WO2001058447A1 - Controlled-release compositions containing opioid agonist and antagonist - Google Patents
Controlled-release compositions containing opioid agonist and antagonist Download PDFInfo
- Publication number
- WO2001058447A1 WO2001058447A1 PCT/US2001/004347 US0104347W WO0158447A1 WO 2001058447 A1 WO2001058447 A1 WO 2001058447A1 US 0104347 W US0104347 W US 0104347W WO 0158447 A1 WO0158447 A1 WO 0158447A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- opioid
- antagonist
- dosage form
- opioid agonist
- release
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5084—Mixtures 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
- A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, 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
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5005—Wall or coating material
- A61K9/501—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/5073—Microcapsules 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
- A61K9/5078—Microcapsules 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 with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules 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
- A61K9/51—Nanocapsules; Nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Opioids also known as opioid agonists
- Opioid agonists are a group of drugs that exhibit opium or morphme-hke properties
- Opioid agonists are known in the literature and to those skilled m the art (Merck Manual, 16th Ed (1992)) Because of their analgesic efficac ⁇ opioid agonists have been used to provide pain relief to patients
- Side effects are also associated with the use of opioid analgesics
- opioid agonists such as morphine are associated with side effects, including nausea, vomiting, pru ⁇ tis, urinary retention, and respiratory depression Gan, et al vol 87, No 5, 1075-1081 (1997)
- Chronic use of morphine has also been reported to increase physical dependence and increase tolerance of the drug, Shen et al , Bram Res , ⁇ ol 597, 74-83 (1992), and to induce constipation
- the selective enliancement of analgesic potency of the opioid agonist occurs while simultaneously attenuating development of physical dependence, tolerance and othei undesnable side effects caused by the chronic administration of the opioid agonist
- the invention is dnected to a controlled release oral dosage form comprising opioid agonist and opioid antagonist, wherein the dosage form releases the opioid agonist and the antagonist in a contiolled-release mannei
- the invention is further directed to a controlled-release dosage fonri comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release late, such that when combined into the controlled-release dosage fonn, the opioid agonist and the antagonist aie released from the dosage form at appropriately similar times
- the invention is further directed to a contiolled-release dosage fonn comp ⁇ sing opioid agonist and opioid antagonist, wheie the opioid agonist is present in an amount that is analgesically effective when administered to a human and wheiem the opioid antagonist is present in an amount which does not cause a reduction in the level of analgesia provided by the dosage form to a non-therapeutic level
- the opioid antagonist is also present in an amount that is effective in reducing opioid-related side effects
- the controlled release dosage form comprises a transde ⁇ nal delivery system, an oral mucosal delivery system, a composition for intranasal administration, an injectable composition, and a solid oral composition.
- the present invention comprises a controlled release dosage form that delivers an opioid agonist and an opioid antagonist over an extended period of time.
- the dosage form includes an amount of an opioid agonist, preferably a biomodally-acting opioid agonist, and an amount of an opioid antagonist, and upon " administration the dosage form delivers an analgesic or sub-analgesic amount of the opioid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
- Certain embodiments of the invention are directed to controlled-release dosage forms comprising an opioid agonist and the opioid antagonist, wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage fonn, the opioid agonist and the antagonist are released from the dosage fonn at appropriately similar times.
- the present invention is also directed to the use of the above-mentioned controlled release fo ⁇ riulations for maintenance treatement of previously detoxified opiate addicts.
- the opioid agonist is selected from the group consisting of hydromorphone, oxycodone, hydrocodone, morphine, phamiaceutically acceptable salts thereof and mixtures thereof.
- the opioid agonist is a bimodally-acting opioid agonist selected from, e.g., morphine, codeine, fentanyl analogs, pentazocine, buprenorphine, methadone, enkephalins, dynorphins, endo ⁇ hins, and similarly acting opioid alkaloids and opioid peptides.
- the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, pharmaceutically acceptable salt thereof and mixtures thereof.
- the present invention is directed to controlled-release dosage forms comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled-release of the opioid agonist and controlled-release of the opioid antagonist.
- the release rate of the agonist and the antagonist from the dosage fomi are controlled to maintain an analgesically effective amount of the agonist in the blood throughout the dosing period and to maintain the concentration of the opioid antagonist throughout the dosing period sufficient for decreasing the side effects associated with the opioid agonist but not sufficient to negate the analgesic efficacy of the agonist.
- the invention is directed to controlled release solid dosage forms that release an opioid agonist and an opioid antagonist over an extended period of time.
- the dosage form includes an amount of an opioid agonist, preferably a biomodally-acting opioid agonist, and an amount of an opioid antagonist, and upon oral administration the dosage form releases an analgesic or sub-analgesic amount of the opioid agonist over the dosing interval, along with an amount of the opioid antagonist effective to enhance the analgesic potency of the opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
- the present invention is further directed to a controlled-release solid oral dosage form comprising an opioid agonist and an opioid antagonist, the dosage form providing controlled- release of the opioid agonist and controlled-release of the opioid antagonist, the dosage form, when administered to patients, providing analgesia together with reduction of side effects associated with the opioid agonist. It is preferred that such dosage form releases the opioid agonist and the antagonist at substantially proportionate rates. Preferably, the release rates of the opioid agonist and antagonist are approximately proportionate over time, more preferably over a dosing period.
- the controlled-release composition of the present invention provides reduction of opioid associated side effects, e.g., nausea, vomiting, pruritis, urinary retention, respiratory depression, constipation, physical dependence, tolerance, hyperexcitability, and hyperalgeia.
- opioid associated side effects e.g., nausea, vomiting, pruritis, urinary retention, respiratory depression, constipation, physical dependence, tolerance, hyperexcitability, and hyperalgeia.
- controlled-release dosage form refers to a dosage form which provides a longer period of pharmacological response after the administration of the agonist and the antagonist than is ordinarily provided after the administration of the rapid release dosage form.
- the controlled-release dosage form releases the opioid agonist and the opioid agonist from the dosage form at such a rate that blood (e.g., plasma) concentration (levels) are maintained within the analgesically effective range (above the minimum effective analgesic concentration or "MEAC”) over a dosing period.
- the opioid antagonist is released from the controlled-release dosage form at such a rate that blood (e.g., plasma) concentration of the antagonist are maintained within the pha ⁇ riacologically effective range for reducing the opioid agonist associated side effects over a dosing period.
- the opioid antagonist is delivered from the controlled-release dosage form at such a rate that the controlled release formulations provide the benefits set forth in the above-mentioned Crain, et al. patents, namely, enhancement of the analgesic potency of the opioid agonist while simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
- the analgesic efficacy may be greater than that reflected by blood plasma levels of the opioid agonist.
- the controlled release obtained via in-vitro dissolution testing of the formulation i.e., measuring the release of the opioid agonist and the opioid antagonist
- Such in-vitro testing may be undertaken utilizing the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100 ipm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37° C.
- the analytical method may be, e.g., high performance liquid chromatography.
- the controlled-release dosage fonn of the present invention is administrable (i.e., provides the requisite effects stated above) at least every 8 hours.
- the controlled release dosage form is administrable twice daily ( every 12 hours), or once-a-day (every 24 hours).
- the transdermal delivery system preferably provides the requisite effect for at least about 3 days.
- the transde ⁇ nal delivery system may be worn on the skin of a human patient for at least about 5 days, and preferably about 7 days, while provided attenuation of the anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
- the opioid antagonist simultaneously provides enliancement of the analgesic potency of the opioid agonist.
- a very low dose of an opioid antagonist is combined with a dose of an opioid agonist (analgesic) so as to enhance the degree of analgesia an attenuate undesired side effects.
- the dosage fom is prepared in a manner which causes the opioid agonist and the opioid antagonist to be delivered when the dosage fonn is administered, e g , to a human patient
- the rate of delivery of the opioid agonist will be such that substantially the e tne dose of opioid agonist contained in the dosage form is dehveied fiom the dosage fonn aftei administration, in those embodiments in which the contiolled release dosage fonn is an oral mucosal delivery system, a composition for mtranasal administration, an mjectable composition, and a solid oral composition
- the rate of delivery of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to attenuate the anti- analgesia, hyperalgesia, hyperexcitability, physical dependence and/or toleiance effects of the opioid agonist during the intended dosmg interval
- rate of deliveiy of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to enhance the analgesic potency of the opioid analgesic during the dosmg interval of the controlled release dosage form It is not necessary that substantially all of the opioid antagonist be delivered from the controlled release dosage fomi to meet
- the rate of delivery of the opioid agonist will be such that a sufficient mean relative release rate (or flux rate) of the opioid agonist contained in the dosage form is delivered from the transdermal dosage form upon administration
- the rate of delivery of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or toleiance effects of the opioid agonist during the intended dosmg interval
- rate of deliveiy of the opioid antagonist will be such that an effective amount of the opioid antagonist is delivered to enhance the analgesic potency of the opioid analgesic during the dosmg interval of the controlled release dosage fonn It is not necessary that substantially all of the opioid antagonist be delivered from the controlled release dosage fonn to meet these goals
- the dose of opioid antagonist which is delivered from the dosage form du ⁇ ng the dosing interval is prefeiably fiom about 100 to about 1000 times less than the dose of the opioid agonist (preferably, bimodally-acting opioid agonist) delivered from the dosage form
- the opioid agonist preferably, bimodally-acting opioid agonist
- excitatoiy opioid receptor antagonists of the invention are preferably seleted from the group consisting of naloxone, naltrexone, diprenorphine, eto ⁇ hine and dihydroeto ⁇ hine. Naltrexone and naloxone are especially preferred in certain embodiments of the invention.
- the controlled release dosage fomis of the present invention preferably deliver the opioid antagonist (e.g., excitatory opioid receptor antagonists) at such a level that the opioid antagonist has selective antagonist action at excitatory, but not inhibitory, opioid receptors.
- the opioid antagonist e.g., excitatory opioid receptor antagonists
- the antagonists preferably enhance the analgesic potency of the agonists, the agonists become effective when administered at reduced doses which would otherwise be subanalgesic. It may be possible to achieve an analgesic effect with 10-100 times lower doses of the (bimodally acting) opioid agonists with the excitatory opioid receptor antagonists of the invention than when the opioid agonist is administered alone.
- the excitatory opioid receptor antagonists may enhance the analgesic effects of the opoid agonists by attenuating the anti-analgesic excitatory side effects of the opioid agonists. Therefore, in certain preferred embodiments of the invention, the opioid agonist is included in the dosage fonn and is delivered in an amount which is less than that which has been typically administered for analgesia. In certain embodiments of the invention, the opioid antagonist is delivered such that the amount of opioid agonist included in the dosage fonn is, e.g., about 10 to about 100 times less than the amount of that opioid agonist typically dosed over the dosing interval.
- Certain embodiments of the invention are directed to controlled-release dosage fomis comprising an opioid agonist and the opioid antagonist wherein the opioid agonist or the opioid antagonist, before it is combined with the other, is treated to modify its release rate, such that when combined into the controlled-release dosage form, the opioid agonist and the antagonist are released from the dosage form at appropriately similar times.
- one of the drugs may be pretreated, e.g., with a controlled release material, to modify its release rate such that when combined into a unitary dosage form with the other drug, the release rates of the two drugs will be substantially similar.
- excitatory opioid receptor antagonists can be administered in the controlled release formulations of the invention along with sub-analgesic doses of opioid receptor agonists for long-tem maintenance treatment of previously detoxified opiate, cocaine and alcohol addicts to prevent protracted physical dependence.
- Opioid agonists useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmo ⁇ hine, bezitramide, bupreno ⁇ hine, buto ⁇ hanol, clonitazene, codeine, desomo ⁇ hine, dextromoramide, dezocine, diampromide, diamo ⁇ hone, dihydrocodeine, dihydromo ⁇ hine, dimenoxadol, dimephep- tanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmo ⁇ hine, etonitazene, fentanyl, heroin, hydrocodone, hydromo ⁇ hone, hydroxypethidine, isomet
- the bimodally-acting opioid agonist is selected from the group consisting of mo ⁇ hine, codeine, fentanyl analogs, pentazocine, methadone, bupreno ⁇ hine, enkephalins, dyno ⁇ hins, endo ⁇ hins and similarly acting opioid alkaloids and opioid peptides.
- the opioid agonist is selected fiom the group consisting of hydiocodone, nioiphine, hydromo ⁇ hone, oxycodone, codeine, levoiphanol, mepe ⁇ dine, methadone, or salts thereof or mixtures thereof
- the opioid agonist is oxycodone or hydiocodone Equianalgesic doses of these opioids, m comparison to a 15 mg dose of hydrocodone, are set forth m Table 1 below
- the opioid agonist is a bnnodally acting opioid agonist
- “Bimodally acting opioid agonists” are opioid agonist that bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain Activation of the inhibitory receptors results in opioid analgesia, wheieas the activation of the excitatory receptors results in undesirable side effects, including the de ⁇ elopment of physical dependence and tolerance to the opioid agonist, anti-analgesic actions, hyperexcitability and hyperalgeia
- Examples of bimodally acting opioid agonists include mo ⁇ hine, codeine, fenfenyl analogs, pentazocine, methadone, bupreno ⁇ lnne, enkephalins, dyno ⁇ hias, endo ⁇ hins and similarly acting opioid alkaloids and opioid peptides
- the excitatory opioid receptor antagonists of the invention are preferably seleted from the group consisting of naloxone, naltrexone, dipreno ⁇ hme, eto ⁇ hine, dihydroeto ⁇ hine, pharmaceutically acceptable salts thereof and mixtures thereof
- Other opioid antagonists are preferably seleted from the group consisting of naloxone, naltrexone, dipreno ⁇ hme, eto ⁇ hine, dihydroeto ⁇ hine, pharmaceutically acceptable salts thereof and mixtures thereof.
- the opioid antagonist is naloxone or naltrexone
- the te ⁇ n "opioid agonist” is mtei changeable with the tenn "opioid” or “opioid analgesic' and shall include the base of the opioid, mixed agonist-antagonists, partial agonists, phannaceutically acceptable salts thereof, steieoisomers thereof, ethers and esters thereof, and mixtures thereof
- opioid antagonist shall include the base, pharmaceutically acceptable salts thereof, stereoisomers thereof, etheis and esters thereof, and mixtures thereof
- the invention disclosed herein is meant to encompass all pharmaceutically acceptable salts thereof of the disclosed opioid agonists and antagonists
- the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, secium salt and the like, alkaline earth metals such as calcium salt, magnesium salt and the like, organic amine salts such as t ⁇ ethylamme salt, pyridine salt, picohne salt, ethanolamme salt, t ⁇ ethanolamme salt, dicyclohexylamme salt, N,N'-d ⁇ benzylethylened ⁇ am ⁇ ne salt and the like, inorganic acid salts such as hydrochlo ⁇ de, hydrobiomide, sulfate, phosphate and the like, organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like, sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfon
- opioid agonists and antagonists disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisome ⁇ c forms
- the present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof
- the compounds described herein contain olefmic double bonds or other centers of geomet ⁇ c asymmetiy, and unless specified otherwise, it is intended to include both E and Z geometric lsomers All tautomers are intended to be encompassed by the present invention as well
- stereoisomers is a general term for all isomers of individual
- chiral center refers to a carbon atom to which four ditfeient gioups aie attached
- enantiomer or “eiiantiome ⁇ c” refers to a molecule that is nonsupe ⁇ mposeable on its minor image and hence optically active wheiem the enantiomei rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction
- racemic refers to a mixture of equal parts of enantiorés and which is optically inactive
- resolution refers to the separation or concentration or depletion of one of the two enantiome ⁇ c forms of a molecule
- the present invention is further directed to a method of decreasing the potential foi abuse of an opioid agonist in an oral dosage fomi
- the method comp ⁇ ses piovidmg the opioid agonist in an oral dosage form as described herein
- the controlled-release compositions of the present invention includes, but is not limited to, a transdermal delivery system, an oral mucosal deliveiy system a composition for intranasal administration, an injectable composition, and a solid oral composition
- a transdermal patch comprises an opioid agonist and an opioid antagonist contained in a reservoir or a matrix, and an adhesive which allows the transdermal device to adhere to the skin, allowing the passage of the active agent from the transdermal device through the skin of the patient Once the agonist antagonist has penetrated the sk layer, the
- the transdennal patch- releases both the opioid agonist and the opioid antagonist in a controlled-release manner, such that the blood levels of the opioid agonist is maintained at an analgesically effective level through out the dosing period, and the blood levels of the antagonist is maintained at a concentration that is sufficient to reduce side effects associated with the opioid agonist but not sufficient to negate the analgesic effectiveness of the opioid.
