 Hoffmann La Roche Analgesic compositions
US3173877A (en) 1957-09-09 1965-03-16 Wyandotte Chemicals Corp Detergent compositions comprising inorganic esters of epoxyhydrocarbon polymers
US3173876A (en) 1960-05-27 1965-03-16 John C Zobrist Cleaning methods and compositions
NL271831A (en) 1960-11-29
US3332950A (en) 1963-03-23 1967-07-25 Endo Lab 14-hydroxydihydronormorphinone derivatives
US3276586A (en) 1963-08-30 1966-10-04 Rosaen Filter Co Indicating means for fluid filters
NL6714885A (en) 1967-11-02 1969-05-06
US3541006A (en) 1968-07-03 1970-11-17 Amicon Corp Ultrafiltration process
US3541005A (en) 1969-02-05 1970-11-17 Amicon Corp Continuous ultrafiltration of macromolecular solutions
US3879555A (en) 1970-11-16 1975-04-22 Bristol Myers Co Method of treating drug addicts
US3676557A (en) 1971-03-02 1972-07-11 Endo Lab Long-acting narcotic antagonist formulations
US3965256A (en) 1972-05-16 1976-06-22 Synergistics Slow release pharmaceutical compositions
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3980766A (en) 1973-08-13 1976-09-14 West Laboratories, Inc. Orally administered drug composition for therapy in the treatment of narcotic drug addiction
US3916889A (en) 1973-09-28 1975-11-04 Sandoz Ag Patient ventilator apparatus
GB1478759A (en) 1974-11-18 1977-07-06 Alza Corp Process for forming outlet passageways in pills using a laser
US4077407A (en) 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
US4063064A (en) 1976-02-23 1977-12-13 Coherent Radiation Apparatus for tracking moving workpiece by a laser beam
US4175119A (en) * 1978-01-11 1979-11-20 Porter Garry L Composition and method to prevent accidental and intentional overdosage with psychoactive drugs
US4176186A (en) 1978-07-28 1979-11-27 Boehringer Ingelheim Gmbh Quaternary derivatives of noroxymorphone which relieve intestinal immobility
NO154582C (en) 1978-10-20 1986-11-05 Ferrosan Ab ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE DIPHENYL-DIBUTYLPIPERAZINE CARBOXAMIDS.
US4200098A (en) 1978-10-23 1980-04-29 Alza Corporation Osmotic system with distribution zone for dispensing beneficial agent
US4285987A (en) 1978-10-23 1981-08-25 Alza Corporation Process for manufacturing device with dispersion zone
US4237140A (en) 1979-05-18 1980-12-02 E. I. Du Pont De Nemours And Company Analgesic mixture of nalbuphine and acetaminophen
US4293539A (en) 1979-09-12 1981-10-06 Eli Lilly And Company Controlled release formulations and method of treatment
IE49324B1 (en) 1979-12-19 1985-09-18 Euro Celtique Sa Controlled release compositions
US4464378A (en) 1981-04-28 1984-08-07 University Of Kentucky Research Foundation Method of administering narcotic antagonists and analgesics and novel dosage forms containing same
US4587118A (en) 1981-07-15 1986-05-06 Key Pharmaceuticals, Inc. Dry sustained release theophylline oral formulation
US4401672A (en) 1981-10-13 1983-08-30 Regents Of The University Of Minnesota Non-addictive narcotic antitussive preparation
US4608376A (en) 1981-10-16 1986-08-26 Carolyn McGinnis Opiate agonists and antagonists
US4987136A (en) 1982-03-16 1991-01-22 The Rockefeller University Method for controlling gastrointestinal dysmotility
US4424205A (en) 1982-03-18 1984-01-03 The Procter & Gamble Company Hydroxyphenylacetamides having analgesic and anti-irritant activity
US4443428A (en) 1982-06-21 1984-04-17 Euroceltique, S.A. Extended action controlled release compositions
US4451470A (en) 1982-07-06 1984-05-29 E. I. Du Pont De Nemours And Company Analgesic, antagonist, and/or anorectic 14-fluoromorphinans
JPS5951223A (en) * 1982-09-17 1984-03-24 Sumitomo Chem Co Ltd Pharmaceutical composition
JPS5951223U (en) 1982-09-28 1984-04-04 曙ブレーキ工業株式会社 Floating caliper type disc brake
US4803208A (en) 1982-09-30 1989-02-07 Sloan-Kettering Institute For Cancer Research Opiate agonists and antagonists
US4681897A (en) 1984-01-16 1987-07-21 The Procter & Gamble Company Pharmaceutical products providing enhanced analgesia
US5266574A (en) * 1984-04-09 1993-11-30 Ian S. Zagon Growth regulation and related applications of opioid antagonists
DE3434946A1 (en) 1984-09-22 1986-04-03 Basf Ag, 6700 Ludwigshafen DIARYLACETYLENE, THEIR PRODUCTION AND USE
US4573995A (en) 1984-10-09 1986-03-04 Alza Corporation Transdermal therapeutic systems for the administration of naloxone, naltrexone and nalbuphine
GB8430346D0 (en) 1984-11-30 1985-01-09 Reckitt & Colmann Prod Ltd Analgesic compositions
US4806341A (en) 1985-02-25 1989-02-21 Rutgers, The State University Of New Jersey Transdermal absorption dosage unit for narcotic analgesics and antagonists and process for administration
GB8514665D0 (en) 1985-06-11 1985-07-10 Eroceltique Sa Oral pharmaceutical composition
FR2585246A1 (en) 1985-07-26 1987-01-30 Cortial PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE
GB8521350D0 (en) 1985-08-28 1985-10-02 Euro Celtique Sa Analgesic composition
US4889860A (en) 1985-09-23 1989-12-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US4760069A (en) 1985-09-23 1988-07-26 Nova Pharmaceutical Corporation Oximes of oxymorphone, naltrexone and naloxone as potent, selective opioid receptor agonists and antagonists