- the amount of antagonist delivered from the transdennal delivery system is effective to enhance the analgesic potency of the opioid agonist delivered from the dosage form.
- Transdermal delivery system providing a controlled-release of an opioid agonist is known.
- Duragesic ® patch (commercially available from Janssen Phannaceutical) contains an opioid agonist (fentanyl) and is said to provide adequate analgesia for up to 48 to 72 hours (2 to 3 days).
- bupreno ⁇ hine an opioid agonist
- bupreno ⁇ hine transdermal delivery systems are of particular interest because bupreno ⁇ hine is a potent, partial agonist opioid analgesic with desirable therapeutic properties.
- bupreno ⁇ hine is 50 to 100 times more potent than mo ⁇ hine, but has a much safer therapeutic index than mo ⁇ hine (see Wallenstein SL, et al. , Crossover Trials in Clinical Analgesic Assays: Studies of Bupreno ⁇ hine and Mo ⁇ hine, Phannacotherapy, G(5): 225-235, 1986 hereby inco ⁇ orated by reference).
- transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Patent No. 5,069,909 (Sharma et al), hereby inco ⁇ orated by reference.
- This patent describes a laminated composite for administering bupreno ⁇ hine transdermally
- transdermal delivery system used in the present invention may also be prepared in accordance with U.S. Patent No. 4,806,341 (Chien et al), hereby inco ⁇ orated by reference.
- This patent describes a transdermal mo ⁇ hinan narcotic analgesic or antagonist (including bupreno ⁇ hine) pharmaceutical polymer matrix dosage unit having a backing layer which is substantially impervious to the bupreno ⁇ hine, and a polymer matrix disc layer which is adhered to the backing layer and which has microdispersed therein effective dosage amounts of the bupreno ⁇ hine.
- compositions for the transdennal delivery of bupreno ⁇ hine comprise bupreno ⁇ hine in a carrier of a polar solvent material selected from the group consisting of C3-C4 diols, C3-
- the transdennal delivery system used in the present invention may also be that described in U.S. Patent No. 4,588,580 (Gale, et. al), hereby inco ⁇ orated by reference. That system comprises a reservoir for the drug having a skin proximal, material releasing surface area in the range of about 5-100 cm 2 and containing between 0.1 and 50% by weight of a skin penneable form of the bupreno ⁇ hine.
- the reservoir contains an aqueous gel comprising up to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%) buprenoiphine, and release rate controlling means disposed in the flow path of the drug to the skin which limits the flux of the bupreno ⁇ hine from the system through the skin.
- the present invention is contemplated to encompass all transdennal formulations, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist.
- the transdermal delivery systems of the invention preferably deliver an analgesic or sub- analgesic amount of the opioid agonist together with an amount of the opioid antagonist effective to attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the opioid agonist.
- the amount of opioid antagonist delivered simultaneously enhances the analgesic potency of the opioid agonist delivered from the transdermal delivery system.
- the transdermal delivery systems may deliver the opioid agonist and/or the opioid antagonist in accordance with first order pharmacokinetics, zero order pharmacokmetics, or both first and zero order phannacokinetics during the dosing interval.
- first order phannacokinetics is defined as plasma concentrations which increase over a specified time period.
- zero order pharmacokinetics contemplates an amount of drug released from a bupreno ⁇ hine formulation which substantially maintains plasma concentrations at a relatively constant level.
- a relatively constant plasma concentration is defined as a concentration which does not decrease more than about 30% over a 48 hour time period.
- transdennal delivery devices when used with respect to transdennal delivery devices means that the transdennal delivery device provides a mean relative release rate or flux of the drug out of the device and through the skin of the patient.
- mean relative release rate is determined from the amount of drug released per unit time from the transdermal delivery device through the skin and into the bloodstream of a human patient. Mean relative release rate may be expressed, e.g, as g drug/cm ⁇ /hr. For example, a transdermal delivery device that releases 1.2 mg of bupreno ⁇ hine over a time period of 72 hours is considered to have a relative release rate of 16.67 g/hr.
- relative release rates may change between any particular time points within a particular dosing interval, and the term therefore only reflects the overall release rate during the particular dosing interval.
- relative release rate should be considered synonomous with the term "flux rate”.
- mean relative release rates are achieved as follows: a mean relative release rate of from about 3 g/hr to about 86 g/hr from initiation of the dosing interval until about 72 hours thereafter; and a mean relative release rate of about 0.3 g/hr to about 9 g/hr from about 72 hours after the initiation of the dosing interval until at least about 120 hours after the initiation of the dosing interval.
- transdermal dosage form is a transdermal patch comprising a backing layer which is impermeable to the active substance, a pressure-sensitive adhesive reservoir layer, and optionally a removable protective layer, the reservoir layer by weight
- ⁇ c comprising 20 to 90% of a polymeric matrix, 0.1 to 30%) of a softening agent, 0.1 to 20% of said opioid agonist and opioid antagonist and 0.1 to 30%o of a solvent for the opioid agonist and opioid antagonist.
- the controlled release dosage fonn can also comprise a transdennal plaster comprising:
- a film layer which comprises a polyester film of 0.5 to 4.9 ⁇ m thickness, 8 to 85 g/mm strength, respectively in the two directions intersecting substantially at right angles, 30 to 150%o elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of 1.0 to 5.0, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B, and wherein said polyester film comprises 0.01 to 1.0% by weight, based on the total weight of said polyester film, of solid fine particles in which
- the average particle size is 0.001 to 3.0 . ⁇ m, and (b) the average particle size is substantially not more than 1.5 times the thickness of said polyester film; and (2) an adhesive layer (a) which is composed of an adhesive containing said opioid agonist and opioid antagonist and further wherein said adhesive layer (a) is laminated on said film layer over the surface in a 2 to 60 ⁇ m thickness.
- the controlled release dosage can be a transdermal patch comprising a laminated composite for administering said opioid agonist and opioid antagonist to an individual transdermally comprising: (a) a polymer backing layer that is substantially impermeable to said opioid agonist and opioid antagonist; and (b) a reservoir layer comprising a water-base acrylate pressure-sensitive adhesive, 1 to 12%) by weight opioid agonist and opioid antagonist and 2 to 25%o by weight of a permeation enhancer comprising propylene glycol monolaurate in combination with capric acid or oleic acid, wherein the skin contact area of the composite is 10 to 100 cm. sup.2 and the rate of administration from the composite is about 1 to about 100 ⁇ g/hr.
- the controlled release dosage form can be a transdermal comprising: (a) a backing layer which is substantially impervious to said opioid agonist and opioid antagonist; and (b) a polymer matrix layer which is adhered to said backing layer and which has dispersed therein said opioid agonist and opioid, said polymer being bioacceptable and
- the controlled release dosage form can be a transdermal patch comprising (a) a polar solvent material selected from the group consisting of C 3 -C 4 diols, C 3 -C 6 triols, and mixtures thereof; and (b) a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures thereof; wherein said polar solvent material and said polar lipid material are present in a weight ratio of solvent materiaklipid material of from about 60:40 to about 99:1.
- the controlled release opioid agonist/antagonist formulation may be prepared as a controlled-release oral mucosal delivery system.
- a controlled-release oral mucosal delivery system is described by McQuinn, R. L. et al, "Sustained Oral Mucosal Delivery in Human Volunteers J. Controlled Release; (34) 1995 (243-250).
- oral mucosal patches were prepared by homogeneously mixing bupreno ⁇ hine free base (8%), Carbopol 934 (52%), polyisobutylene (35%) and polyisoprene (5%, w/w) via a two-roll mill and then compressing the mixture to the appropriate thickness.
- a membrane backing (ethylcellulose) was applied to one side of the compressed material and then circular disks (0.5 cm 2 ) were punched from the material.
- the backing was included in order to retard drug release from one side of the disk and to prohibit adhesion to opposing side tissues.
- Each soft, flexible disk was approximately 0.6 mm thick and contained 2.9 mg bupreno ⁇ hine. These patches were worn by the subjects for 12 hours. Gum and lip application was tested, although adhesion at the gum site was considered superior. After the initial appearance of serum bupreno ⁇ hine (> 25 pg/ml), levels generally increased relatively rapidly and persisted until the patch was removed.
- the present invention is contemplated to encompass all oral mucosal delivery systems, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist.
- the oral mucosal delivery device can comprise a compressed mixture comprising a polymer with a cellulose backing.
- the polymer can be selected from the group consisting of Carbopol 934, polyisobutylene, polyisoprene and mixtures thereof and said cellulose can be an alkylcellulose, e.g., ethylcellulose.
- the controlled release formulations of the present invention may be formulated as a phannaceutical suppository for rectal administration comprising an opioid agonist and an opioid antagonist in a controlled release matrix, and a suppository vehicle (base).
- a phannaceutical suppository for rectal administration comprising an opioid agonist and an opioid antagonist in a controlled release matrix, and a suppository vehicle (base).
- Preparation of controlled release suppository formulations is described in, e.g., U.S. Patent No. 5,215,758, hereby inco ⁇ orated by reference in its entirety.
- the drug Prior to abso ⁇ tion, the drug must be in solution. In the case of suppositories, solution must be preceded by dissolution of the base, or the melting of the base and subsequent partition of the drug from the base into the rectal fluid. The abso ⁇ tion of the drag into the body may be altered by the suppository base.
- the particular base to be used in conjunction with a particular drug must be chosen giving consideration to the physical properties of the drug. For example, lipid-soluble drugs will not partition readily into the rectal fluid, but drugs that are only slightly soluble in the lipid base will partition readily into the rectal fluid.
- the surface area of the drug substance presented to the dissolution solvent medium the pH of the solution, the solubility of the substance in the specific solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium.
- l £ include suppository vehicle, abso ⁇ tion site pH, drug pKa, degiee of lonization, and lipid solubility
- the suppository base chosen should be compatible with the opioid agonist antagonist to be mco ⁇ orated into the composition Further, the suppositoiy base is pieferablv non-toxic and nomr ⁇ tatmg to mucous membranes, melts or dissolv es in lectal fluids, and is stable during storage
- the suppository base comprises a fatty acid wax selected from the group consisting of mono-, di- and triglycerides of saturated, natural fatty acids of the chain length C 12 to C 18
- a wax may be used to form the proper shape foi administration via the lectal route
- This system can also be used without wax, but with the addition of diluent filled in a gelatin capsule for both rectal and oral administration
- Suitable commercially available mono-, di- and triglycerides include saturated natural fatty acids of the 12-18 carbon atom chain sold under the trade name Novata TM (types AB, AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henlcel, and Witepsol TM (types H5, H12, H15, H175. H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85), manufactured by Dynamit Nobel
- the amount of base in the suppository is determined by the size (I e actual weight) of the dosage fonn, the amount of alginate and drug used Generally, the amount of suppository base is from about 20 percent to about 90 percent by weight of the total weight of the suppository Preferably, the amount of base in the suppository is fiom about 65 percent to about 80 percent, by weight of the total weight of the suppository
- the controlled-release matrix comprises a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium salt, the calcium salt being in an amount sufficient to cross-link with the sodium alginate and thereby provide controlled-release of the opioid agonist and the antagonist from the matrix when the suppository base melts subsequent to administration.
- the present invention is contemplated to encompass all suppository systems, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist.
- the suppository can comprise a controlled release matrix comprising a pharmaceutically acceptable sodium alginate and a pharmaceutically acceptable calcium, and a suitable vehicle which melts or dissolves in rectal fluids, said calcium salt being in an amount sufficient to cross-link with the sodium alginate and thereby provide a controlled release of said therapeutically active agent from said matrix when said vehicle melts or dissolves.
- the calcium salt can be selected from the group consisting of calcium phosphate, dicalcium phosphate, calcium chloride, calcium carbonate, calcium acetate, calcium gluconate, and mixtures thereof.
- the controlled release formulation of the present invention includes compositions for nasal administration.
- Controlled release dosage forms containing an opioid agonist is described in European Patent No. EP 205282 and PCT Application No. WO 8203768 (both providing controlled release of mo ⁇ hine), and also in U.S. Patent No. 5,629,01 1 (moiphine- 6-glucuronide and mo ⁇ hine-6-sulfate, both being metabolites of mo ⁇ hine).
- Each of these documents are inco ⁇ orated herein by reference in their entireties.
- the present invention is contemplated to encompass all such nasal fomiulations as described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner.
- the nasal composition comprises an opioid agonist and the opioid antagonist in bioadhesive microspheres.
- the microspheres are prepared
- microspheres (crosslinked if necessary) are a preferred material.
- Other materials that can be used to form microspheres include starch derivatives, modified starches such as amylodextrin, gelatin, albumin, collagen, dextran and dextran derivatives, polyvinyl alcohol, polylactide-co-glycolide, hyaluronic acid and derivatives thereof such as benzyl and ethyl esters, gellan gum and derivatives thereof such as benzyl and ethyl esters and pectin and derivatives thereof such as benzyl and ethyl esters.
- derivatives we particularly mean esters and ethers of the parent compound that can be unfunctionalised or functionalised to contain, for example, ionic groupings.
- Suitable starch derivatives include hydro xyethyl starch, hydroxypropyl starch, carboxymethyl starch, cationic starch, acetylated starch, phosphorylated starch, succinate derivatives of starch and grafted starches.
- Such starch derivatives are well known and described in the art (for example Modified Starches: Properties and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)).
- Suitable dextran derivatives include, diethylaminoethyl-dextran (DEAE-dextran) , dextran sulphate, dextran methyl-benzylamide sulphonates, dextran methyl-benzylamide carboxylates, carboxymethyl dextran, diphosphonate dextran, dextran hydrazide, palmitoyldextran and dextran phosphate.
- DEAE-dextran diethylaminoethyl-dextran
- dextran sulphate dextran methyl-benzylamide sulphonates
- dextran methyl-benzylamide carboxylates carboxymethyl dextran
- diphosphonate dextran dextran hydrazide
- palmitoyldextran dextran phosphate
- albumin microspheres may be made using the water- in-oil emulsification method where a dispersion of albumin is produced in a suitable oil by homogenization techniques or stirring techniques, with the addition if necessary of small amounts of an appropriate surface active agent.
- the size of the microspheres is largely dictated by the speed of stirring or homogenization conditions.
- the agitation can be provided by a simple laboratory stirrer or by more sophisticated devices such as a microfluidizer or homogenizer.
- Emulsification techniques are also used to produce starch microspheres as described in GB 1 518 121 and EP 223 303 as well as for the preparation of microspheres of gelatin.
- Proteinaceous microspheres may also be prepared by coacervation methods such as
- the controlled-release nasal composition according to the invention can be administered by any appropriate method according to their fomi
- a composition comprising microspheres or a powder can be administered using a nasal insufflatoi device Examples of these are already employed for commercial powder systems intended for nasal application (e g Fisons Lomudal System)
- the insufflator produces a finely divided cloud of the dry powder or microspheres
- the insufflator is preferably provided with means to ensure administration of a substantiall) fixed amount of the composition
- the powder or microspheres may be used directly with an insufflator which is provided with a bottle or container for the powdei oi microspheres
- the powder or microspheres may be filled into a capsule such as a gelatin capsule, oi other single dose device adapted for nasal administration
- the insufflatoi preferably has means to break open the capsule or other device
- a composition comprising a solution or dispersion in an aqueous medium can be administered as a spray using an appropriate device such as a metered dose aerosol valve or a metered dose pump
- an appropriate device such as a metered dose aerosol valve or a metered dose pump
- a gas or liquid propellant can be used Details of other devices can be found in the pharmaceutical literature (see for example Bell, A Intranasal Delivery Devices, in Drag Delivery Devices Fundamentals and Applications, Tyle P (ed), Dekker, New York, 1988), Remington's Pharmaceutical Sciences, Mack Publishing Co , 1975
- the present invention is contemplated to encompass all nasal formulations, e g , the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-ielease manner along with the opioid agonist
- the intranasal formulation can comprise an effective amount of an abso ⁇ tion promoting agent to allow nasal abso ⁇ tion of the agents after nasal admimstiation of the composition
- the abso ⁇ tion promoting agent can be selected from the group
- 1Z consisting of a cationic polymer, a surface active agent, a chelating agent, a mucolytic agent, a cyclodextrin, and combinations thereof.
- the controlled-release injectable compositions containing an opioid antagonist is described in, e.g., U.S. Patent No. 5,942,241 to Chasin et al, which is inco ⁇ orated herein by reference in its entirety.
- the present invention is contemplated to encompass all such injectable formulations, with the inclusion of an opioid antagonist, such that the opioid antagonist is also released in a controlled-release manner along with the opioid agonist.
- the controlled-release injectable composition comprise an opioid agonist and antagonist in controlled-release microparticles, e.g., microspheres or microcapsules.
- the slow release of the drugs is brought about through controlled diffusion out of the matrix and/or selective breakdown of the coating of the preparation or selective breakdown of a polymer matrix.
- the slow release formulation is prepared as microspheres in a size distribution range suitable for local infiltration or injection.
- the diameter and shape of the microspheres or other particles can be manipulated to modify the release characteristics. For example, larger diameter microspheres will typically provide slower rates of release and reduced tissue penetration and smaller diameters of microspheres will produce the opposite effects, relative to microspheres of different mean diameter but of the same composition.
- other particle shapes such as, for example, cylindrical shapes, can also modify release rates by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape.
- the diameter of injectable microspheres are in a size range from, for example, from about 5 microns to about 200 microns in diameter. In a more preferred embodiment, the microspheres range in diameter from about 20 to about 120 microns.
- biodegradable materials may be utilized to provide the controlled release injectable dosage forms. Any pharmaceutically acceptable biodegradable polymers known to those skilled in the art may be utilized. It is preferred that the biodegradable polymers known to those skilled in the art.
- ⁇ i controlled release material degrade in vivo over a period of less than about two years, with at least 50%) of the controlled release material degrading within about one year, and more preferably six months or less. More preferably, the controlled release material will degrade significantly within one to three months, with at least 50%o of the material degrading into non- toxic residues which are remov ed by the body, and 100%o of the drag being released within a time period from about two weeks to about two months.
- the controlled release material should preferably degrade by hydrolysis, and most preferably by surface erosion, rather than by bulk erosion, so that release is not only sustained but also provides desirable release rates. However, the pharmacokinetic release profile of these formulations may be first order, zero order, bi- or multi-phasic, to provide the desired reversible local anesthetic effect over the desired time period.
- the controlled release material should be biocompatible. In the case of polymeric materials, biocompatibility is enhanced by recrystallization of either the monomers forming the polymer and/or the polymer Using standard techniques.
- Suitable biodegradable polymers can be utilized as the controlled release material.
- the polymeric material may comprise a polylactide, a polyglycolide, a poly(lactide-co- glycolide), a polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes, polysaccharides, proteinaceous polymers, soluble derivatives of polysaccharides, soluble derivatives of proteinaceous polymers, polypeptides, polyesters, and polyorthoesters or mixtures or blends of any of these.
- the polysaccharides may be poly-l,4-glucans, e.g., starch glycogen, amylose, amylopectin, and mixtures thereof.
- the biodegradable hydrophilic or hydrophobic polymer may be a water-soluble derivative of a poly-l,4-glucan, including hydrolyzed amylopectin, hydroxyalkyl derivatives of hydrolyzed amylopectin such as hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch, and the like.
- HES hydroxyethyl starch
- hydroxyethyl amylose dialdehyde starch
- Preferred controlled release materials which are useful in the fomiulations of the invention include the polyanhydrides, co-polymers of lactic acid and glycolic acid wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e., 80%o or less lactic acid to 20%o or more glycolic acid by weight), and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride.
- Other useful polymers include protein polymers such as gelatin and fibrin and polysaccharides such as hyaluronic acid. Since polylactic acid takes at least one year to
- this polymer should be utilized by itself only in circumstances where such a degradation rate is desirable or acceptable.
- the polymeric material may be prepared by any method known to those skilled in the art.
- this copolymer may be prepared by the procedure set forth in U.S. Pat. No. 4,293,539 (Ludwig, et al.), the disclosure of which is hereby inco ⁇ orated by reference in its entirety.
- Ludwig prepares such copolymers by condensation of lactic acid and glycolic acid in the presence of a readily removable polymerization catalyst (e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H).
- a readily removable polymerization catalyst e.g., a strong acid ion-exchange resin such as Dowex HCR-W2-H.
- the amount of catalyst is not critical to the polymerization, but typically is from about 0.01 to about 20 parts by weight relative to the total weight of combined lactic acid and glycolic acid.
- the polymerization reaction may be conducted without solvents at a temperature from about 100 C. to about 250 C. for about 48 to about 96 hours, preferably under a reduced pressure to facilitate removal of water and byproducts.
- the copolymer is then recovered by filtering the molten reaction mixture to remove substantially all of the catalyst, or by cooling and then dissolving the reaction mixture in an organic solvent such as dichloromethane or acetone and then filtering to remove the catalyst.
- the substrates of the presently described formulations in certain preferred embodiments are manufactured using a method that evenly disperses the local anesthetic throughout the formulation, such as emulsion preparation, solvent casting, spray drying or hot melt, rather than a method such as compression molding.
- a desired release profile may be achieved by using a mixture of polymers having different release rates.
- microspheres Methods for manufacture of microspheres are well known and are typified in the following examples. Examples of suitable methods of making microspheres include solvent evaporation, phase separation and fluidized bed coating.
- the local anesthetic agent if soluble in organic solvents, may be entrapped in the biodegradable polymer by dissolving the polymer in a volatile organic solvent, adding the drag to the organic phase, emulsifying the organic phase in water which contains less than 2%> polyvinyl alcohol, and finally removing the solvent under vacuum to form discrete, hardened monolithic microspheres.
- Phase separation microencapsulation procedures are suitable for entrapping water- soluble agents in the polymer to prepare microcapsules and microspheres.
- Phase separation involves coacervation of the polymer from an organic solvent by addition of a nonsolvent such as silicone oil.
- the microspheres may be prepared by the process of Ramstack et al., 1995, in published international patent application WO 95/13799, the disclosure of which is inco ⁇ orated herein in its entirety.
- the Ramstack et al. process essentially provides for a first phase, including an active agent and a polymer, and a second phase, that are pumped through a static mixer into a quench liquid to fonn microparticles containing the active agent.
- the first and second phases can optionally be substantially immiscible and the second phase is preferably free from solvents for the polymer and the active agent and includes an aqueous solution of an emulsifier.
- the drag is dissolved in an organic solvent along with the polymer.
- the solution is then processed, e.g., through a Wurster air suspension coating apparatus to fonn the final microcapsule product.
- the present invention is contemplated to encompass all injectable formulations, e.g., the technologies described above, with the inclusion of an opioid antagonist, such that the opioid antagonist is released in a controlled-release manner along with the opioid agonist.
- injectable composition can comprise a plurality of substrates in a pha ⁇ naceutically acceptable medium for injection, said substrates comprising an effective amount of a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof.
- a biocompatible, biodegradable controlled release material comprising a polymer selected from the group consisting of polyanhydrides, copolymers of lactic acid and glycolic acid, poly(lactic) acid, poly(glycolic) acid, polyesters, polyorthoesters, proteins, polysaccharides and combinations thereof.
- the opioid agonist and antagonist combination may be formulated as a controlled- release oral dosage fomi, including tablets and capsules.
- the controlled-release oral dosage form provides a controlled release of an opioid agonist and a
- X.G controlled-ielease of an opioid antagonist such that when the dosage fonn is admmisteied to a human, the blood levels of the agonist is maintained throughout the dosmg period at an analgesically effective level, and the antagonist at a level sufficient to decrease the side effects associated with the opioid agonist but not sufficient to negate the analgesic effect of the opioid agonist
- release rate refers to a rate at which a diug is released from the dosage fomi
- the release pattern of a drug is a function of its properties, such as its physicochemical properties Solubility is one such property Since drug must be in solution before they can be absorbed into the body
- the release rate of the diug from an oral dosage form may be measured, for example, by measuring the dissolution rate of the drug from the dosage fonn using an in ⁇ ltro test method conducted undei standardized conditions, e g , U S P paddle, 100 ⁇ m m simulated gast ⁇ c fluid for the first hour and thereafter in simulated intestinal fluid
- lelease rate may be used as a sunogate measure of drug delivery m-vivo
- the ratio of the opioid agonist to the antagonist in the controlled-release oral dosage form is about 1 1 to about 100 1 by weight In preferred embodiments, the ratio of the opioid agonist with the antagonist is about 40 1 to about 50 1 by weight, more preferably about 20 1 In other preferred embodiments of the invention the amount of the opioid receptor antagonist administered is about 100 to about 1000 fold less than the amount of the opioid agonist administered
- controlled-release oral dosage forms accoiding the invention may be prepared using the methods available to one skilled in the art
- controlled-release tablets comprise the opioid agonist and antagonist in a controlled release matrix
- the controlled-release matrix may include hydrophilic and/oi hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the opioid may be used in accordance with the present invention
- the opioid agonist particles may, alternatively or additionally, be film coated with a material that pennits lelease of the opioid agonist at a sustained rate in an aqueous medium The film coat is chosen so as
- sustained release coating formulations of 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 dosage forms comprising an opioid agonist and opioid antagonist may optionally be coated with one or more materials suitable for the regulation of the opioid agonist release or for the protection of the formulation.
- coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid.
- a pH-dependent coating serves to release the opioid in desired areas of the gastro-intestinal (GI) tract, e.g., the stomach or small intestine, such that an abso ⁇ tion profile is provided which is capable of providing at least about eight hours and preferably about twelve hours to up to about twenty- four hours of analgesia to a patient.
- GI gastro-intestinal
- the coating is designed to achieve optimal release of the opioid regardless of pH- changes in the environmental fluid, e.g., the GI tract. It is also possible to fo ⁇ nulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine.
- Formulations according to the invention that utilize pH-dependent coatings to obtain formulations may also impart a repeat-action effect whereby unprotected drug is coated over the enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract.
- Coatings which are pH- dependent may be used in accordance with the present invention include shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like.
- the substrate e.g., tablet core bead, matrix particle
- the opioid agonist/opioid antagonist combination is coated with a hydrophobic material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof.
- the coating may be applied in the form of an organic or aqueous solution or dispersion.
- the coating may be applied to obtain a weight gain from about 2 to about 25%) of the substrate in order to obtain a desired sustained release profile. Coatings derived from aqueous dispersions
- sustained release formulations and coatings which may be used in accordance with the present invention include Assignee's U.S. Patent Nos. 5,324,351 ; 5,356,467, and 5,472,712, hereby inco ⁇ orated by reference in their entirety.
- Cellulosic materials and polymers including alkylcelluloses, provide hydrophobic materials well suited for coating the beads according to the invention.
- one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulose polymers may be readily employed, singly or in any combination, as all or part of a hydrophobic coating according to the invention.
- Aquacoaf FMC Co ⁇ ., Philadelphia, Pennsylvania, U.S.A.
- Aquacoat 8 is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same 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. The plasticizer is not inco ⁇ orated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat with a suitable plasticizer prior to use.
- the hydrophobic mateiial comprising the controlled release coating is a phannaceutically acceptable acrylic polymei, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acryhc acid), poly(methacryhc acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(meth> l methacrylate) copolymer, polyaciylamide, aminoalkyl methacrylate copolymer, poly(methacryhc acid anhydride), and glycidyl methacrylate copolymers
- the acrylic polymer is comprised of one oi more ammonio methacrylate copolymers
- Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention
- Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media
- Eudragit " L is a methacrylic acid copolymei hich does not swell at about pH ⁇ 5 7 and is soluble at about pH > 6
- Eudragit S does not swell at about pH ⁇ 6 5 and is soluble at about pH > 7
- Eudragit " RL and Eudragit " RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent
- Eudragit " RL30D and Eudragit RS30D are copolymers of acrylic and methacrylic esters with 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 *8 RL30D and 1 :40 in Eudragit 8 RS30D.
- the mean molecular weight is about 150,000.
- the code designations RL (high pe ⁇ neability) and RS (low permeability) refer to the permeability properties of these agents.
- Eudragit RL/RS mixtures are 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 of the present invention may be mixed together in any desired ratio in order to ultimately obtain a sustained release formulation having a desirable dissolution profile. Desirable sustained release fonnulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit " RL, 50%o Eudragit " RL and 50%> Eudragit * RS, and 10% Eudragit 8 RL:Eudragit ⁇ 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit 8 L.
- the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the sustained release coating.
- a plasticizer into an ethylcellulose coating containing sustained release coating before using the same as a coating material.
- the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-fonner. Concentration of the plasticizer, however, can only be properly detennined after careful experimentation with the particular coating solution and method of application.
- plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although it is possible that other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
- Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
- Other plasticizers which have proved to be 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.
- Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
- a hydrophobic controlled release coating material is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads, which are already coated with an opioid agonist
- a plurality of the resultant solid controlled release beads may thereafter be placed in a gelatin capsule, with the opioid antagonist in a substantially non-releasable fonn.
- the dosage form provides an effective controlled release dose of the opioid agonist when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
- the controlled release bead formulations of the present invention slowly release the opioid agonist, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids.
- the controlled release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the hydrophobic material, altering the manner in which the plasticizer is added to the hydrophobic material, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc.
- the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
- Spheroids or beads coated w ith an opioid agonist may be prepaied, e g , by dissoh mg the drug in water and then spiaymg the solution onto a substiate, foi example, nu panel 18 20 beads, using a Wuster insert
- additional ingiedients aie also added pnoi to coating the beads m order to assist the binding of the opioid to the beads, and/or to color the solution, etc
- a product which includes hydioxypropylmethylcellulose, etc with or without colorant e g , Opadry " , commercially available from Colorcon, Inc
- the resultant coated substrate, in this example beads may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled release coating
- a suitable barrier agent is one which comprises hydroxypropylmethylcellulose
- the beads may then be overcoated with an aqueous dispersion of the hydrophobic material
- the aqueous dispersion of hydrophobic mate ⁇ al prefeiably further includes an effective amount of plasticizer, e g triethyl citrate
- plasticizer e g triethyl citrate
- Pre-formulated aqueous dispersions of ethylcellulose, such as Aquacoat " or Surelease " may be used If Surelease ' is used, it is not necessary to separately add a plasticizer
- pre-formulated aqueous dispersions of acrylic polymers such as Eudragit 8 can be used
- the coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (l e , water), a colorant to provide elegance and product distinction Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material
- color may be added to Aquacoat via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low sheai to the plasticized Aquacoat
- any suitable method of providing color to the fomiulations of the present invention may be used Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments The inco ⁇ oration of pigments, may, however, increase the retard effect of the coating Plasticized hydrophobic material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment
- the release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, I e , adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating
- I e adjusted to a desired rate
- the ratio of hydrophobic material to water soluble material is determined by, among other factors, the release rate required and the solubility chaiacte ⁇ stics of the materials selected
- the release-modifying agents which function as pore-formeis may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use
- the pore-formers may comprise one or more hydiophihc materials such as hydroxypropylmethylcellulose
- the release-modifying agent may also comprise a semi-permeable polymer
- the release- modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing
- the sustained release coatings of the present invention can also include erosion-promoting agents such as starch and gums
- the sustained release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain
- the sustained release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like.
- the passageway may be fonned by such methods as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are hereby inco ⁇ orated by reference).
- the passageway can have any shape such as round, triangular, square, elliptical, irregular, etc.
- the controlled release formulation is achieved via a matrix having a controlled release coating as set forth above.
- the present invention also comprises sustained-release tablets comprising an opioid agonist and opioid antagonist particles, wherein the agonist and the antagonist are dispersed in a controlled release matrix that affords in-vitro dissolution rates of the opioid agonist within the preferred ranges and that releases the opioid agonist in a pH-dependent or pH-independent manner.
- the materials suitable for inclusion in a controlled release matrix will depend on the method used to form the matrix.
- a matrix in addition to the opioid agonist and the opioid antagonist may include hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials.
- Such matrices may also include digestible, long chain ( - C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes, and stearyl alcohol; and polyalkylene glycols.
- acrylic polymers especially Eudragit " RSPO - the cellulose ethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses, are preferred.
- the oral dosage fonn may contain between 1% and 80%> (by weight) of at least one hydrophilic or hydrophobic material.