US4730048A (en) 1985-12-12 1988-03-08 Regents Of The University Of Minnesota Gut-selective opiates
US4719215A (en) 1986-03-07 1988-01-12 University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
US4861781A (en) 1986-03-07 1989-08-29 The University Of Chicago Quaternary derivatives of noroxymorphone which relieve nausea and emesis
GB8613688D0 (en) 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
GB8613689D0 (en) 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
EP0249347B1 (en) 1986-06-10 1994-06-29 Euroceltique S.A. Controlled release dihydrocodeine composition
US4769372A (en) 1986-06-18 1988-09-06 The Rockefeller University Method of treating patients suffering from chronic pain or chronic cough
US4785000A (en) 1986-06-18 1988-11-15 The Rockefeller University Method of treating patients suffering from chronic pain or chronic cough
US4970075A (en) 1986-07-18 1990-11-13 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US4861598A (en) 1986-07-18 1989-08-29 Euroceltique, S.A. Controlled release bases for pharmaceuticals
US5356900A (en) 1986-10-07 1994-10-18 Bernard Bihari Method of treating chronic herpes virus infections using an opiate receptor antagonist
GB8626098D0 (en) 1986-10-31 1986-12-03 Euro Celtique Sa Controlled release hydromorphone composition
US4806543A (en) 1986-11-25 1989-02-21 Board Of Trustees Of The Leland Stanford Junior University Method and compositions for reducing neurotoxic injury
GB8628728D0 (en) 1986-12-02 1987-01-07 Euro Celtique Sa Spheroids
GB8705083D0 (en) 1987-03-04 1987-04-08 Euro Celtique Sa Spheroids
GB8728294D0 (en) 1987-12-03 1988-01-06 Reckitt & Colmann Prod Ltd Treatment compositions
DE3812567A1 (en) 1988-04-15 1989-10-26 Basf Ag METHOD FOR PRODUCING PHARMACEUTICAL MIXTURES
US4873076A (en) 1988-04-29 1989-10-10 Baker Cummins Pharmaceuticals, Inc. Method of safely providing anesthesia or conscious sedation
GB8813064D0 (en) 1988-06-02 1988-07-06 Euro Celtique Sa Controlled release dosage forms having defined water content
US4882335A (en) 1988-06-13 1989-11-21 Alko Limited Method for treating alcohol-drinking response
US4939149A (en) 1988-10-24 1990-07-03 The United States Of America As Represented By The Department Of Health And Human Services Resiniferatoxin and analogues thereof to cause sensory afferent C-fiber and thermoregulatory desensitization
US5236714A (en) 1988-11-01 1993-08-17 Alza Corporation Abusable substance dosage form having reduced abuse potential
US5026556A (en) 1988-11-10 1991-06-25 Norwich Eaton Pharmaceuticals, Inc. Compositions for the transdermal delivery of pharmaceutical actives
CA2002492A1 (en) 1988-11-11 1990-05-11 Sandra T. A. Malkowska Pharmaceutical ion exchange resin composition
US5403868A (en) * 1988-12-23 1995-04-04 Sandoz Ltd. Capsaicin derivatives
US5102887A (en) 1989-02-17 1992-04-07 Arch Development Corporation Method for reducing emesis and nausea induced by the administration of an emesis causing agent
US5096715A (en) 1989-11-20 1992-03-17 Alko Ltd. Method and means for treating alcoholism by extinguishing the alcohol-drinking response using a transdermally administered opiate antagonist
US5240711A (en) 1989-11-29 1993-08-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system comprising as active component buprenorphine
US5075341A (en) 1989-12-01 1991-12-24 The Mclean Hospital Corporation Treatment for cocaine abuse
ES2081477T3 (en) 1990-04-24 1996-03-16 Teijin Ltd PATCH.
US5086058A (en) 1990-06-04 1992-02-04 Alko Ltd. Method for treating alcoholism with nalmefene
US5069909A (en) 1990-06-20 1991-12-03 Cygnus Therapeutic Systems Transdermal administration of buprenorphine
FR2669336B1 (en) 1990-11-20 1993-01-22 Adir NOVEL OXAZOLO PYRIDINES DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
HU208633B (en) 1991-02-04 1993-12-28 Alkaloida Vegyeszeti Gyar Process for production of analgetic compositions as applicable for blocking of opioid-binding spaces /2-receptors/ causing respiration depression
US5486362A (en) * 1991-05-07 1996-01-23 Dynagen, Inc. Controlled, sustained release delivery system for treating drug dependency
US5149538A (en) 1991-06-14 1992-09-22 Warner-Lambert Company Misuse-resistive transdermal opioid dosage form
KR100221695B1 (en) 1991-08-12 1999-09-15 그린 마틴, 브라이언 쥐 테슬리 Pharmaceutical spheroid formulation
RU2121346C1 (en) 1991-09-06 1998-11-10 МакНейлэб, Инк. Composition containing substance tramadol and acetaminophen and a method of treatment using thereof
US5215758A (en) * 1991-09-11 1993-06-01 Euroceltique, S.A. Controlled release matrix suppository for pharmaceuticals
US5225440A (en) 1991-09-13 1993-07-06 The United States Of America As Represented By The Department Of Health And Human Services Attenuation of the opioid withdrawal syndrome by inhibitors of nitric oxide synthase
EP0623155A4 (en) 1991-09-18 1995-01-11 Transcontinental Marketing Gro One coat protective system for a surface.