- the hydrophobic material is a hydrocarbon
- the hydrocarbon preferably has a melting point of between 25 ° and 90°C.
- fatty (aliphatic) alcohols are preferred.
- the oral dosage form may contain up to 60% (by weight) of at least one digestible, long chain hydrocarbon.
- the oral dosage form contains up to 60% (by weight) of at least one polyalkylene glycol as part of the controlled release matrix.
- the hydrophobic material is preferably selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
- alkylcelluloses acrylic and methacrylic acid polymers and copolymers
- shellac acrylic and methacrylic acid polymers and copolymers
- zein hydrogenated castor oil
- hydrogenated vegetable oil or mixtures thereof.
- the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(mefhacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
- acrylic acid and methacrylic acid copolymers including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalky
- the hydrophobic material is selected from materials such as hydroxyalkylcelluloses such as hydroxypropylmethylcellulose and mixtures of the foregoing.
- Preferred hydrophobic materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends.
- the hydrophobic materials useful in the invention have a melting point from about 30° to about 200 °C, preferably from about 45 ° to about 90 °C.
- the list is not meant to be exclusive, and any pharmaceutically acceptable hydrophobic material or hydrophilic material which is capable of imparting controlled release of the opioid agonist and opioid antagonist may be used in accordance with the present invention.
- the hydrophobic material may comprise natural or synthetic waxes , fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri- glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic aid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones.
- Suitable waxes include, for example, beeswax, glycowax, castor wax and camauba wax.
- a wax-like substance is defined as any material which is normally solid at room temperature and ha&a melting point of from about 30° to about 100°C.
- Suitable hydrophobic materials which may be used in accordance with the present invention include digestible, long chain (C 8 -C 50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and natural and synthetic waxes. Hydrocarbons having a melting point of between 25 ° and 90°C are preferred. Of the long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred in certain embodiments.
- the oral dosage form may contain up to 60%) (by weight) of at least one digestible, long chain hydrocarbon.
- hydrophobic materials may be included in the matrix formulations. If an additional hydrophobic material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, camauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive.
- An example of a suitable matrix comprises at least one water soluble hydroxyalkyl cellulose, at least one C n -C 3b , preferably C 14 -C 22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol.
- the at least one hydroxyalkyl cellulose is preferably a hydroxy (C, to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethylcellulose.
- the amount of the at least one hydroxyalkylcellulose in the present oral dosage form will be determined, inter alia, by the precise rate of opioid release required.
- the at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
- the amount of the at least one aliphatic alcohol in the present oral dosage form will be detem ined, as above, by the precise rate of opioid release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage fonn. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20%o and 50%o (by wt) of the at least one aliphatic alcohol.
- the combined weight of the at least one aliphatic alcohol and the at least one polyalkylene glycol preferably constitutes between 20%o and 50%. (by wt) of the total dosage.
- the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least one aliphatic alcohol/ polyalkylene glycol determines, to a considerable extent, the release rate of the opioid from the formulation.
- a ratio of the at least one hydroxyalkyl cellulose to the at least one aliphatic alcohol/polyalkylene glycol of between 1 :2 and 1 :4 is preferred, with a ratio of between 1 :3 and 1 :4 being particularly preferred.
- the at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol.
- the number average molecular weight of the at least one polyalkylene glycol may be, for example, polypropylene glycol or, which is preferred, polyethylene glycol.
- one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000.
- Another suitable controlled release matrix would comprise an alkylcellulose (especially ethyl cellulose), a C 12 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol.
- the matrix includes a pharmaceutically acceptable combination of at least two hydrophobic materials.
- a controlled release matrix may also contain suitable quantities of other materials, e.g. diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art.
- any method of preparing a matrix fomiulation known to those skilled in the art may be used.
- inco ⁇ oration in the matrix may be effected, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and opioid agonist/opioid antagonist; (b) mixing the hydroxyalkyl cellulose containing granules with at least one C 12 - C 35 aliphatic alcohol; and (c) optionally, compressing and shaping the granules.
- the granules are fonned by wet granulating the hydroxyalkylcellulose/opioid agonist/opioid antagonist with water.
- the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the opioid.
- a spheronizing agent together with the active ingredient can be spheronized to fomi spheroids.
- Microcrystalline cellulose is preferred.
- a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (Trade Mark, FMC Co ⁇ oration).
- the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxypropylcellulose,
- the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymei, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose
- the sustained release coating will generally include a hydiophobic material such as (a) a wax, either alone oi in admixture with a fatty alcohol, or (b) shellac or zein
- Sustained release matrices can also be prepared via melt-granulation or melt-extrusion techniques
- melt-granulation techniques involve melting a normally solid hydrophobic material, e g a wax, and mco ⁇ oratmg a powdered drug therein
- a sustained release dosage form it may be necessary to inco ⁇ orate an additional hydrophobic substance, e g ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic material
- an additional hydrophobic substance e g ethylcellulose or a water-insoluble acrylic polymer
- the additional hydrophobic material may comprise one or more water-insoluble waxlike thermoplastic substances possibly mixed with one or more wax-like thennoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances
- the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases
- Useful water-insoluble wax-like substances may be those with a water-solubility that is lower than about 1 5,000 (w/w)
- a sustained release matrix may also contain suitable quantities of other materials, e g , diluents, lubricants, binders, granulating aids, colorants, flavorants and ghdants that are conventional in the pharmaceutical art The quantities of these additional materials will be sufficient to provide the desned effect to the desired formulation
- a sustained release matrix inco ⁇ orating melt-extruded multiparticulates may also contain suitable quantities of other materials, e g diluents, lubricants, binders, granulating aids, colorants, flavoiants and ghdants that are conventional m the pharmaceutical art in amounts up to about 50%o by weight of the particulate if desired
- the preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the opioid agonist, opioid antagonist, together with at least one hydrophobic material and preferably the additional hydrophobic material to obtain a homogeneous mixture.
- the homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same.
- the resulting homogeneous mixture is then extruded to form strands.
- the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
- the strands are cooled and cut into multiparticulates.
- the extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the opioid agonist and antagonist for a time period of from about 8 to about 24 hours.
- An optional process for preparing the melt extrusions of the present invention includes directly metering into an extruder a hydrophobic material, the opioid agonist and antagonist, and an optional binder; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm.
- a relatively continuous manufacturing procedure is realized.
- the diameter of the extruder aperture or exit port can also be adjusted to vary the thickness of the extruded strands.
- the exit part of the extruder need not be round; it can be oblong, rectangular, etc.
- the exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc.
- melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice.
- melt-extruded multiparticulate(s) and “melt-extruded multiparticulate system(s)” and “melt-extruded particles” shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic material as described
- melt-extruded multiparticulates will be of a range of fiom about 0 1 to about 12 mm in length and e a diameter of from about 0 1 to about 5 mm
- melt-extruded multiparticulates can be an> geometrical shape within this size range
- the extrudate may simply be cut into desned lengths and divided into unit doses of the therapeutically active agent without the need of a spheromzation step
- oral dosage fomis are prepaied to include an effective amount of melt-extruded multiparticulates ithin a capsule
- a pluiahty of the melt-extruded multiparticulates may be placed in a gelatin capsule m an amount sufficient to provide an effective sustained release dose when ingested and contacted b> gastric fluid
- a suitable amount of the multiparticulate extuidate is combined with the coated opioid antagonist particles and compressed into an oral tablet using conventional tabletmg equipment using standard techniques Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, (Arthur Osol, editor), 1553-1593 (1980), inco ⁇ orated by reference herein
- the extrudate can be shaped into tablets as set forth in U S Patent No 4,957,681 (Khmesch, et al ), described in additional detail above and hereby inco ⁇ orated by reference
- the sustained release melt-extruded multiparticulate systems or tablets can be coated, or the gelatin capsule can be furthei coated, with a sustained release coating such as the sustained release coatings described above
- a sustained release coating such as the sustained release coatings described above
- Such coatings piefeiably include a sufficient amount of hydrophobic material to obtain a weight gain level from about 2 to about 30 percent, although the overcoat may be greater depending upon the physical properties of the particular opioid analgesic compound utilized and the desired release rate, among other things
- the melt-extruded unit dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more of the therapeutically active agents disclosed above before being encapsulated Furthennoie, the unit dosage forms can also include an amount of an immediate lelease opioid agonist for piompt theiapeutic effect
- the immediate release opioid agonist may be inco ⁇ orated, e g , as separate pellets within a gelatin capsule, or may be coated on the suiface of the multiparticulates aftei preparation of the dosage forms (e g , controlled release coating or matrix-based)
- the unit dosage forms of the present invention may also contain a combination of controlled release beads and matrix multiparticulates to achieve a desired effect
- the sustained release formulations of the present invention preferably slowly release the opioid agonist, e g , when ingested and exposed to gastric fluids, and then to intestinal fluids
- the sustained release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of retardant, I e , hydrophobic mateiial, by varying the amount of plasticizer relative to hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc
- the melt extruded mate ⁇ al is piepaied without the inclusion of the opioid agonist and/or coated opioid antagonist particles, which aie added thereafter to the extrudate
- Such formulations typically will have the drugs blended together with the extruded matrix material, and then the mixture would be tableted m order to provide a slow release of the opioid agonist
- Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to tempeiatures needed for softening the hydrophobic material and/ or the retardant material
- the opioid antagonist is present as granulates conip ⁇ smg the opioid antagonist dispersed in a first controlled release matrix
- the opioid agonist is present as granulates comprising the opioid agonist dispersed in a second controlled-release matrix, the first controlled-release matrix providing controlled-release of the opioid antagonist and the second matrix providing controlled-release of the opioid agonist
- the first and second matrices cause the opioid agonist and the opioid antagonist to be released at substantially the same rate
- the opioid antagonist is prepared as granulates comprising the antagonist dispersed m a controlled-release matrix, said granulates being combined with the opioid agonist and a further controlled release material, such that the opioid antagonist and opioid agomst are preferably released at substantially the same rate
- the oral dosage form of the present invention may further include, in addition to an opioid agonist and antagonist, one or more drugs that may or may not act synergistically therewith.
- a combination of two opioid agonists may be included in the dosage form, in addition to the opioid antagonist.
- the dosage form may include two opioid agonist having different properties, such as half-life, solubility, potency, and a combination of any of the foregoing.
- one or more opioid agonist is included and a further non-opioid drug is also included, in addition to the opioid antagonist.
- non-opioid drags would preferably provide additional analgesia, and include, for example, aspirin, acetaminophen; non-steroidal anti-inflammatory drugs ("NSAIDS"), e.g., ibuprofen, ketoprofen, etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a mo ⁇ hinan such as dextrometho ⁇ han or dextro ⁇ han, or ketamine; cycooxygenase-II inhibitors ("COX-II inhibitors"); and/or glycine receptor antagonists.
- NAIDS non-steroidal anti-inflammatory drugs
- NMDA N-methyl-D-aspartate
- COX-II inhibitors cycooxygenase-II inhibitors
- the invention allows for the use of lower doses of the opioid analgesic by virtue of the inclusion of an additional non- opioid agonist, such as an NSAID or a COX-2 inhibitor.
- an additional non- opioid agonist such as an NSAID or a COX-2 inhibitor.
- Suitable non-steroidal anti-inflammatory agents including ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piro- profen, ca ⁇ rofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, pir
- N-methyl-D-aspartate (NMDA) receptor antagonists are well known in the art, and encompass, for example, mo ⁇ hinans such as dextrometho ⁇ han or dextro ⁇ han, ketamine, d- methadone or pharmaceutically acceptable salts thereof.
- NMDA antagonist is also deemed to encompass drugs that block a major intracellular consequence of NMDA-receptor activation, e.g.
- a ganglioside such as GM, or GT lb a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N- (6-aminothexyl)-5-chloro-l-naphthalenesulfonamide.
- addictive drugs e.g., narcotic analgesics such as mo ⁇ hine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838 (both to Mayer, et al), and to treat chronic pain in U.S. Pat. No.
- NMDA antagonist may be included alone, or in combination with a local anesthetic such as lidocaine, as described in these Mayer, et.al. patents.
- COX-2 inhibitors have been reported in the art and many chemical structures are known to produce inhibition of cyclooxygenase-2. COX-2 inhibitors are described, for example, in U.S. Patent Nos. 5,616,601 ; 5,604,260; 5,593,994; 5,550,142; 5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422; 5,510,368; 5,436,265; 5,409,944; and 5,130,311, all of which are hereby inco ⁇ orated by reference.
- COX-2 inhibitors include celecoxib (SC-58635), DUP-697, flosulide (CGP-28238), meloxicam, 6- methoxy-2 naphthylacetic acid (6-MNA), MK-966 (also known as Vioxx), nabumetone (prodrag for 6-MNA), nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations thereof.
- Dosage levels of COX-2 inhibitor on the order of from about 0.005 mg to about 140 mg per kilogram of body weight per day are therapeutically effective in combination with an opioid analgesic.
- about 0.25 mg to about 7 g per patient per day of a COX-2 inhibitor is administered in combination with an opioid analgesic.
- a non-opioid drag can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drugs, local anesthetics, and the like.
- the controlled release oral dosage fonn comprises an opioid agonist and an opioid antagonist m combination with acetominophen
- Acetaminophen is an analgesic/antipyretic drug which has been utilized for treating mild to moderate pam such as headache, neuralgia, and musculoskeletal pam
- the recommended daily adult dose is about 325 to about 650 mg every 4 hours, not to exceed a total dose of 4 g in 24 hours
- the maximum dose of immediate release acetaminophen is generally considered to be about 1000 mg
- the combination fomiulations and methods of the piesent invention may include such acetaminophen doses as those set forth abo ⁇ e, or lower doses pei 4 hour dosmg interval
- controlled release formulations prepared m accordance with the present invention include a greater total acetominophen dose than the 325 - 650 mg dose, but that dose will be released in a controlled-release manner over a longer dosmg interval (e g , over 8 hours or more)
- acetaminophen and opioid agonist in the formulations and method of the present invention may be similar or the same as dosages which are already commercially available and accepted by clinicians
- Acetaminophen is commercially available in the United States in fixed combination with opioid agonists , namely, codeine, oxycodone and hydrocodone
- Typical oral capsule dosages of acetaminophen codeine combinations include 325 mg acetaminophen and 15 mg codeine phosphate, 325 mg acetaminophen and 30 mg codeine phosphate and 325 mg acetaminophen and 60 mg codeine phosphate
- Tablets typically include 300 mg acetaminophen and 7 5 mg codeine phosphate, 300 mg acetaminophen and 15 mg codeine phosphate, 300 mg acetaminophen and 30 mg codeine phosphate, and 300 mg acetaminophen and 60 mg codeine phosphate
- Hydrocodone/acetammophen capsules are typically available in fixed combinations of 5 mg hydrocodone (as the bitartrate salt) and 500 mg acetaminophen
- Hydrocodone/acetammophen tablets are typically available m fixed combinations of 500 mg acetaminophen and 2 5 mg hydrocodone bitartrate, 500 mg acetaminophen and 5 mg
- Oxycodone/acetaminophen capsules and caplets are available in fixed combination of 5 mg oxycodone (as the hydrochloride salt) and 500 mg acetaminophen, and in tablets as 5 mg oxycodone hydrochloride and 325 mg acetaminophen.
- the opioid agonist/opioid antagonist/acetaminophen combinations encompassed herein will have greater or lesser dosages of either the opioid agonist or acetaminophen, and that the ratio of opioid agonist to acetaminophen will vary based on the particular opioid agonist and opioid antagonist chosen for a formulation and the amount of opioid antagonist included therein, among other things.
- the oral dosage fomi comprises an opioid agonist (hydrocodone or oxycodone) and opioid antagonist (naltrexone, naloxone and nalmefene) and acetaminophen.
- a non-opioid drug can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drags, local anesthetics, and the like.
- the objective of this Example is to prepare a controlled release naltrexone bead (antagonist) to be inco ⁇ orated into controlled release opioid products (agonist).
- NXCR Naltrexone controlled release bead
- MSCR Mo ⁇ hine sulfate controlled release beads
- Apparatus- USP Type II (paddle), 50 ⁇ m at 37°C.
- the NXCR beads were found to have the following dissolution results:
- the MSCR beads were found to have the following dissolution results-
- Naltrexone controlled release pellets are developed which can be incoiporated into hard gelatin capsules containing other opioid controlled release pellets.
- Hydromo ⁇ hone HCl controlled release pellets (HHCR) are fomiulated as an example to be mixed with Naltrexone CR pellets and the mixture is encapsulated.
- Controlled release tablets containing an opioid agonist (oxycodone HCl) and opioid antagonist (naltrexone HCl) are prepared in which both drags are present as granulates, the granulates comprising the opioid agonist and the antagonist dispersed in a controlled release matrix.
- the granulates are combined with melted wax (stearyl alcohol) to produce waxed
- Naltrexone HCl into the plasticized solution.
- Granulation Place Oxycodone HCl, Spray Dried Lactose, and Povidone into a fluid bed granulator and apply the above solution.
- Milling Pass the granulation through a rotating impeller mill.
- Cooling Cool the waxed granulation in a fluid bed dryer.
- Milling Pass the cooled waxed granulation through a rotating impeller mill.
- Blending Blend the milled waxed granulation, Talc and Magnesium
- Compression Compress the resultant granulation using a tablet press.
- Controlled release tablets containing an opioid agonist (mo ⁇ hine sulfate) and opioid antagonist (naltrexone HCl) are prepared.
- the controlled release tablets comprise granulates comprising the opioid agonist and the antagonist dispersed in a controlled-release matrix.
- the granulates are combined with melted wax (cetostearyl alcohol) to produce waxed granulates, which are then milled and mixed with other excipients and compressed into tablets.
- Compression Compress the resultant granulation using a tablet press.
- Controlled-release capsules containing an opioid agonist (hydromo ⁇ hone HCl) and opioid antagonist (naltrexone ) are prepared.
- Extruded drag-containing pellets are prepared by combining a wax with ethylcellulose and Eudragit and feeding the mixture into a twin screw extruder. The pellets are then filled into hard gelatin capsules.
- Pelletizing Cut the cooled strands into pellets using a Pelletizer.
- Controlled-release tablets containing an opioid agonist (hydrocodone bitartrate) and opioid antagonist (naltrexone HCl) are prepared.
- the tablets contain the drugs in the fonn of extruded pellets.
- Blending Blend the milled extrudate and Magnesium Stearate.
- Compression Compress the resultant granulation using a tablet press.
- Controlled release tablets containing an opioid agonist (mo ⁇ hine sulfate) and opioid antagonist (naltrexone HCl) are prepared.
- opioid antagonist is treated with a controlled-release carrier (Eudragit RS 30D) to modify its release rate before it is combined with the opioid agonist and fonnulated into a controlled-release tablet.
- Pre-Granulation Pre-granulate the Naltrexone HCl in a fluid bed granulator by applying the above solution.
- Milling Pass the granulation through a mill.
- Cooling Cool the waxed granulation in a fluid bed dryer.
- Milling Pass the cooled waxed granulation through a mill. 10. Blending Blend the milled waxed granulation, Talc and Magnesium
- Compression Compress the resultant granulation using a tablet press.
- a transdermal patch is prepared in accordance with the disclosure of WO 96/19975 for Example 1 therein as follows, with the modification that a requisite amount of naltrexone is included: 1.139 g of a 47.83 w/% polyacrylate solution with a selfnetting acrylate copolymers containing 2-ethylhexylacrylates, vinyl acetates, acrylic acid (dissolving agent:ethylacetate:heptan:isopropanol:toluol:acetylacetonate in the ratio of 37:26:26:4:1), 100 g laevulinic acid, 150 g oleyloleate, 100 g polyvinylpyrollidone, 150 g ethanol, 200 g ethyl acetate and 100 g bupreno ⁇ hine base and 1 g naltrexone are homogenized.
- the mixture is stirred for about 2 hours and then examined visually to detennine if all solid substances have been dissolved.
- the mixture is put onto a 420 mm wide, transparent polyester foil, since the surface weight of the dried layer of paste is 80 g per m.sup.2.
- the polyester foil which can be dissolved again with treatment of silicone serves as a protective layer.
- the solvent is removed by drying with heated air which is led over a moist lane. With this treatment of warmth not only do solvents evaporate but the the laevulinic acid melts as well.
- the sealing film is covered with a polyester foil 15 .mu.ab. A surface of about 16 cm 2 is cut with the help of the appropriate cutting tool, and the rims that have been left between the individual systems are removed.
- Example 8 The fonnulation utilized for Example 8 is substantially the same as that described in Example 3 of WO 96/19975, which is prepared in accordance with Example 8 and is stated therein to include 10% bupreno ⁇ hine (with a proportional amount of naltrexone as set forth in Example above), 10%) levulinic acid, 10% polyvinylpyrollidone, 10% oleyloeate, the remainder comprising polyacrylate.
- the total of bupreno ⁇ hine included in the transdennal patch is about 10 mg
- the active surface area is about 12.5 cm 2
- the patch size may be, e.g., about 30.6 cm 2 .
- the dosing regimen was one (1) patch containing 10 mg bupreno ⁇ hine base and O.lmg naltrexone /patch reservoir applied to the subject's skin and maintained in contact with the skin for a time period of seven (7) days.
- active agent 10 parts (consisting of hydromo ⁇ hone and naltrexone in a 10:1 ratio); DC-360 polysiloxane medical fluid (20 cps), 10 parts; silicone (medical-grade) 382 elastomer, 80 parts; catalyst M, 20 drops per 100 g. of the mixture.
- the active agent is thoroughly dispersed in the 80 parts of Silastic medical-grade 382 elastomer by using a high torque mixer (sold by Cole-Parmer Company) at about 1000 RPM.
- the medicated polymer sheet is removed from the device maker and is cut into circular discs of about 3-20 sq cm
- the discs are attached to a backing layer of heat sealable polyester film which is laminated to aluminum foil This laminate is sold by 3M Company as Scotchpak 1006
- the medicated discs are attached using an adhesive polymei solution, which is a silicone adhesive polymer sold by Dow Coming as DC-355 Alternately, the discs can be fonned directly on the backing layer
- the skm permeation enhancei -adhesive film is made using the following ingredients skm permeation enhancer, 6 5 parts, acetone 30 parts, and adhesive polymer solution, 100 parts
- the skm permeation enhancer-adhesive layer is made by dissolving the 6 5 parts by weight of a skin permeation enhancer in 30 parts of acetone
- the acetone solution then is added to 100 parts of a silicone adhesive solution sold by Dow-Commg undei the designation DC-355
- the mixture is thoroughly mixed to form a homogeneous mixture of skm permeation enhancer and adhesive polymer, which is applied to a strip of a release liner which is a sihconized, or a Teflon-coated polyester film to permit easy removal of the release liner just prior to application of the final polymer niat ⁇ x disc dosage unit to the subject to be transdennally treated
- the adhesive mixture is applied at a controlled thickness
- the fonned layer has a thickness of about 50-200 microns
- the layer is d ⁇ ed completely in ⁇ acuum to remove volatile matter
- the skin permeation enhancer-adhesive polymer layer with release liner is applied onto the active agent-containing polymer matrix disc with the attached backing layei undei a constant pressure to provide a firmly adhered strip of a four-layeied structuie as follows
- the strip is cut to provide the transdennal polymer matrix dosage units which are circular in shape and have an area of about 10 sq. cm.
- the above polymer matrix disc dosage units are made using the following skin permeation enhancers: 1 -dodecylazacycloheptan-2-one (sold under the trademark Azone), propyl myristate and propyl oleate.
- transdermal abso ⁇ tion of the active agent from the polymer matrix dosage units of this invention is evaluated by using a skin specimen from a "hairless" mouse or human cadaver by following the procedure described by P. R. Keshary and Y. W. Cliien, in Drug Develop. & Ind. Pharm., 10 (6) 883-913 (1984).
- Oral mucosal patches are prepared by homogeneously mixing bupreno ⁇ hine free base and naltrexone (8%>, in a 20: 1 ratio), Carbopol 934 (52%>), polyisobutylene (35%>) and polyisoprene (5%>, w/w) via a two-roll mill and then compressing the mixture to the appropriate thickness.
- a membrane backing ethylcellulose
- circular disks 0.5 cm 2
- the backing is included in order to retard drug release from one side of the disk and to prohibit adhesion to opposing side tissues.
- Each soft, flexible disk is approximately 0.6 mm thick and contains approximately 3 mg bupreno ⁇ hine and an appropriate amount of naltrexone.
- the patches are suitable for gum and lip application.
- Novata-B is a mixture of mono-, di- and triglycerides based on saturated natural fatty acids of the chain lengths C I2 to C lg , with a specific melting range (33.4 degrees C-25.5 degrees C).
- the suppositories were prepared according to the following method: mo ⁇ hine sulphate powder, naltrexone HCL powder, sodium alginate and calcium phosphate were all passed through a #200 sieve, individually. All three powders were intimately mixed in a suitable mixing apparatus. Novata B was melted in a stainless steel pot, keeping the temperature below 60 degrees C.
- the mixed powder was then added to the completely melted wax (around 50 degrees C) with constant stirring.
- the temperature was then cooled slowly to 40 degrees C and kept constant at that temperature.
- the uniform suspension was then transferred to a automated suppository filing kettle, and continuously stirred at 38 degrees C.
- the suppository shells were filled to the suggested fill weight at a temperature of about 37 degrees C (e.g., between 36 degrees-38 degrees C). The suppositories were allowed to cool, then sealed.
- Example 15 a bioadhesive powder formulation of mo ⁇ h ⁇ ne-6-glucuromde and naltrexone is prepared using microspheres of cross-linked starch
- the microspheies aie prepared by the method described in EP 223302
- a preferred size of microspheres is 1-100 ⁇ m
- the formulation may be prepared by dissolving 75mg of the agonist and a sufficient amount of naltrexone in 30 ml water and mixed with 1 g of starch microspheres
- the product is freeze-dned to produce a free flowing powder
- the powder can be administered to the nasal cavity using an insufflator device
- Example 16 the bioadhesive microsphere system disclosed in Example 15 are prepared but in addition an abso ⁇ tion enhancing agent is employed.
- a preferred matenal is lysophosphatidyl glycerol (LPG) 100 mg LPG is added to the suspension of the mo ⁇ hme metabolite and microspheres
- Example 17 a liquid fomiulation is prepared with added abso ⁇ tion enhancing agent as follows 150 mg of mo ⁇ hme-6-glucuron ⁇ de and a sufficient amount of naltrexone are dissolved in 10 ml of a 0 5%o solution of medium viscosity grade of Chitosan (80% degiee of deacetylation, Protan Limited)
- the substituted cyclodext ⁇ n material dimethyl- beta - cyclodext ⁇ n (Sigma Chemical Comp) is added to provide a concentration of 5%
- the liquid formulation can be administered using a conventional pump spray device
- Example 18 the formulation disclosed in Example 17 is prepared but in the place of the dimethyl-beta-cyclodext ⁇ n, alpha-cyclodextrm (Sigma Chemical Co ) at the same concentration of 50 mg/ml is added
- Example 19 the microsphere fomiulation described in Example 16 is prepared but instead of the enhancing agent, a chelating agent in the fonn of EDTA is employed. 50 mg of EDTA is added to the suspension of nio ⁇ hine metabolite and niicrospheres. The product is freeze dried as detailed in Example 15.
- bupreno ⁇ hine/naltrexone microspheres are prepared by dissolving the agents and the polymer in ethyl acetate.
- the polymer is 50:50 poly (D,L) lactic co- glycolic acid which has a mole percent composition of 50%) lactide and 50%o glycolide.
- This dispersed phase is then added to a solution of polyvinyl alcohol (PVA) in water (the continuous phase) with stirring.
- PVA polyvinyl alcohol
- the resulting emulsion is monitored for droplet size, which is in turn controlled by the rate of stirring.
- the emulsion is then added to water to extract the solvent and to harden the microspheres.
- the mixture is then filtered and the niicrospheres are dried under vacuum at room temperature.
- the desired particle size fraction is then collected by sieving.
- the microspheres are then suspended in a suitable media for injection such as water.