US5226331A (en) 1991-10-03 1993-07-13 General Electric Company Apparatus and method for measuring the particle number rate and the velocity distribution of a sprayed stream
US5656295A (en) 1991-11-27 1997-08-12 Euro-Celtique, S.A. Controlled release oxycodone compositions
US5266331A (en) 1991-11-27 1993-11-30 Euroceltique, S.A. Controlled release oxycodone compositions
US5681585A (en) 1991-12-24 1997-10-28 Euro-Celtique, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5968551A (en) 1991-12-24 1999-10-19 Purdue Pharma L.P. Orally administrable opioid formulations having extended duration of effect
US5478577A (en) 1993-11-23 1995-12-26 Euroceltique, S.A. Method of treating pain by administering 24 hour oral opioid formulations exhibiting rapid rate of initial rise of plasma drug level
US5273760A (en) 1991-12-24 1993-12-28 Euroceltigue, S.A. Stabilized controlled release substrate having a coating derived from an aqueous dispersion of hydrophobic polymer
US5286493A (en) 1992-01-27 1994-02-15 Euroceltique, S.A. Stabilized controlled release formulations having acrylic polymer coating
US5472712A (en) 1991-12-24 1995-12-05 Euroceltique, S.A. Controlled-release formulations coated with aqueous dispersions of ethylcellulose
US5580578A (en) * 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5958459A (en) 1991-12-24 1999-09-28 Purdue Pharma L.P. Opioid formulations having extended controlled released
GB9203689D0 (en) * 1992-02-20 1992-04-08 Euro Celtique Sa Pharmaceutical composition
GB9204354D0 (en) 1992-02-28 1992-04-08 Biokine Tech Ltd Compounds for medicinal use
ATE404201T1 (en) * 1992-06-22 2008-08-15 Univ California GLYCINE RECEPTOR ANTAGONISTS AND THEIR USE
US5352680A (en) 1992-07-15 1994-10-04 Regents Of The University Of Minnesota Delta opioid receptor antagonists to block opioid agonist tolerance and dependence
US5256669A (en) 1992-08-07 1993-10-26 Aminotek Sciences, Inc. Methods and compositions for treating acute or chronic pain and drug addiction
US5324351A (en) 1992-08-13 1994-06-28 Euroceltique Aqueous dispersions of zein and preparation thereof
US5580876A (en) 1992-09-21 1996-12-03 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US5472943A (en) 1992-09-21 1995-12-05 Albert Einstein College Of Medicine Of Yeshiva University, Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other opioid agonists
US6096756A (en) 1992-09-21 2000-08-01 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US5633259A (en) * 1992-09-21 1997-05-27 United Biomedical, Inc. Method for identification of low/non-addictive opioid analgesics and the use of said analgesics for treatment of opioid addiction
USRE36547E (en) * 1992-09-21 2000-02-01 Albert Einstein College Of Medicine Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
US5512578A (en) * 1992-09-21 1996-04-30 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists
US5869097A (en) * 1992-11-02 1999-02-09 Alza Corporation Method of therapy comprising an osmotic caplet
US5604260A (en) * 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
JPH0710745Y2 (en) 1993-01-27 1995-03-15 吉範 安田 Nursing sheets
US5321012A (en) 1993-01-28 1994-06-14 Virginia Commonwealth University Medical College Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance
US5585348A (en) 1993-02-10 1996-12-17 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Use of excitatory opioid receptor antagonists to prevent growth factor-induced hyperalgesia
CA2115792C (en) * 1993-03-05 2005-11-01 David J. Mayer Method for the treatment of pain
US5352683A (en) 1993-03-05 1994-10-04 Virginia Commonwealth University Medical College Of Virginia Method for the treatment of chronic pain
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
NZ260408A (en) 1993-05-10 1996-05-28 Euro Celtique Sa Controlled release preparation comprising tramadol
US5457208A (en) 1993-06-21 1995-10-10 Regents Of The University Of Minnesota Kappa opioid receptor antagonists
JPH0710745A (en) * 1993-06-22 1995-01-13 Tanabe Seiyaku Co Ltd Oral preparation for release-starting time control type intestinal delivery
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
US5436265A (en) 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
IL110014A (en) 1993-07-01 1999-11-30 Euro Celtique Sa Solid controlled-release oral dosage forms of opioid analgesics
US5879705A (en) 1993-07-27 1999-03-09 Euro-Celtique S.A. Sustained release compositions of morphine and a method of preparing pharmaceutical compositions
GB9319568D0 (en) 1993-09-22 1993-11-10 Euro Celtique Sa Pharmaceutical compositions and usages
US5500227A (en) * 1993-11-23 1996-03-19 Euro-Celtique, S.A. Immediate release tablet cores of insoluble drugs having sustained-release coating
US6210714B1 (en) * 1993-11-23 2001-04-03 Euro-Celtique S.A. Immediate release tablet cores of acetaminophen having sustained-release coating
US5891471A (en) * 1993-11-23 1999-04-06 Euro-Celtique, S.A. Pharmaceutical multiparticulates
KR100354702B1 (en) 1993-11-23 2002-12-28 유로-셀티크 소시에떼 아노뉨 Manufacturing method and sustained release composition of pharmaceutical composition
US5834477A (en) 1993-12-08 1998-11-10 The United States Of America As Represented By The Secretary Of The Army Opiate analgesic formulation with improved safety
US5376662A (en) 1993-12-08 1994-12-27 Ockert; David M. Method of attenuating nerve injury induced pain
US5843480A (en) 1994-03-14 1998-12-01 Euro-Celtique, S.A. Controlled release diamorphine formulation
US5411745A (en) * 1994-05-25 1995-05-02 Euro-Celtique, S.A. Powder-layered morphine sulfate formulations
US6077533A (en) 1994-05-25 2000-06-20 Purdue Pharma L.P. Powder-layered oral dosage forms
US5460826A (en) 1994-06-27 1995-10-24 Alza Corporation Morphine therapy
US5616601A (en) * 1994-07-28 1997-04-01 Gd Searle & Co 1,2-aryl and heteroaryl substituted imidazolyl compounds for the treatment of inflammation
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
US5593994A (en) * 1994-09-29 1997-01-14 The Dupont Merck Pharmaceutical Company Prostaglandin synthase inhibitors
GB9422154D0 (en) * 1994-11-03 1994-12-21 Euro Celtique Sa Pharmaceutical compositions and method of producing the same
US5965161A (en) 1994-11-04 1999-10-12 Euro-Celtique, S.A. Extruded multi-particulates
ES2377126T3 (en) * 1994-12-12 2012-03-22 Omeros Corporation Irrigation solution and use thereof for perioperative inhibition of pain, inflammation and / or spasms in a vascular structure
GB9426102D0 (en) * 1994-12-23 1995-02-22 Merck Sharp & Dohme Pharmacuetical compositions
US5552422A (en) 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
US5578725A (en) 1995-01-30 1996-11-26 Regents Of The University Of Minnesota Delta opioid receptor antagonists
US5639780A (en) * 1995-05-22 1997-06-17 Merck Frosst Canada, Inc. N-benzyl indol-3-yl butanoic acid derivatives as cyclooxygenase inhibitors
US5604253A (en) * 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5510368A (en) * 1995-05-22 1996-04-23 Merck Frosst Canada, Inc. N-benzyl-3-indoleacetic acids as antiinflammatory drugs
US5762963A (en) * 1995-06-07 1998-06-09 Emory University Method and compositions for controlling oral and pharyngeal pain using capsaicinoids
HUP9700322A3 (en) 1995-06-09 2001-03-28 Euro Celtique Sa Formulations and methods for providing prolonged local anesthesia
SG80553A1 (en) 1995-07-20 2001-05-22 Tanabe Seiyaku Co Pharmaceutical preparation in form of coated capsule releasable at lower part of digestive tract
JP3185206B2 (en) * 1995-07-20 2001-07-09 田辺製薬株式会社 Lower digestive tract release coated capsule formulation
GB9517883D0 (en) 1995-09-01 1995-11-01 Euro Celtique Sa Improved pharmaceutical ion exchange resin composition
GB9519363D0 (en) 1995-09-22 1995-11-22 Euro Celtique Sa Pharmaceutical formulation
US5811126A (en) 1995-10-02 1998-09-22 Euro-Celtique, S.A. Controlled release matrix for pharmaceuticals
CA2239301A1 (en) 1995-12-06 1997-06-12 Charles Howard Mitch Composition for treating pain
US6103258A (en) 1996-04-12 2000-08-15 Simon; David Lew Salts and bases of the 17-(Cyclopropylmethyl)-4,5 alpha-epoxy-6-Methylenemorphinan-3,14 diol molecule for optimizing dopamine homeostasis during administration of opioid analgesics
US5968547A (en) 1997-02-24 1999-10-19 Euro-Celtique, S.A. Method of providing sustained analgesia with buprenorphine
US5780479A (en) 1997-04-04 1998-07-14 Regents Of The University Of Minnesota Use of opioid antagonists to treat impulse-control disorders
JPH10338634A (en) * 1997-04-11 1998-12-22 Grelan Pharmaceut Co Ltd Medicinal composition
WO1999001111A1 (en) 1997-07-02 1999-01-14 Euro-Celtique, S.A. Stabilized sustained release tramadol formulations
US5891919A (en) * 1997-09-19 1999-04-06 Burlington Bio-Medical & Scientific Corp. Denatonium capsaicinate and methods of producing the same
US5972954A (en) 1997-11-03 1999-10-26 Arch Development Corporation Use of methylnaltrexone and related compounds
US20030059471A1 (en) * 1997-12-15 2003-03-27 Compton Bruce Jon Oral delivery formulation
AU773642C (en) * 1997-12-22 2006-04-06 Mundipharma Pty Limited Opioid agonist/antagonist combinations
US6375957B1 (en) * 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
ATE238040T1 (en) * 1999-01-29 2003-05-15 Disphar Int Bv PHARMACEUTICAL COMPOSITIONS
GB9905558D0 (en) 1999-03-11 1999-05-05 Reckitt & Colmann Prod Ltd Improvements in or relating to organic compositions
US6087362A (en) * 1999-03-16 2000-07-11 Pentech Pharmaceuticals, Inc. Apomorphine and sildenafil composition
US6716449B2 (en) * 2000-02-08 2004-04-06 Euro-Celtique S.A. Controlled-release compositions containing opioid agonist and antagonist
PT2092936E (en) * 2000-02-08 2013-06-20 Euro Celtique Sa Tamper-resistant oral opioid agonist formulations
US20030064122A1 (en) * 2001-05-23 2003-04-03 Endo Pharmaceuticals, Inc. Abuse resistant pharmaceutical composition containing capsaicin
US7968119B2 (en) * 2001-06-26 2011-06-28 Farrell John J Tamper-proof narcotic delivery system
US7332182B2 (en) * 2001-08-06 2008-02-19 Purdue Pharma L.P. Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant
US20030044458A1 (en) * 2001-08-06 2003-03-06 Curtis Wright Oral dosage form comprising a therapeutic agent and an adverse-effect agent
US7144587B2 (en) 2001-08-06 2006-12-05 Euro-Celtique S.A. Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent
US7141250B2 (en) 2001-08-06 2006-11-28 Euro-Celtique S.A. Pharmaceutical formulation containing bittering agent
DE10250084A1 (en) 2002-10-25 2004-05-06 Grünenthal GmbH Dosage form protected against abuse
US8906413B2 (en) 2003-05-12 2014-12-09 Supernus Pharmaceuticals, Inc. Drug formulations having reduced abuse potential
US7201920B2 (en) * 2003-11-26 2007-04-10 Acura Pharmaceuticals, Inc. Methods and compositions for deterring abuse of opioid containing dosage forms
US7867511B2 (en) 2004-01-23 2011-01-11 Travanti Pharma Inc. Abuse potential reduction in abusable substance dosage form

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3493657A (en) * 1961-03-14 1970-02-03 Mozes Juda Lewenstein Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine
US3773955A (en) * 1970-08-03 1973-11-20 Bristol Myers Co Analgetic compositions
US3966940A (en) * 1973-11-09 1976-06-29 Bristol-Myers Company Analgetic compositions
US4457933A (en) * 1980-01-24 1984-07-03 Bristol-Myers Company Prevention of analgesic abuse
US4582835A (en) * 1983-12-06 1986-04-15 Reckitt & Colman Products Limited Analgesic compositions
US4738973A (en) * 1985-09-11 1988-04-19 National Research Development Corporation Pharmaceutical compositions and medical uses of dioxopiperidine derivatives
US5935975A (en) * 1986-03-17 1999-08-10 Robert J. Schaap Agonist-antagonist combination to reduce the use of nicotine and other drugs