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SI200130879T SI1255547T1 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
JP2001557557A JP2003522144A (en) | 2000-02-08 | 2001-02-08 | Controlled release compositions comprising opioid agonists and antagonists |
KR1020027010121A KR20020071032A (en) | 2000-02-08 | 2001-02-08 | Controlled-release composition containing opioid agonist and antagonist |
IL15105801A IL151058A0 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
DE60135441T DE60135441D1 (en) | 2000-02-08 | 2001-02-08 | COMPOSITIONS WITH CONTROLLED RELEASE CONTAINING AN OPIOID AGONIST AND ANTAGONIST |
AU36877/01A AU776904B2 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
BR0108379-1A BR0108379A (en) | 2000-02-08 | 2001-02-08 | Controlled release compositions containing opioid agonist and antagonist, method for preparing a controlled release opioid analgesic formulation with increased analgesic potency and delivery system through the dermis for an opioid analgesic |
EP01909087A EP1255547B1 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
MXPA02007690A MXPA02007690A (en) | 2000-02-08 | 2001-02-08 | Controlled release compositions containing opioid agonist and antagonist. |
CA002400578A CA2400578C (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
HU0204163A HUP0204163A2 (en) | 2000-02-08 | 2001-02-08 | Controlled-release composition containing opioid agonist and antagonist and process for its preparation |
EA200200839A EA200200839A1 (en) | 2000-02-08 | 2001-02-08 | COMPOSITIONS WITH CONTROLLED GRIPBACK, CONTAINING AN AGONIST AND ANTAGONIST OF OPIOIDS |
DK01909087T DK1255547T3 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
NO20023729A NO20023729L (en) | 2000-02-08 | 2002-08-07 | Controlled release preparations containing opioid agonist and antagonist |
HK03102267.9A HK1051487A1 (en) | 2000-02-08 | 2003-03-28 | Controlled-release compositions containing opioid agonist and antagonist |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18136900P | 2000-02-08 | 2000-02-08 | |
US60/181,369 | 2000-02-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001058447A1 true WO2001058447A1 (en) | 2001-08-16 |
Family
ID=22663996
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/004346 WO2001058451A1 (en) | 2000-02-08 | 2001-02-08 | Tamper-resistant oral opioid agonist formulations |
PCT/US2001/004347 WO2001058447A1 (en) | 2000-02-08 | 2001-02-08 | Controlled-release compositions containing opioid agonist and antagonist |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2001/004346 WO2001058451A1 (en) | 2000-02-08 | 2001-02-08 | Tamper-resistant oral opioid agonist formulations |
Country Status (35)
Country | Link |
---|---|
US (15) | US6696088B2 (en) |
EP (6) | EP2283842B1 (en) |
JP (10) | JP2003522146A (en) |
KR (2) | KR20020071032A (en) |
CN (3) | CN1423559A (en) |
AP (1) | AP1665A (en) |
AT (1) | ATE431145T1 (en) |
AU (2) | AU776904B2 (en) |
BG (1) | BG65828B1 (en) |
BR (2) | BR0108379A (en) |
CA (1) | CA2400567C (en) |
CY (2) | CY1109270T1 (en) |
CZ (1) | CZ299991B6 (en) |
DE (1) | DE60138706D1 (en) |
DK (5) | DK2517710T3 (en) |
EA (1) | EA004876B1 (en) |
EE (1) | EE05171B1 (en) |
ES (5) | ES2540103T3 (en) |
GE (1) | GEP20053614B (en) |
HK (3) | HK1051487A1 (en) |
HU (2) | HU229705B1 (en) |
IL (5) | IL151057A0 (en) |
ME (1) | ME00398B (en) |
MX (2) | MXPA02007686A (en) |
NO (2) | NO324717B1 (en) |
NZ (1) | NZ520554A (en) |
OA (1) | OA12215A (en) |
PL (1) | PL210845B1 (en) |
PT (6) | PT2283842E (en) |
RS (1) | RS50407B (en) |
SI (5) | SI1299104T1 (en) |
SK (1) | SK287107B6 (en) |
TW (1) | TWI292317B (en) |
UA (1) | UA79069C2 (en) |
WO (2) | WO2001058451A1 (en) |
Cited By (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002092060A1 (en) * | 2001-05-11 | 2002-11-21 | Endo Pharmaceuticals, Inc. | Abuse-resistant controlled-release opioid dosage form |
WO2002092059A1 (en) * | 2001-05-11 | 2002-11-21 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
WO2003013433A2 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Sequestered antagonist formulations |
WO2003070191A2 (en) * | 2002-02-19 | 2003-08-28 | Euro-Celtique, S.A. | Tamper-resistant transdermal opioid delivery devices |
WO2003080183A1 (en) * | 2002-03-19 | 2003-10-02 | Euro-Celtique S.A. | Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids |
WO2004004693A1 (en) | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
WO2004006929A1 (en) * | 2002-07-11 | 2004-01-22 | Taiho Pharmaceutical Co., Ltd. | Composition for nasal absorption |
DE10237056A1 (en) * | 2002-08-09 | 2004-03-04 | Grünenthal GmbH | Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential |
WO2004052346A1 (en) * | 2002-12-05 | 2004-06-24 | Eurand, Inc. | Pharmaceutical compositions containing indistinguishable drug components |
EP1444977A1 (en) * | 2003-02-07 | 2004-08-11 | Novosis AG | Transdermal therapeutic delivery system with a butenolide |
WO2005000310A1 (en) * | 2003-06-27 | 2005-01-06 | Euro-Celtique S.A. | Multiparticulates |
JP2005506351A (en) * | 2001-10-18 | 2005-03-03 | ネクター セラピューティックス エイエル,コーポレイション | Polymer conjugate opioid antagonist |
WO2005037318A2 (en) * | 2003-10-15 | 2005-04-28 | Pain Therapeutics, Inc. | Treatment of arthritic conditions, chronic inflammation or pain |
EP1542658A1 (en) * | 2002-08-15 | 2005-06-22 | Euro-Celtique S.A. | Pharmaceutical compositions |
EP1551372A1 (en) * | 2002-09-20 | 2005-07-13 | Alpharma, Inc. | Sequestering subunit and related compositions and metohds |
JP2005526094A (en) * | 2002-03-19 | 2005-09-02 | イオニクス ファーマシューティカルズ リミテッド | Formulation |
WO2005107726A2 (en) * | 2004-04-27 | 2005-11-17 | Pain Therapeutics, Inc. | Method for the treatment of back pain |
EP1615615A2 (en) * | 2003-04-21 | 2006-01-18 | Euro-Celtique S.A. | Pharmaceutical products |
WO2006024881A2 (en) * | 2004-08-31 | 2006-03-09 | Euro-Celtique S.A. | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
JP2006508021A (en) * | 2002-03-26 | 2006-03-09 | ユーロ−セルティーク エス.エイ. | Sustained release gel coating composition |
EP1639997A1 (en) * | 2002-04-05 | 2006-03-29 | Euro-Celtique S.A. | Matrix for sustained, invariant and independant release of active compounds |
US20060177381A1 (en) * | 2002-02-15 | 2006-08-10 | Howard Brooks-Korn | Opiopathies |
JP2006524261A (en) * | 2003-04-21 | 2006-10-26 | ユーロ−セルティーク エス.エイ. | Anti-modified dosage form containing coextrusion adverse agent particles and process for producing the same |
EP1718258A2 (en) * | 2004-02-23 | 2006-11-08 | Euro-Celtique S.A. | Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheres |
WO2006124890A1 (en) * | 2005-05-13 | 2006-11-23 | Alpharma, Inc. | Morphine sulphate formulations |
WO2006124898A1 (en) * | 2005-05-13 | 2006-11-23 | Alpharma, Inc. | Morphine sulfate formulations |
WO2007016563A2 (en) * | 2005-08-01 | 2007-02-08 | Alpharma Inc. | Alcohol resistant pharmaceutical formulations |
EP1771160A2 (en) * | 2005-01-28 | 2007-04-11 | Euroceltique S.A. | Alcohol resistant dosage forms |
WO2007070632A2 (en) * | 2005-12-13 | 2007-06-21 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
EP1810678A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of morphine and naloxone for drug substitution |
EP1810714A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of a combination of heroin and naloxon for drug substitution |
WO2008011595A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophobic abuse deterrent delivery system |
WO2008011194A2 (en) * | 2006-07-21 | 2008-01-24 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
WO2008063301A2 (en) * | 2006-10-11 | 2008-05-29 | Alpharma, Inc. | Pharmaceutical compositions |
GB2447014A (en) * | 2007-03-01 | 2008-09-03 | Reckitt Benckiser Healthcare | Analgesic composition comprising a specific ratio of buprenorphine and naltrexone |
WO2008109462A2 (en) * | 2007-03-02 | 2008-09-12 | Farnam Companies, Inc. | Sustained release pellets comprising wax-like material |
WO2009106831A2 (en) * | 2008-02-28 | 2009-09-03 | Syntropharma Limited | Pharmaceutical composition |
US7682634B2 (en) | 2006-06-19 | 2010-03-23 | Alpharma Pharmaceuticals, Llc | Pharmaceutical compositions |
US7771707B2 (en) | 2004-06-12 | 2010-08-10 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
EP2319540A1 (en) * | 2002-02-22 | 2011-05-11 | Shire LLC | Sustained release pharmaceutical compounds to prevent abuse of controlled substances |
WO2011112956A1 (en) * | 2010-03-12 | 2011-09-15 | Government Of The Usa, As Represented By The Sec., Dept. Of Health And Human Services | Agonist/antagonist compositions and methods of use |
WO2010121600A3 (en) * | 2009-04-22 | 2011-10-27 | Lars Holger Hermann | Particulate pharmaceutical composition having an opioid and an opioid antagonist |
WO2011141490A1 (en) * | 2010-05-10 | 2011-11-17 | Euro-Celtique S.A. | Combination of active loaded granules with additional actives |
EP2448406A1 (en) * | 2009-02-26 | 2012-05-09 | Relmada Therapeutics, Inc. | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
WO2012089738A1 (en) * | 2010-12-28 | 2012-07-05 | Euro-Celtique S.A. | A combination of an opioid agonist and an opioid antagonist in the treatment of parkinson's disease |
WO2012052169A3 (en) * | 2010-10-21 | 2012-07-26 | Phoeme Gmbh | Particulate pharmaceutical composition containing an opioid and an opioid antagonist |
US8309122B2 (en) | 2001-07-06 | 2012-11-13 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US8389007B2 (en) | 2001-08-06 | 2013-03-05 | Purdue Pharma L.P. | Pharmaceutical composition containing gelling agent |
WO2013096811A2 (en) | 2011-12-21 | 2013-06-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
US8557291B2 (en) | 2002-07-05 | 2013-10-15 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
WO2013153145A1 (en) * | 2012-04-12 | 2013-10-17 | Lts Lohmann Therapie-Systeme Ag | Oral film containing opiate enteric-release beads |
US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
US8623412B2 (en) | 2002-09-23 | 2014-01-07 | Elan Pharma International Limited | Abuse-resistant pharmaceutical compositions |
AU2011205222B2 (en) * | 2006-07-21 | 2014-02-27 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
US8679533B2 (en) | 2002-07-25 | 2014-03-25 | Pharmacia Corporation | Pramipexole once-daily dosage form |
US8840928B2 (en) | 2002-07-05 | 2014-09-23 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US8889176B2 (en) | 2003-01-10 | 2014-11-18 | Depomed, Inc. | Method of managing or treating pain |
US8920836B2 (en) | 2004-02-12 | 2014-12-30 | Euro-Celtique S.A. | Particulates |
US8969371B1 (en) | 2013-12-06 | 2015-03-03 | Orexigen Therapeutics, Inc. | Compositions and methods for weight loss in at risk patient populations |
US9107837B2 (en) | 2006-06-05 | 2015-08-18 | Orexigen Therapeutics, Inc. | Sustained release formulation of naltrexone |
US9125868B2 (en) | 2006-11-09 | 2015-09-08 | Orexigen Therapeutics, Inc. | Methods for administering weight loss medications |
US9149533B2 (en) | 2013-02-05 | 2015-10-06 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9211253B2 (en) | 2014-03-14 | 2015-12-15 | Lightlake Therapeutics Inc. | Nasal drug products and methods of their use |
USRE45822E1 (en) | 2001-08-06 | 2015-12-22 | Purdue Pharma L.P. | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US9233073B2 (en) | 2010-12-23 | 2016-01-12 | Purdue Pharma L.P. | Tamper resistant solid oral dosage forms |
US9248123B2 (en) | 2010-01-11 | 2016-02-02 | Orexigen Therapeutics, Inc. | Methods of providing weight loss therapy in patients with major depression |
US9271940B2 (en) | 2009-03-10 | 2016-03-01 | Purdue Pharma L.P. | Immediate release pharmaceutical compositions comprising oxycodone and naloxone |
US9308202B2 (en) | 2006-11-21 | 2016-04-12 | Purdue Pharma L.P. | Transdermal therapeutic system for administering the active substance buprenorphine |
US9393206B2 (en) | 2010-12-22 | 2016-07-19 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
WO2016124788A1 (en) | 2015-02-06 | 2016-08-11 | Jacques Seguin | Pharmaceutical composition and device for treating pain |
US9457005B2 (en) | 2005-11-22 | 2016-10-04 | Orexigen Therapeutics, Inc. | Compositions and methods for increasing insulin sensitivity |
US9468747B2 (en) | 2014-03-14 | 2016-10-18 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
WO2016091805A3 (en) * | 2014-12-08 | 2016-12-15 | Develco Pharma Schweiz Ag | Naloxone monopreparation and multi-layer tablet |
US9549903B2 (en) | 2011-12-12 | 2017-01-24 | Purdue Pharma L.P. | Transdermal delivery system comprising buprenorphine |
US9561177B2 (en) | 2014-03-14 | 2017-02-07 | Adapt Pharma Limited | Nasal drug products and methods of their use |
WO2017044789A1 (en) * | 2015-09-09 | 2017-03-16 | Micell Technologies, Inc. | Biopharma application of micell technology |
US9616030B2 (en) | 2013-03-15 | 2017-04-11 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9633575B2 (en) | 2012-06-06 | 2017-04-25 | Orexigen Therapeutics, Inc. | Methods of treating overweight and obesity |
US9642801B2 (en) | 2008-10-30 | 2017-05-09 | Gruenenthal Gmbh | And potent tapentadol dosage forms |
EP3175846A1 (en) * | 2003-04-08 | 2017-06-07 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
US9700508B2 (en) | 2010-05-10 | 2017-07-11 | Euro-Celtique S.A. | Pharmaceutical compositions comprising hydromorphone and naloxone |
US9737530B1 (en) | 2016-06-23 | 2017-08-22 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
US9814679B2 (en) | 2009-06-05 | 2017-11-14 | Euro-Celtique S.A. | Tamper resistant dosage form comprising a matrix and melt-extruded particulates comprising a drug |
US9814710B2 (en) | 2013-11-13 | 2017-11-14 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
EP3177270A4 (en) * | 2014-08-07 | 2018-01-24 | Mucodel Pharma LLC | Chemically stable and oromucosally absorbable gel compositions of a pharmaceutical active agent in a multi-chambered delivery system |
US9901539B2 (en) | 2011-12-21 | 2018-02-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
US9993433B2 (en) | 2010-05-10 | 2018-06-12 | Euro-Celtique S.A. | Manufacturing of active-free granules and tablets comprising the same |
US10004729B2 (en) | 2002-07-05 | 2018-06-26 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
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 |
US10085937B2 (en) | 2014-03-14 | 2018-10-02 | Adapt Pharma Limited | Nasal drug products and methods of their use |
WO2018208241A1 (en) * | 2017-05-10 | 2018-11-15 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Formulation and optimization of controlled release tablets of morphine sulphate |
US10238647B2 (en) | 2003-04-29 | 2019-03-26 | Nalpropion Pharmaceuticals, Inc. | Compositions for affecting weight loss |
US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
US10493027B2 (en) | 2014-08-07 | 2019-12-03 | Mucodel Pharma Llc | Chemically stable compositions of a pharmaceutical active agent in a multi- chambered delivery system for mucosal delivery |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US10835488B2 (en) | 2016-06-16 | 2020-11-17 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
WO2021019506A1 (en) * | 2019-07-31 | 2021-02-04 | Vetagro International S.R.L. | Multiparticulate microparticle controlled release formulation comprising combination of amino acids and phytocompound |
US11077055B2 (en) | 2015-04-29 | 2021-08-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
EP3936112A1 (en) * | 2020-07-07 | 2022-01-12 | Occlugel | Hydrophilic degradable microspheres for delivering buprenorphine |
US11324741B2 (en) | 2008-05-30 | 2022-05-10 | Nalpropion Pharmaceuticals Llc | Methods for treating visceral fat conditions |
US11529345B2 (en) | 2013-06-04 | 2022-12-20 | Lts Lohmann Therapie-Systeme Ag | Buprenorphine transdermal delivery system |
Families Citing this family (227)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR9813826A (en) * | 1997-12-22 | 2000-10-10 | Euro Celtique Sa | Potential for abusive use of oral administration of analgesic opioids |
SI2266564T1 (en) | 1997-12-22 | 2013-07-31 | Euro-Celtique S.A. | Pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
US10179130B2 (en) | 1999-10-29 | 2019-01-15 | Purdue Pharma L.P. | Controlled release hydrocodone formulations |
CN102716101A (en) | 1999-10-29 | 2012-10-10 | 欧罗赛铁克股份有限公司 | Controlled release hydrocodone formulations |