US4798725A (en) * 1986-06-16 1989-01-17 Norwich Eaton Pharmaceuticals, Inc. Sustained release capsule
US6368629B1 (en) * 1994-04-22 2002-04-09 Yamanouchi Pharmaceutical Company Ltd. Colon-specific drug release system
US5866164A (en) * 1996-03-12 1999-02-02 Alza Corporation Composition and dosage form comprising opioid antagonist
US6228863B1 (en) * 1997-12-22 2001-05-08 Euro-Celtique S.A. Method of preventing abuse of opioid dosage forms
US6228398B1 (en) * 1998-11-02 2001-05-08 Elan Corporation, Plc Multiparticulate modified release composition
US20030004177A1 (en) * 2001-05-11 2003-01-02 Endo Pharmaceuticals, Inc. Abuse-resistant opioid dosage form

Cited By (193)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9205082B2 (en) 1997-12-22 2015-12-08 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US8932630B1 (en) 1997-12-22 2015-01-13 Purdue Pharma L.P Opioid agonist/antagonist combinations
US8936808B1 (en) 1997-12-22 2015-01-20 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US9474750B2 (en) 1997-12-22 2016-10-25 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US8822487B2 (en) 1997-12-22 2014-09-02 Purdue Pharma L.P. Opioid agonist/opioid antagonist/acetaminophen combinations
US8673355B2 (en) 1997-12-22 2014-03-18 Purdue Pharma L.P. Opioid agonist/antagonist combinations
US9480685B2 (en) 2001-05-11 2016-11-01 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9511066B2 (en) 2001-05-11 2016-12-06 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9168252B2 (en) 2001-05-11 2015-10-27 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9283221B2 (en) 2001-05-11 2016-03-15 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US8969369B2 (en) 2001-05-11 2015-03-03 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9084729B2 (en) 2001-05-11 2015-07-21 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9161937B2 (en) 2001-05-11 2015-10-20 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9283216B2 (en) 2001-05-11 2016-03-15 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9358230B1 (en) 2001-05-11 2016-06-07 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9345701B1 (en) 2001-05-11 2016-05-24 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US9056051B2 (en) 2001-05-11 2015-06-16 Purdue Pharma L.P. Abuse-resistant controlled-release opioid dosage form
US8329216B2 (en) 2001-07-06 2012-12-11 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US8309122B2 (en) 2001-07-06 2012-11-13 Endo Pharmaceuticals Inc. Oxymorphone controlled release formulations
US20090192183A1 (en) * 2001-07-06 2009-07-30 Endo Pharmaceuticals, Inc. Oxymorphone Controlled Release Formulations
US20030129234A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Methods of making sustained release formulations of oxymorphone
US20080262013A1 (en) * 2001-07-06 2008-10-23 Endo Pharmaceuticals, Inc. Oxymorphone controlled release formulations
US7276250B2 (en) 2001-07-06 2007-10-02 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US20070098794A1 (en) * 2001-07-06 2007-05-03 Haui-Hung Kao Oxymorphone controlled release formulations
US20070134328A1 (en) * 2001-07-06 2007-06-14 Endo Pharmaceuticals, Inc. Oxymorphone controlled release formulations
US20030129230A1 (en) * 2001-07-06 2003-07-10 Penwest Pharmaceuticals Company Sustained release formulations of oxymorphone
US20030091635A1 (en) * 2001-09-26 2003-05-15 Baichwal Anand R. Opioid formulations having reduced potential for abuse
US20070140975A1 (en) * 2001-09-26 2007-06-21 Penwest Pharmaceuticals Co. Opioid formulations having reduced potential for abuse
US20050245556A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Pharmaceutical preparation containing oxycodone and naloxone
US10420762B2 (en) 2002-04-05 2019-09-24 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US9555000B2 (en) 2002-04-05 2017-01-31 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US8846090B2 (en) 2002-04-05 2014-09-30 Euro-Celtique S.A. Matrix for sustained, invariant and independent release of active compounds
US9655855B2 (en) 2002-04-05 2017-05-23 Purdue Pharma L.P. Matrix for sustained, invariant and independent release of active compounds
US8846091B2 (en) 2002-04-05 2014-09-30 Euro-Celtique S.A. Matrix for sustained, invariant and independent release of active compounds
US20050245483A1 (en) * 2002-04-05 2005-11-03 Bianca Brogmann Matrix for sustained, invariant and independent release of active compounds
US9907793B2 (en) 2002-04-05 2018-03-06 Purdue Pharma L.P. Pharmaceutical preparation containing oxycodone and naloxone
US10369109B2 (en) 2002-06-17 2019-08-06 Grünenthal GmbH Abuse-proofed dosage form
US9675610B2 (en) 2002-06-17 2017-06-13 Grünenthal GmbH Abuse-proofed dosage form
US7815934B2 (en) 2002-09-20 2010-10-19 Alpharma Pharmaceuticals, Llc Sequestering subunit and related compositions and methods
EP2422773A2 (en) 2002-09-20 2012-02-29 Alpharma, Inc. Sequestering subunit and related compositions and methods
EP2422772A2 (en) 2002-09-20 2012-02-29 Alpharma, Inc. Sequestering subunit and related compositions and methods
EP2422775A2 (en) 2002-09-20 2012-02-29 Alpharma, Inc. Sequestering subunit and related compositions and methods
US20040131552A1 (en) * 2002-09-20 2004-07-08 Alpharma, Inc. Sequestering subunit and related compositions and methods
WO2004026283A1 (en) 2002-09-20 2004-04-01 Alpharma, Inc. Sequestering subunit and related compositions and metohds
US20100098758A1 (en) * 2002-10-25 2010-04-22 Gruenenthal Gmbh Abuse-Resistant Dosage Form
US20050214223A1 (en) * 2002-10-25 2005-09-29 Gruenenthal Gmbh Abuse-safeguarded dosage form
US20050186139A1 (en) * 2002-10-25 2005-08-25 Gruenenthal Gmbh Abuse-proofed dosage form
US20090238868A1 (en) * 2003-04-08 2009-09-24 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US20100098771A1 (en) * 2003-04-08 2010-04-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US20040202717A1 (en) * 2003-04-08 2004-10-14 Mehta Atul M. Abuse-resistant oral dosage forms and method of use thereof
US8425933B2 (en) 2003-04-08 2013-04-23 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US20080166405A1 (en) * 2003-04-08 2008-07-10 Mehta Atul M Abuse-resistant oral dosage forms and method of use thereof
US8703186B2 (en) 2003-04-08 2014-04-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US8182836B2 (en) 2003-04-08 2012-05-22 Elite Laboratories, Inc. Abuse-resistant oral dosage forms and method of use thereof
US8075872B2 (en) * 2003-08-06 2011-12-13 Gruenenthal Gmbh Abuse-proofed dosage form
US20080247959A1 (en) * 2003-08-06 2008-10-09 Grunenthal Gmbh Form of administration secured against misuse
US20070183979A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20070048228A1 (en) * 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
US20050031546A1 (en) * 2003-08-06 2005-02-10 Johannes Bartholomaus Abuse-proffed dosage form
US20060193782A1 (en) * 2003-08-06 2006-08-31 Johannes Bartholomaus Abuse-proofed dosage form
US8114383B2 (en) 2003-08-06 2012-02-14 Gruenenthal Gmbh Abuse-proofed dosage form
US20070183980A1 (en) * 2003-08-06 2007-08-09 Elisabeth Arkenau-Maric Dosage form that is safeguarded from abuse
US8192722B2 (en) 2003-08-06 2012-06-05 Grunenthal Gmbh Abuse-proof dosage form
US9629807B2 (en) 2003-08-06 2017-04-25 Grünenthal GmbH Abuse-proofed dosage form
US8420056B2 (en) 2003-08-06 2013-04-16 Grunenthal Gmbh Abuse-proofed dosage form
US10058548B2 (en) 2003-08-06 2018-08-28 Grünenthal GmbH Abuse-proofed dosage form
US20080311049A1 (en) * 2003-08-06 2008-12-18 Grunenthal Gmbh Abuse-proof dosage form
US8309060B2 (en) 2003-08-06 2012-11-13 Grunenthal Gmbh Abuse-proofed dosage form
US10130591B2 (en) 2003-08-06 2018-11-20 Grünenthal GmbH Abuse-proofed dosage form
EP1660048A1 (en) * 2003-08-12 2006-05-31 Endo Pharmaceuticals Inc. Method for deterring abuse of opioids by combination with non-release formulation of emetic
US20060165602A1 (en) * 2003-08-12 2006-07-27 Galer Bradley S Method for deterring abuse of opioids by combination with non-release formulation of emetic
EP1660048A4 (en) * 2003-08-12 2009-07-08 Endo Pharmaceuticals Inc Method for deterring abuse of opioids by combination with non-release formulation of emetic
US11224576B2 (en) 2003-12-24 2022-01-18 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US20070003616A1 (en) * 2003-12-24 2007-01-04 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20090029170A1 (en) * 2004-02-12 2009-01-29 Geoffrey Gerard Hayes Extrusion
US20070298103A1 (en) * 2004-02-12 2007-12-27 Euro-Celtique S.A. Particulates
US9603802B2 (en) 2004-02-12 2017-03-28 Euro-Celtique S.A. Extrusion
US8920836B2 (en) * 2004-02-12 2014-12-30 Euro-Celtique S.A. Particulates
US20050236741A1 (en) * 2004-04-22 2005-10-27 Elisabeth Arkenau Process for the production of an abuse-proofed solid dosage form
US20080317854A1 (en) * 2004-04-22 2008-12-25 Grunenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20050271594A1 (en) * 2004-06-04 2005-12-08 Groenewoud Pieter J Abuse resistent pharmaceutical composition
US20130190341A1 (en) * 2004-06-04 2013-07-25 Camurus Ab High bioavailability opioid formulations
US8518925B2 (en) 2004-06-08 2013-08-27 Euro-Celtique S.A. Opioids for the treatment of the chronic obstructive pulmonary disease (COPD)
US20070185147A1 (en) * 2004-06-08 2007-08-09 Euro-Celtique S.A. Opioids for the treatment of the restless leg syndrome
US11844865B2 (en) 2004-07-01 2023-12-19 Grünenthal GmbH Abuse-proofed oral dosage form
US20060002860A1 (en) * 2004-07-01 2006-01-05 Johannes Bartholomaus Abuse-proofed oral dosage form
US20060002859A1 (en) * 2004-07-01 2006-01-05 Elisabeth Arkenau Process for production of an abuse-proofed solid dosage form
US8114384B2 (en) 2004-07-01 2012-02-14 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US8323889B2 (en) 2004-07-01 2012-12-04 Gruenenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20060039864A1 (en) * 2004-07-01 2006-02-23 Johannes Bartholomaus Abuse-proofed oral dosage form
US20080312264A1 (en) * 2004-07-01 2008-12-18 Grunenthal Gmbh Process for the production of an abuse-proofed solid dosage form
US20070259045A1 (en) * 2005-01-28 2007-11-08 Euro-Celtique S.A. Alcohol Resistant Dosage Forms
US10675278B2 (en) 2005-02-04 2020-06-09 Grünenthal GmbH Crush resistant delayed-release dosage forms
US20060188447A1 (en) * 2005-02-04 2006-08-24 Elisabeth Arkenau-Maric Process for the production of an abuse-proofed dosage form
US20100151028A1 (en) * 2005-02-04 2010-06-17 Grunenthal Gmbh Crush resistant delayed-release dosage forms
US20080311197A1 (en) * 2005-02-04 2008-12-18 Grunenthal Gmbh Process for the production of an abuse-proofed dosage form
US20060193914A1 (en) * 2005-02-04 2006-08-31 Judy Ashworth Crush resistant delayed-release dosage forms
US10729658B2 (en) 2005-02-04 2020-08-04 Grünenthal GmbH Process for the production of an abuse-proofed dosage form
US10258235B2 (en) 2005-02-28 2019-04-16 Purdue Pharma L.P. Method and device for the assessment of bowel function
US20110172259A1 (en) * 2005-02-28 2011-07-14 Euro-Celtique S.A. Dosage form containing oxycodone and naloxone
EP1861072A2 (en) * 2005-03-14 2007-12-05 Massachusetts Institute Of Technology Nanocells for diagnosis and treatment of diseases and disorders
US9060950B2 (en) * 2005-06-13 2015-06-23 Paul H. Rosenberg, Proximate Concepts, LLC. Emetic embedded capsule
US20080102113A1 (en) * 2005-06-13 2008-05-01 Paul Rosenberg Emetic embedded capsule
US20070020339A1 (en) * 2005-07-20 2007-01-25 Pharmorx Inc. Compositions and methods for controlling abuse of medications
US20070212414A1 (en) * 2006-03-08 2007-09-13 Penwest Pharmaceuticals Co. Ethanol-resistant sustained release formulations