SI1299104T1 (en) | 2000-02-08 | 2009-10-31 | Euro Celtique Sa | Tamper-resistant oral opioid agonist formulations |
EP2283829A1 (en) | 2000-10-30 | 2011-02-16 | Euro-Celtique S.A. | Controlled release hydrocodone formulations |
US7858118B2 (en) * | 2001-04-11 | 2010-12-28 | Galephar Pharmaceutical Research, Inc. | Extended release composition containing Tramadol |
US7968119B2 (en) * | 2001-06-26 | 2011-06-28 | Farrell John J | Tamper-proof narcotic delivery system |
DK1404331T3 (en) * | 2001-07-06 | 2008-01-28 | Penwest Pharmaceuticals Co | Sustained release formulations of oxymorphone |
SI1416842T1 (en) * | 2001-07-18 | 2009-06-30 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
US7842307B2 (en) * | 2001-08-06 | 2010-11-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling agent |
US7141250B2 (en) * | 2001-08-06 | 2006-11-28 | Euro-Celtique S.A. | Pharmaceutical formulation containing bittering agent |
DK1414451T3 (en) | 2001-08-06 | 2009-08-10 | Euro Celtique Sa | Opioid agonist formulations with release and sequenced antagonist |
US20150031718A1 (en) * | 2001-08-06 | 2015-01-29 | Purdue Pharma L.P. | Pharmaceutical Formulation Containing Opioid Agonist, Opioid Antagonist and Gelling Agent |
US7332182B2 (en) * | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
US7157103B2 (en) * | 2001-08-06 | 2007-01-02 | Euro-Celtique S.A. | Pharmaceutical formulation containing irritant |
US7144587B2 (en) * | 2001-08-06 | 2006-12-05 | Euro-Celtique S.A. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and bittering agent |
US20030049317A1 (en) * | 2001-08-30 | 2003-03-13 | Lindsay David R. | Method and composition for reducing the danger and preventing the abuse of controlled release pharmaceutical formulations |
US20030091635A1 (en) * | 2001-09-26 | 2003-05-15 | Baichwal Anand R. | Opioid formulations having reduced potential for abuse |
FR2830447B1 (en) * | 2001-10-09 | 2004-04-16 | Flamel Tech Sa | MICROPARTICULAR ORAL GALENIC FORM FOR DELAYED AND CONTROLLED RELEASE OF PHARMACEUTICAL ACTIVE INGREDIENTS |
US8101209B2 (en) * | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
EP1450824A4 (en) * | 2001-11-02 | 2005-09-28 | Elan Corp Plc | Pharmaceutical composition |
CN1652752A (en) | 2002-03-14 | 2005-08-10 | 欧罗赛铁克股份有限公司 | Naltrexone hydrochloride compositions |
WO2003084517A2 (en) * | 2002-04-09 | 2003-10-16 | Flamel Technologies | Oral suspension of amoxicillin capsules |
PT1492511E (en) | 2002-04-09 | 2009-04-09 | Flamel Tech Sa | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
US8440220B2 (en) | 2002-04-23 | 2013-05-14 | Durect Corporation | Transdermal analgesic systems with reduced abuse potential |
US20040156844A1 (en) * | 2002-05-22 | 2004-08-12 | Curtis Wright | Tamper resistant oral dosage form |
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
AU2003272601B2 (en) * | 2002-09-20 | 2009-05-07 | Alpharma Pharmaceuticals, Llc | Sustained-release opioid formulations and methods of use |
DE10250084A1 (en) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Dosage form protected against abuse |
WO2004041328A2 (en) | 2002-10-31 | 2004-05-21 | Euro-Celtique S.A. | Pharmaceutical identification |
US7524515B2 (en) | 2003-01-10 | 2009-04-28 | Mutual Pharmaceuticals, Inc. | Pharmaceutical safety dosage forms |
AR047936A1 (en) * | 2003-04-30 | 2006-03-15 | Purdue Pharma Ltd | MANIFULATION RESISTANT TRANSDERMIC DOSAGE FORM |
US8790689B2 (en) * | 2003-04-30 | 2014-07-29 | Purdue Pharma L.P. | Tamper resistant transdermal dosage form |
EP2112920B1 (en) | 2003-06-26 | 2018-07-25 | Intellipharmaceutics Corp. | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
US20060165790A1 (en) * | 2003-06-27 | 2006-07-27 | Malcolm Walden | Multiparticulates |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
US8075872B2 (en) * | 2003-08-06 | 2011-12-13 | Gruenenthal Gmbh | Abuse-proofed dosage form |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
NZ545202A (en) * | 2003-08-06 | 2010-03-26 | Gruenenthal Chemie | Abuse-proofed dosage form comprising opiods and a high molecular weight polyethylene oxide |
DE102004032051A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Process for the preparation of a secured against misuse, solid dosage form |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
AU2004277898B2 (en) * | 2003-09-25 | 2009-04-02 | Euro-Celtique S.A. | Pharmaceutical combinations of hydrocodone and naltrexone |
SI1663229T1 (en) * | 2003-09-25 | 2010-08-31 | Euro Celtique Sa | Pharmaceutical combinations of hydrocodone and naltrexone |
WO2005044243A2 (en) | 2003-10-30 | 2005-05-19 | Alza Corporation | Transdermal analgesic systems having reduced abuse potential |
US8883204B2 (en) * | 2003-12-09 | 2014-11-11 | Purdue Pharma L.P. | Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same |
CA2548834C (en) * | 2003-12-09 | 2009-08-11 | Euro-Celtique S.A. | Tamper resistant co-extruded dosage form containing an active agent and an adverse agent and process of making same |
PT1729730E (en) * | 2004-03-30 | 2009-04-06 | Euro Celtique Sa | Tamper resistant dosage form comprising an adsorbent and an adverse agent |
TWI483944B (en) * | 2004-03-30 | 2015-05-11 | Euro Celtique Sa | Oxycodone hydrochloride composition,pharmaceutical dosage form,sustained release oral dosage form,and pharmaceutically acceptable package having less than 25 ppm 14-hydroxycodeinone |
EP1604666A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the Chronic Obstructive Pulmonary Disease (COPD) |
EP1604667A1 (en) * | 2004-06-08 | 2005-12-14 | Euro-Celtique S.A. | Opioids for the treatment of the restless leg syndrome |
DE102004032103A1 (en) * | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
US8394409B2 (en) * | 2004-07-01 | 2013-03-12 | Intellipharmaceutics Corp. | Controlled extended drug release technology |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
EP2431026A1 (en) | 2004-08-13 | 2012-03-21 | Boehringer Ingelheim International GmbH | Extended release pellet formulation containing Pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof |
US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
US7226619B1 (en) | 2004-09-07 | 2007-06-05 | Pharmorx Inc. | Material for controlling diversion of medications |
US7827983B2 (en) * | 2004-12-20 | 2010-11-09 | Hewlett-Packard Development Company, L.P. | Method for making a pharmaceutically active ingredient abuse-prevention device |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
FR2881652B1 (en) * | 2005-02-08 | 2007-05-25 | Flamel Technologies Sa | MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING |
FR2889810A1 (en) * | 2005-05-24 | 2007-02-23 | Flamel Technologies Sa | ORAL MEDICINAL FORM, MICROPARTICULAR, ANTI-MEASUREMENT |
EP1695700A1 (en) * | 2005-02-28 | 2006-08-30 | Euro-Celtique S.A. | Dosage form containing oxycodone and naloxone |
PL1895994T3 (en) | 2005-05-13 | 2011-02-28 | Alza Corp | Multilayer drug delivery system with barrier against reservoir material flow |
ES2277743B2 (en) * | 2005-06-02 | 2008-12-16 | Universidade De Santiago De Compostela | NANOPARTICLES THAT INCLUDE QUITOSANE AND CYCLODEXTRINE. |
WO2006133733A1 (en) * | 2005-06-13 | 2006-12-21 | Flamel Technologies | Oral dosage form comprising an antimisuse system |
EP2431088A1 (en) | 2005-08-02 | 2012-03-21 | Sol-Gel Technologies Ltd. | Metal oxide coating of water insoluble ingredients |
US8329744B2 (en) * | 2005-11-02 | 2012-12-11 | Relmada Therapeutics, Inc. | Methods of preventing the serotonin syndrome and compositions for use thereof |
US20090082466A1 (en) * | 2006-01-27 | 2009-03-26 | Najib Babul | Abuse Resistant and Extended Release Formulations and Method of Use Thereof |
WO2008134071A1 (en) * | 2007-04-26 | 2008-11-06 | Theraquest Biosciences, Inc. | Multimodal abuse resistant extended release formulations |
US8652529B2 (en) | 2005-11-10 | 2014-02-18 | Flamel Technologies | Anti-misuse microparticulate oral pharmaceutical form |
US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
SG169334A1 (en) * | 2006-01-21 | 2011-03-30 | Abbott Gmbh & Co Kg | Dosage form and method for the delivery of drugs of abuse |
US20070185145A1 (en) * | 2006-02-03 | 2007-08-09 | Royds Robert B | Pharmaceutical composition containing a central opioid agonist, a central opioid antagonist, and a peripheral opioid antagonist, and method for making the same |
US7939567B2 (en) * | 2006-02-24 | 2011-05-10 | Blue Blood Biotech Corp. | Dextromethorphan-based method for treating acne |
ZA200807571B (en) | 2006-03-01 | 2009-08-26 | Ethypharm Sa | Crush-resistant tablets intended to prevent accidental misuse and unlawful diversion |
US20070212414A1 (en) * | 2006-03-08 | 2007-09-13 | Penwest Pharmaceuticals Co. | Ethanol-resistant sustained release formulations |
CN101400343B (en) | 2006-03-16 | 2012-01-11 | 特瑞斯制药股份有限公司 | Modified release formulations containing drug-ion exchange resin complexes |
GB0606124D0 (en) * | 2006-03-28 | 2006-05-03 | Reckitt Benckiser Healthcare | Buprenorphine derivatives and uses thereof |
CA2648280C (en) * | 2006-04-03 | 2014-03-11 | Isa Odidi | Controlled release delivery device comprising an organosol coat |
JP2009535409A (en) * | 2006-05-03 | 2009-10-01 | コーワ ファーマシューティカルズ アメリカ,インコーポレイティド | Acute pain medicine based on fast-acting diclofenac-opioid composition |
US10960077B2 (en) * | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
US20080069891A1 (en) | 2006-09-15 | 2008-03-20 | Cima Labs, Inc. | Abuse resistant drug formulation |
US8765178B2 (en) | 2006-07-19 | 2014-07-01 | Watson Laboratories, Inc. | Controlled release formulations and associated methods |
SA07280459B1 (en) | 2006-08-25 | 2011-07-20 | بيورديو فارما إل. بي. | Tamper Resistant Oral Pharmaceutical Dosage Forms Comprising an Opioid Analgesic |
EP1897543A1 (en) | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
WO2008027442A2 (en) * | 2006-08-30 | 2008-03-06 | Theraquest Biosciences, Llc | Abuse deterrent oral pharmaceutical formulations of opioid agonists and method of use |
US8445018B2 (en) | 2006-09-15 | 2013-05-21 | Cima Labs Inc. | Abuse resistant drug formulation |
US8187636B2 (en) * | 2006-09-25 | 2012-05-29 | Atlantic Pharmaceuticals, Inc. | Dosage forms for tamper prone therapeutic agents |
JP5484062B2 (en) | 2006-12-04 | 2014-05-07 | オレクソ・アクチエボラゲット | Novel non-abuse pharmaceutical composition comprising opioids |
EA200970724A1 (en) | 2007-02-01 | 2010-02-26 | Сол-Джел Текнолоджиз Лтд. | COMPOSITIONS FOR LOCAL APPLICATION CONTAINING PEROXIDE AND RETINOID |
DE102007011485A1 (en) | 2007-03-07 | 2008-09-11 | Grünenthal GmbH | Dosage form with more difficult 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 |
ES2692437T3 (en) | 2007-08-13 | 2018-12-03 | Abuse Deterrent Pharmaceutical Llc | Abuse-resistant drugs, method of use and method of preparation |
HUE027537T2 (en) * | 2007-09-03 | 2016-10-28 | Nanotherapeutics Inc | Particulate compositions for delivery of poorly soluble drugs |
WO2009079518A1 (en) * | 2007-12-17 | 2009-06-25 | Alpharma Pharmaceuticals. Llc | Pharmaceutical composition |
US20100151014A1 (en) * | 2008-12-16 | 2010-06-17 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
EP2224805A4 (en) * | 2007-12-17 | 2013-10-16 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
US20100266645A1 (en) * | 2007-12-17 | 2010-10-21 | Alfred Liang | Pharmaceutical compositions |
AU2015200313B2 (en) * | 2007-12-17 | 2016-12-01 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
CA2707980C (en) | 2007-12-17 | 2015-05-12 | Labopharm Inc. | Misuse preventative, controlled release formulation |
CA2709950A1 (en) * | 2007-12-17 | 2009-07-09 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
KR101616246B1 (en) | 2008-01-25 | 2016-05-02 | 그뤼넨탈 게엠베하 | Pharmaceutical dosage form |
MX2010012039A (en) | 2008-05-09 | 2010-11-30 | Gruenenthal Gmbh | Process for the preparation of an intermediate powder formulation and a final solid dosage form under usage of a spray congealing step. |
SI2317991T1 (en) * | 2008-07-07 | 2017-09-29 | Euro-Celtique S.A. | Use of opioid antagonists for treating urinary retention |
WO2010044842A1 (en) * | 2008-10-16 | 2010-04-22 | University Of Tennessee Research Foundation | Tamper resistant oral dosage forms containing an embolizing agent |
ES2414856T3 (en) * | 2008-12-12 | 2013-07-23 | Paladin Labs Inc. | Narcotic drug formulations with decreased addiction potential |
JP5667575B2 (en) | 2008-12-16 | 2015-02-12 | パラディン ラブス インコーポレーテッド | Controlled release formulation to prevent misuse |
CA2750144C (en) | 2008-12-31 | 2016-10-25 | Upsher-Smith Laboratories, Inc. | Opioid-containing oral pharmaceutical compositions and methods |
RU2015138422A (en) | 2009-07-22 | 2018-12-25 | Грюненталь Гмбх | STABLE DURING OXIDATION, STRONG-BREAKED DOSAGE FORM |
MX2012000317A (en) | 2009-07-22 | 2012-02-08 | Gruenenthal Gmbh | Hot-melt extruded controlled release dosage form. |
BR112012008317A2 (en) | 2009-09-17 | 2016-03-22 | Upsher Smith Lab Inc | sustained release product comprising a combination of a non-opioid amine and a non-steroidal anti-inflammatory drug |
WO2011095314A2 (en) | 2010-02-03 | 2011-08-11 | Grünenthal GmbH | Preparation of a powdery pharmaceutical composition by means of an extruder |
WO2011143120A1 (en) | 2010-05-11 | 2011-11-17 | Cima Labs Inc. | Alcoholres i stant metoprolol - containing extended - release oral dosage forms |
ES2487244T3 (en) | 2010-09-02 | 2014-08-20 | Grünenthal GmbH | Handling resistant dosage form comprising an anionic polymer |
CA2808219C (en) | 2010-09-02 | 2019-05-14 | Gruenenthal Gmbh | Tamper resistant dosage form comprising inorganic salt |
DE102010048883A1 (en) | 2010-10-19 | 2012-04-19 | Lars Holger Hermann | Use of buprenorphine for abuse protection in pharmaceutical compositions containing a opioid full-agonist |
US8623409B1 (en) | 2010-10-20 | 2014-01-07 | Tris Pharma Inc. | Clonidine formulation |
CN102068697B (en) * | 2010-12-30 | 2013-10-16 | 宜昌人福药业有限责任公司 | Opiates painkiller and opiate receptor antagonist-containing medicinal composition |
EP2670400A1 (en) | 2011-02-02 | 2013-12-11 | Alpharma Pharmaceuticals LLC | Pharmaceutical composition comprising opioid agonist and sequestered antagonist |
WO2012112952A1 (en) | 2011-02-17 | 2012-08-23 | QRxPharma Ltd. | Technology for preventing abuse of solid dosage forms |
WO2013003845A1 (en) * | 2011-06-30 | 2013-01-03 | Neos Therapeutics, Lp | Abuse resistant drug forms |
CA2839123A1 (en) | 2011-07-29 | 2013-02-07 | Grunenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
AU2012292418B2 (en) | 2011-07-29 | 2017-02-16 | Grunenthal Gmbh | Tamper-resistant tablet providing immediate drug release |
EP2744572B1 (en) | 2011-08-18 | 2017-12-13 | BioDelivery Sciences International, Inc. | Abuse-resistant mucoadhesive devices for delivery of buprenorphine |
PL2915525T3 (en) | 2011-09-19 | 2022-01-17 | Orexo Ab | Sublingual abuse-resistant tablets comprising buprenorphine and naloxone |
TW201336529A (en) * | 2011-12-09 | 2013-09-16 | Purdue Pharma Lp | Pharmaceutical dosage forms comprising poly( ε -caprolactone) and polyethylene oxide |
MX356421B (en) | 2012-02-28 | 2018-05-29 | Gruenenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer. |
TW201811332A (en) | 2012-04-17 | 2018-04-01 | 美商普渡製藥有限合夥事業 | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
CN104394851B (en) | 2012-04-18 | 2017-12-01 | 格吕伦塔尔有限公司 | Anti-distort and anti-agent amount are come down in torrents pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
US10111837B2 (en) | 2012-05-14 | 2018-10-30 | Antecip Bioventures Ii Llc | Dosage forms for oral administration of zoledronic acid or related compounds |
US10463682B2 (en) | 2012-05-14 | 2019-11-05 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating low back pain |
US10004756B2 (en) | 2014-05-15 | 2018-06-26 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US10028908B2 (en) | 2012-05-14 | 2018-07-24 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US10092581B2 (en) | 2014-05-15 | 2018-10-09 | Antecip Bioventures Ii Llc | Osteoclast inhibitors such as zoledronic acid for low back pain treatment |
US9616078B2 (en) | 2012-05-14 | 2017-04-11 | Antecip Bioventures Ii Llc | Dosage forms for oral administration of zoledronic acid or related compounds for treating disease |
US8865757B1 (en) | 2014-05-28 | 2014-10-21 | Antecip Bioventures Ii Llp | Therapeutic compositions comprising imidazole and imidazolium compounds |