EP2526932A1 (en) 2006-06-19 2012-11-28 Alpharma Pharmaceuticals, LLC Pharmaceutical composition
US20080069871A1 (en) * 2006-07-21 2008-03-20 Vaughn Jason M Hydrophobic abuse deterrent delivery system
US9504699B2 (en) 2006-08-03 2016-11-29 Hznp Limited Delayed-release glucocorticoid treatment of rheumatoid disease
US8920838B2 (en) 2006-08-03 2014-12-30 Horizon Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid disease
WO2008024490A2 (en) * 2006-08-24 2008-02-28 Theraquest Biosciences, Inc. Oral pharmaceutical formulations of abuse deterrent cannabinoids and method of use
WO2008024490A3 (en) * 2006-08-24 2008-10-16 Theraquest Biosciences Inc Oral pharmaceutical formulations of abuse deterrent cannabinoids and method of use
US9763931B2 (en) 2006-08-30 2017-09-19 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9370512B2 (en) 2006-08-30 2016-06-21 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9101625B2 (en) 2006-08-30 2015-08-11 Purdue Pharma L.P. Buprenorphine-wafer for drug substitution therapy
US9861628B2 (en) 2006-08-30 2018-01-09 Rhodes Pharmaceuticals L.P. Buprenorphine-wafer for drug substitution therapy
US20090004267A1 (en) * 2007-03-07 2009-01-01 Gruenenthal Gmbh Dosage Form with Impeded Abuse
US8722086B2 (en) 2007-03-07 2014-05-13 Gruenenthal Gmbh Dosage form with impeded abuse
US20090124650A1 (en) * 2007-06-21 2009-05-14 Endo Pharmaceuticals, Inc. Method of Treating Pain Utilizing Controlled Release Oxymorphone Pharmaceutical Compositions and Instructions on Effects of Alcohol
US8802156B2 (en) * 2007-11-14 2014-08-12 Laboratorios Farmacéuticos Rovi, S.A. Pharmaceutical forms for the release of active compounds
US20120022020A1 (en) * 2007-11-14 2012-01-26 Laboratorios Farmaceuticos Rovi S.A. Pharmaceutical forms for the release of active compounds
US8691270B2 (en) 2007-12-17 2014-04-08 Paladin Labs Inc. Misuse preventative, controlled release formulation
US20090175937A1 (en) * 2007-12-17 2009-07-09 Labopharm, Inc. Misuse Preventative, Controlled Release Formulation
US8486448B2 (en) 2007-12-17 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8920834B2 (en) 2007-12-17 2014-12-30 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8920833B2 (en) 2007-12-17 2014-12-30 Paladin Labs Inc. Misuse preventative, controlled release formulation
US10064856B2 (en) 2008-01-09 2018-09-04 Local Pharma, Inc. Pharmaceutical compositions
US20170348304A1 (en) * 2008-01-09 2017-12-07 Locl Pharma, Inc. Pharmaceutical compositions
US20170348305A1 (en) * 2008-01-09 2017-12-07 Locl Pharma, Inc. Pharmaceutical compositions
US20090202634A1 (en) * 2008-01-25 2009-08-13 Grunenthal Gmbh Pharmaceutical dosage form
US9750701B2 (en) 2008-01-25 2017-09-05 Grünenthal GmbH Pharmaceutical dosage form
US8383152B2 (en) 2008-01-25 2013-02-26 Gruenenthal Gmbh Pharmaceutical dosage form
US20120178771A1 (en) * 2008-03-08 2012-07-12 Najib Babul Oral Pharmaceutical Compositions of Buprenorphine and Method of Use
US20110082214A1 (en) * 2008-05-09 2011-04-07 Gruenthal Gmbh Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US9161917B2 (en) 2008-05-09 2015-10-20 Grünenthal GmbH Process for the preparation of a solid dosage form, in particular a tablet, for pharmaceutical use and process for the preparation of a precursor for a solid dosage form, in particular a tablet
US20110177133A1 (en) * 2008-07-07 2011-07-21 Michael Hopp Use of opioid antagonists for treating urinary retention
US20110305658A1 (en) * 2008-12-11 2011-12-15 L'oreal S.A. Lengthening mascara composition
US20110237615A1 (en) * 2008-12-12 2011-09-29 Paladin Labs Inc. Narcotic Drug Formulations with Decreased Abuse Potential
US8460640B2 (en) 2008-12-12 2013-06-11 Paladin Labs, Inc. Narcotic drug formulations with decreased abuse potential
US8927013B2 (en) 2008-12-16 2015-01-06 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8486449B2 (en) 2008-12-16 2013-07-16 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8685447B2 (en) 2008-12-16 2014-04-01 Paladin Labs Inc. Misuse preventative, controlled release formulation
US8927014B2 (en) 2008-12-16 2015-01-06 Paladin Labs Inc. Misuse preventative, controlled release formulation
US20100239662A1 (en) * 2008-12-16 2010-09-23 Miloud Rahmouni Misuse preventative, controlled release formulation
US20100222312A1 (en) * 2009-01-26 2010-09-02 Nitec Pharma Ag Delayed-release glucocorticoid treatment of asthma
US20100196427A1 (en) * 2009-01-30 2010-08-05 Nitec Pharma Ag Delayed-release glucocorticoid treatment of rheumatoid arthritis by improving signs and symptoms, showing major or complete clinical response and by preventing from joint damage
US9820983B2 (en) 2009-03-10 2017-11-21 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
US9271940B2 (en) 2009-03-10 2016-03-01 Purdue Pharma L.P. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
US10532030B2 (en) 2009-07-08 2020-01-14 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US10016368B2 (en) 2009-07-08 2018-07-10 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US10080721B2 (en) 2009-07-22 2018-09-25 Gruenenthal Gmbh Hot-melt extruded pharmaceutical dosage form
US10493033B2 (en) 2009-07-22 2019-12-03 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US9925146B2 (en) 2009-07-22 2018-03-27 Grünenthal GmbH Oxidation-stabilized tamper-resistant dosage form
US20110187017A1 (en) * 2010-02-03 2011-08-04 Grunenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9579285B2 (en) 2010-02-03 2017-02-28 Gruenenthal Gmbh Preparation of a powdery pharmaceutical composition by means of an extruder
US9636303B2 (en) 2010-09-02 2017-05-02 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
US10300141B2 (en) 2010-09-02 2019-05-28 Grünenthal GmbH Tamper resistant dosage form comprising inorganic salt
US10695297B2 (en) 2011-07-29 2020-06-30 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10864164B2 (en) 2011-07-29 2020-12-15 Grünenthal GmbH Tamper-resistant tablet providing immediate drug release
US10201502B2 (en) 2011-07-29 2019-02-12 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release
US9655853B2 (en) 2012-02-28 2017-05-23 Grünenthal GmbH Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
US10335373B2 (en) 2012-04-18 2019-07-02 Grunenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
US10912772B2 (en) 2012-07-26 2021-02-09 Camurus Ab Opioid formulations
US11110084B2 (en) 2012-07-26 2021-09-07 Camurus Ab Opioid formulations
US11135215B2 (en) 2012-07-26 2021-10-05 Camurus Ab Opioid formulations
US9937164B2 (en) 2012-07-26 2018-04-10 Camurus Ab Opioid formulations
US20150110874A1 (en) * 2013-01-09 2015-04-23 Douglas A. Saltel Sustained release formulations of lorazepam
US8999393B1 (en) * 2013-01-09 2015-04-07 Edgemont Pharmaceuticals Llc Sustained release formulations of lorazepam
US10154966B2 (en) 2013-05-29 2018-12-18 Grünenthal GmbH Tamper-resistant dosage form containing one or more particles
US9737490B2 (en) 2013-05-29 2017-08-22 Grünenthal GmbH Tamper resistant dosage form with bimodal release profile
US10624862B2 (en) 2013-07-12 2020-04-21 Grünenthal GmbH Tamper-resistant dosage form containing ethylene-vinyl acetate polymer
US10071089B2 (en) 2013-07-23 2018-09-11 Euro-Celtique S.A. Combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation
US10449547B2 (en) 2013-11-26 2019-10-22 Grünenthal GmbH Preparation of a powdery pharmaceutical composition by means of cryo-milling
US9913814B2 (en) 2014-05-12 2018-03-13 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
US9872835B2 (en) 2014-05-26 2018-01-23 Grünenthal GmbH Multiparticles safeguarded against ethanolic dose-dumping
US9700516B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US10293046B2 (en) 2014-07-15 2019-05-21 Intellipharmaceutics Corp. Compositions and methods for reducing overdose
US9700515B2 (en) 2014-07-15 2017-07-11 Isa Odidi Compositions and methods for reducing overdose
US10653776B2 (en) 2014-07-15 2020-05-19 Intellipharmaceutics Corp. Compositions and methods for reducing overdose
US9522119B2 (en) 2014-07-15 2016-12-20 Isa Odidi Compositions and methods for reducing overdose
US9801939B2 (en) 2014-07-15 2017-10-31 Isa Odidi Compositions and methods for reducing overdose
US9855263B2 (en) 2015-04-24 2018-01-02 Grünenthal GmbH Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US10478429B2 (en) 2015-10-07 2019-11-19 Patheon Softgels, Inc. Abuse deterrent dosage forms
US9861629B1 (en) 2015-10-07 2018-01-09 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9943513B1 (en) 2015-10-07 2018-04-17 Banner Life Sciences Llc Opioid abuse deterrent dosage forms
US9849125B1 (en) 2015-11-03 2017-12-26 Banner Lifie Sciences LLC Anti-overingestion dosage forms
US10772840B2 (en) 2016-03-04 2020-09-15 Charleston Laboratories, Inc. Sumatriptan promethazine pharmaceutical compositions
US10335405B1 (en) 2016-05-04 2019-07-02 Patheon Softgels, Inc. Non-burst releasing pharmaceutical composition
AU2017258853B2 (en) * 2016-11-08 2019-05-16 Alpex Pharma Sa Extended release tablet comprising a weight-loss drug
US10335375B2 (en) 2017-05-30 2019-07-02 Patheon Softgels, Inc. Anti-overingestion abuse deterrent compositions
US10758532B2 (en) 2018-12-11 2020-09-01 Satsuma Pharmaceuticals, Inc. Compositions, devices, and methods for treating or preventing headaches
CN114401746A (en) * 2019-08-12 2022-04-26 耶路撒冷希伯来大学伊森姆研究发展有限公司 Pharmaceutical compositions and composites comprising combinations of opiate antagonists and methods of use thereof

Also Published As

Publication number Publication date
RU2004106620A (en) 2005-04-10
JP5143995B2 (en) 2013-02-13
KR100893895B1 (en) 2009-04-20
BR0211781A (en) 2004-07-27
HK1067524A1 (en) 2005-04-15
JP2013189447A (en) 2013-09-26
JP5485538B2 (en) 2014-05-07
JP2009132711A (en) 2009-06-18
ATE450259T1 (en) 2009-12-15
USRE45822E1 (en) 2015-12-22
EP1414459B1 (en) 2009-12-02
US7384653B2 (en) 2008-06-10
HUP0401066A2 (en) 2004-08-30
CY1109816T1 (en) 2014-09-10
DE20220838U1 (en) 2004-05-19
SI1414459T1 (en) 2010-04-30
KR20090005247A (en) 2009-01-12
JP2005520783A (en) 2005-07-14
PT1414459E (en) 2010-03-03
WO2003013538A1 (en) 2003-02-20
AU2008202531A1 (en) 2008-07-03
CA2456601C (en) 2012-04-24
MXPA04001098A (en) 2004-05-20
EP1414459A1 (en) 2004-05-06
KR20040043181A (en) 2004-05-22
US20050063909A1 (en) 2005-03-24
CA2456601A1 (en) 2003-02-20
DK1414459T3 (en) 2010-04-12
ES2337664T3 (en) 2010-04-28

Similar Documents

Publication Publication Date Title
USRE45822E1 (en) Oral dosage form comprising a therapeutic agent and an adverse-effect agent
EP2283842B1 (en) Tamper-resistant oral opioid agonist formulations
US7682633B2 (en) Pharmaceutical composition
EP2179724B1 (en) Tamper-resistant products for delivery of opioids and other drugs apt to be abused
US20090041838A1 (en) Anti-Misuse Microparticulate Oral Drug Form
US20070264326A1 (en) Anti-misuse oral microparticle medicinal formulation
AU2017204639A1 (en) Pharmaceutical composition comprising opioid agonist and sequestered antagonist
WO2008063301A2 (en) Pharmaceutical compositions
AU2011205217B2 (en) Oral dosage form comprising a therapeutic agent and an adverse-effect agent
AU2002326529A1 (en) Oral dosage form comprising a therapeutic agent and an adverse-effect agent

Legal Events

Date Code Title Description
AS Assignment

Owner name: EURO-CELTIQUE, S.A., LUXEMBOURG

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WRIGHT, IV, CURTIS;CARPANZANO, ANTHONY E.;REEL/FRAME:013451/0229;SIGNING DATES FROM 20021015 TO 20021021

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: PURDUE PHARMA L.P., CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:EURO-CELTIQUE S.A.;REEL/FRAME:020244/0081

Effective date: 20071212