US10173986B2 (en) | 2012-05-14 | 2019-01-08 | Antecip Bioventures Ii Llc | Methods for the safe administration of imidazole or imidazolium compounds |
US9820999B2 (en) | 2012-05-14 | 2017-11-21 | Antecip Bioventures Ii Llc | Neridronic acid for treating complex regional pain syndrome |
US9707245B2 (en) | 2012-05-14 | 2017-07-18 | Antecip Bioventures Ii Llc | Neridronic acid for treating complex regional pain syndrome |
US9675626B2 (en) | 2012-05-14 | 2017-06-13 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9700570B2 (en) | 2014-05-27 | 2017-07-11 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9861648B2 (en) | 2012-05-14 | 2018-01-09 | Antecip Boiventures Ii Llc | Osteoclast inhibitors for knee conditions |
US9949993B2 (en) | 2012-05-14 | 2018-04-24 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
US11654152B2 (en) | 2012-05-14 | 2023-05-23 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating disease |
US9867839B2 (en) | 2012-05-14 | 2018-01-16 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for joint conditions |
US9827192B2 (en) | 2012-05-14 | 2017-11-28 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9795622B2 (en) | 2012-05-14 | 2017-10-24 | Antecip Bioventures Ii Llc | Neridronic acid for treating pain associated with a joint |
US8802658B2 (en) | 2012-05-14 | 2014-08-12 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating disease |
US9655908B2 (en) | 2012-05-14 | 2017-05-23 | Antecip Bioventures Ii Llc | Neridronic acid molecular complex for treating complex regional pain syndrome |
US9956237B2 (en) | 2012-05-14 | 2018-05-01 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for knee conditions |
US10413561B2 (en) | 2012-05-14 | 2019-09-17 | Antecip Bioventures Ii Llc | Neridronic acid and other bisphosphonates for treating complex regional pain syndrome and other diseases |
US9956234B2 (en) | 2012-05-14 | 2018-05-01 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for joint conditions |
US10034890B2 (en) | 2012-05-14 | 2018-07-31 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9877977B2 (en) | 2012-05-14 | 2018-01-30 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9694023B2 (en) | 2012-05-14 | 2017-07-04 | Antecip Bioventures Ii Llc | Methods for the safe administration of imidazole or imidazolium compounds |
US10016445B2 (en) | 2012-05-14 | 2018-07-10 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9999629B2 (en) | 2012-05-14 | 2018-06-19 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9956238B2 (en) | 2014-05-15 | 2018-05-01 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
US10039773B2 (en) | 2012-05-14 | 2018-08-07 | Antecip Bioventures Ii Llc | Neridronic acid for treating arthritis |
US9782421B1 (en) | 2012-05-14 | 2017-10-10 | Antecip Bioventures Ii Llc | Neridronic acid molecular complex for treating complex regional pain syndrome |
US9707247B2 (en) | 2012-05-14 | 2017-07-18 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
US9827256B2 (en) | 2014-05-27 | 2017-11-28 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating lower back pain |
US10350227B2 (en) | 2012-05-14 | 2019-07-16 | Antecip Bioventures Ii Llc | Neridronic acid for treating complex regional pain syndrome |
US9943531B2 (en) | 2014-08-08 | 2018-04-17 | Antecip Bioventures Ii Llc | Osteoclast inhibitors such as zoledronic acid for low back pain treatment |
US10016446B2 (en) | 2012-05-14 | 2018-07-10 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating Paget's disease of bone |
US9844559B2 (en) | 2012-05-14 | 2017-12-19 | Antecip Bioventures Ii Llc | Neridronic acid for treating bone marrow lesions |
US9427403B2 (en) | 2012-05-14 | 2016-08-30 | Antecip Bioventures Ii Llc | Methods for the safe administration of imidazole or imidazolium compounds |
US9999628B2 (en) | 2012-05-14 | 2018-06-19 | Antecip Bioventures Ii Llc | Neridronic acid for treating complex regional pain syndrome |
US9895383B2 (en) | 2012-05-14 | 2018-02-20 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9770457B2 (en) | 2012-05-14 | 2017-09-26 | Antecip Bioventures Ii Llc | Neridronic acid for treating bone marrow lesion |
US9289441B2 (en) | 2014-08-08 | 2016-03-22 | Antecip Bioventures Ii Llc | Osteoclast inhibitors such as zoledronic acid for low back pain treatment |
US9211257B2 (en) | 2012-05-14 | 2015-12-15 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for knee conditions |
US10493085B2 (en) | 2012-05-14 | 2019-12-03 | Antecip Bioventures Ii Llc | Neridronic acid and other bisphosphonates for treating complex regional pain syndrome and other diseases |
US9867840B2 (en) | 2014-05-27 | 2018-01-16 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9669040B2 (en) | 2012-05-14 | 2017-06-06 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US10080765B2 (en) | 2012-05-14 | 2018-09-25 | Antecip Bioventures Ii Llc | Neridronic acid for treating complex regional pain syndrome |
US9925203B2 (en) | 2012-05-14 | 2018-03-27 | Antecip Bioventures Ii Llc | Compositions for administration of zoledronic acid or related compounds for treating low back pain |
US9901589B2 (en) | 2012-05-14 | 2018-02-27 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US10413560B2 (en) | 2012-05-14 | 2019-09-17 | Antecip Bioventures Ii Llc | Dosage forms for oral administration of zoledronic acid or related compounds for treating disease |
US9789128B2 (en) | 2012-05-14 | 2017-10-17 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US10028969B2 (en) | 2012-05-14 | 2018-07-24 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
US9717747B2 (en) | 2012-05-14 | 2017-08-01 | Antecip Bioventures Ii Llc | Osteoclast inhibitors for knee conditions |
US9662343B2 (en) | 2012-05-14 | 2017-05-30 | Antecip Bioventures Ii Llc | Compositions for oral administration of zoledronic acid or related compounds for treating complex regional pain syndrome |
WO2014011830A1 (en) | 2012-07-12 | 2014-01-16 | Mallinckrodt Llc | Extended release, abuse deterrent pharmaceutical compositions |
US9687465B2 (en) | 2012-11-27 | 2017-06-27 | Sol-Gel Technologies Ltd. | Compositions for the treatment of rosacea |
KR101659983B1 (en) * | 2012-12-31 | 2016-09-26 | 주식회사 삼양바이오팜 | Melt-extruded release controlled pharmaceutical composition and oral dosage form comprising the same |
US9517208B2 (en) | 2013-03-15 | 2016-12-13 | Purdue Pharma L.P. | Abuse-deterrent dosage forms |
US20140275038A1 (en) | 2013-03-15 | 2014-09-18 | Inspirion Delivery Technologies, Llc | Abuse deterrent compositions and methods of use |
ITTO20130284A1 (en) * | 2013-04-09 | 2014-10-10 | Fond Istituto Italiano Di Tecnologia | PROCEDURE FOR THE PRODUCTION OF SHAPED POLYMERIC MICROPARTELS |
CA2907950A1 (en) | 2013-05-29 | 2014-12-04 | Grunenthal Gmbh | Tamper-resistant dosage form containing one or more particles |
AR096438A1 (en) | 2013-05-29 | 2015-12-30 | Gruenenthal Gmbh | DOSAGE FORM RESISTANT TO INDEBITED USE WITH BIMODAL RELEASE PROFILE, PROCESS |
BR112016000194A8 (en) | 2013-07-12 | 2019-12-31 | Gruenenthal Gmbh | tamper-resistant dosage form containing ethylene vinyl acetate polymer |
US9770514B2 (en) | 2013-09-03 | 2017-09-26 | ExxPharma Therapeutics LLC | Tamper-resistant pharmaceutical dosage forms |
US20150118300A1 (en) | 2013-10-31 | 2015-04-30 | Cima Labs Inc. | Immediate Release Abuse-Deterrent Granulated Dosage Forms |
WO2015065546A2 (en) | 2013-10-31 | 2015-05-07 | Cima Labs Inc. | Abuse-deterrent dosage forms |
CN105934241B (en) | 2013-11-26 | 2020-06-05 | 格吕伦塔尔有限公司 | Preparation of powdered pharmaceutical composition by cryogenic grinding |
WO2015173195A1 (en) | 2014-05-12 | 2015-11-19 | Grünenthal GmbH | Tamper resistant immediate release capsule formulation comprising tapentadol |
JP2017516789A (en) | 2014-05-26 | 2017-06-22 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Multiparticulates protected against ethanol overdose |
US9127069B1 (en) | 2014-06-11 | 2015-09-08 | Antecip Bioventures LLC | Compositions comprising rank/rankl antagonists and related compounds for treating pain |
CA2910865C (en) | 2014-07-15 | 2016-11-29 | Isa Odidi | Compositions and methods for reducing overdose |
US9132096B1 (en) | 2014-09-12 | 2015-09-15 | Alkermes Pharma Ireland Limited | Abuse resistant pharmaceutical compositions |
US10729685B2 (en) | 2014-09-15 | 2020-08-04 | Ohemo Life Sciences Inc. | Orally administrable compositions and methods of deterring abuse by intranasal administration |
US9849124B2 (en) | 2014-10-17 | 2017-12-26 | Purdue Pharma L.P. | Systems and methods for treating an opioid-induced adverse pharmacodynamic response |
CA2970065A1 (en) | 2014-12-08 | 2016-06-16 | Cima Labs Inc. | Immediate release abuse-deterrent granulated dosage forms |
EP3285745A1 (en) | 2015-04-24 | 2018-02-28 | Grünenthal GmbH | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
EP3344997B1 (en) * | 2015-08-31 | 2020-11-18 | Regents of the University of Minnesota | Opioid receptor modulators and use thereof |
US11590228B1 (en) | 2015-09-08 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine compositions |
CA2998259A1 (en) | 2015-09-10 | 2017-03-16 | Grunenthal Gmbh | Protecting oral overdose with abuse deterrent immediate release formulations |
US9943513B1 (en) | 2015-10-07 | 2018-04-17 | Banner Life Sciences Llc | Opioid abuse deterrent dosage forms |
GB201520390D0 (en) * | 2015-11-19 | 2016-01-06 | Euro Celtique Sa | Composition |
US10335405B1 (en) | 2016-05-04 | 2019-07-02 | Patheon Softgels, Inc. | Non-burst releasing pharmaceutical composition |
US10532385B2 (en) | 2016-06-29 | 2020-01-14 | Disposerx, Inc. | Disposal of medicaments |
WO2018012627A1 (en) * | 2016-07-15 | 2018-01-18 | シャープ株式会社 | Air blowing apparatus and air conditioner |
US10335375B2 (en) | 2017-05-30 | 2019-07-02 | Patheon Softgels, Inc. | Anti-overingestion abuse deterrent compositions |
US11590081B1 (en) | 2017-09-24 | 2023-02-28 | Tris Pharma, Inc | Extended release amphetamine tablets |
CA3078844A1 (en) * | 2017-10-09 | 2019-04-18 | Rhodes Pharmaceuticals L.P. | Pharmaceutical resinate compositions and methods of making and using thereof |
EP3473246A1 (en) | 2017-10-19 | 2019-04-24 | Capsugel Belgium NV | Immediate release abuse deterrent formulations |
US10624856B2 (en) | 2018-01-31 | 2020-04-21 | Dharma Laboratories LLC | Non-extractable oral solid dosage forms |
CN109232748B (en) * | 2018-09-26 | 2019-06-11 | 哈尔滨工业大学 | The cyclisation hybrid peptide and its synthetic method and application that the enkephalins of multidigit point modification is mutually coupled with neurotensin (8-13) |
US20220105085A1 (en) * | 2019-01-31 | 2022-04-07 | Relmada Therapeutics, Inc. | Abrasion-resistant opioid formulations which resist abuse and include a sequestered opioid antagonist |
EP3965733A4 (en) | 2019-05-07 | 2023-01-11 | Clexio Biosciences Ltd. | Abuse-deterrent dosage forms containing esketamine |
WO2021005501A1 (en) * | 2019-07-10 | 2021-01-14 | Intas Pharmaceuticals Ltd. | Naltrexone formulation |
US11918689B1 (en) | 2020-07-28 | 2024-03-05 | Tris Pharma Inc | Liquid clonidine extended release composition |
WO2023146983A1 (en) * | 2022-01-26 | 2023-08-03 | Aardvark Therapeutics, Inc. | Liquid resin extended-release oral naltrexone formulation for treating autism-related disorders |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0205282A2 (en) * | 1985-06-11 | 1986-12-17 | Euroceltique S.A. | Oral pharmaceutical composition |
US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
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 |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | 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 |
US5942241A (en) * | 1995-06-09 | 1999-08-24 | Euro-Celtique, S.A. | Formulations and methods for providing prolonged local anesthesia |
US5968547A (en) * | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
US5998434A (en) * | 1995-12-06 | 1999-12-07 | Eli Lilly And Company | Composition for treating pain |
Family Cites Families (223)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US316889A (en) | 1885-04-28 | Soil pulverizer and leveler | ||
US2770569A (en) | 1952-08-01 | 1956-11-13 | Hoffmann La Roche | Analgesic compositions |
US3493657A (en) | 1961-03-14 | 1970-02-03 | Mozes Juda Lewenstein | Therapeutic compositions of n-allyl-14-hydroxy - dihydronormorphinane and morphine |
US3332950A (en) | 1963-03-23 | 1967-07-25 | Endo Lab | 14-hydroxydihydronormorphinone derivatives |
US3773955A (en) | 1970-08-03 | 1973-11-20 | Bristol Myers Co | Analgetic compositions |
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 |
GB1390772A (en) | 1971-05-07 | 1975-04-16 | Endo Lab | Oral narcotic composition |
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 |
US3916889A (en) | 1973-09-28 | 1975-11-04 | Sandoz Ag | Patient ventilator apparatus |
US3966940A (en) * | 1973-11-09 | 1976-06-29 | Bristol-Myers Company | Analgetic compositions |
GB1478759A (en) | 1974-11-18 | 1977-07-06 | Alza Corp | Process for forming outlet passageways in pills using a laser |
US4063064A (en) | 1976-02-23 | 1977-12-13 | Coherent Radiation | Apparatus for tracking moving workpiece by a laser beam |
US4176186A (en) | 1978-07-28 | 1979-11-27 | Boehringer Ingelheim Gmbh | Quaternary derivatives of noroxymorphone which relieve intestinal immobility |
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 |
US4457933A (en) | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
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 |
EP0103636B1 (en) | 1982-03-16 | 1990-09-12 | Rockefeller University | Use of opium antagonists for the manufacture of medicaments for controlling gastrointestinal dysmotility |
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 |
US4803208A (en) | 1982-09-30 | 1989-02-07 | Sloan-Kettering Institute For Cancer Research | Opiate agonists and antagonists |
GB8332556D0 (en) | 1983-12-06 | 1984-01-11 | Reckitt & Colmann Prod Ltd | Analgesic compositions |
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 |
CA1267092A (en) | 1985-02-25 | 1990-03-27 | Martin D. Hynes | Analgesic composition containing codeine |
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 |
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 |
DE3687575T2 (en) | 1985-09-06 | 1993-07-01 | Baker Norton Pharma | USE OF 6-METHYLENE-6-DESOXY-N-CYCLOPROPYLMETHYL-14-HYDROXYDIHYDRONORMORPHINE. |
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 |
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 |
DE219243T1 (en) | 1985-10-11 | 1987-09-24 | Monolithic Memories, Inc., Santa Clara, Calif., Us | METHOD FOR PRODUCING A BIPOLAR TRANSISTOR. |
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 |
US5316759A (en) | 1986-03-17 | 1994-05-31 | Robert J. Schaap | Agonist-antagonist combination to reduce the use of nicotine and other drugs |
US4673679A (en) * | 1986-05-14 | 1987-06-16 | E. I. Du Pont De Nemours And Company | Use of prodrugs of 3-hydroxymorphinans to prevent bitter taste upon buccal, nasal or sublingual administration |
GB8613689D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
GB8613688D0 (en) | 1986-06-05 | 1986-07-09 | Euro Celtique Sa | Pharmaceutical composition |
ES2058111T3 (en) | 1986-06-10 | 1994-11-01 | Euro Celtique Sa | COMPOSITION OF CONTROLLED RELEASE OF DIHYDROCODEIN. |
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 |
US5356900A (en) | 1986-10-07 | 1994-10-18 | Bernard Bihari | Method of treating chronic herpes virus infections using an opiate receptor antagonist |
DE3636075A1 (en) * | 1986-10-23 | 1988-04-28 | Merck Patent Gmbh | COSMETIC PREPARATIONS |
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 |
US4831781A (en) * | 1987-11-02 | 1989-05-23 | Dayton Extruded Plastics, Inc. | Window assembly of rigid plastics material |
GB8728294D0 (en) | 1987-12-03 | 1988-01-06 | Reckitt & Colmann Prod Ltd | Treatment compositions |
JPH01279895A (en) * | 1988-01-20 | 1989-11-10 | Baker Cummins Pharmaceut Inc | Glucronic acid derivative of opioid antagonist |
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 |
EP0352361A1 (en) * | 1988-07-29 | 1990-01-31 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
US5236714A (en) | 1988-11-01 | 1993-08-17 | Alza Corporation | Abusable substance dosage form having reduced abuse potential |
CA2002492A1 (en) | 1988-11-11 | 1990-05-11 | Sandra T. A. Malkowska | Pharmaceutical ion exchange resin composition |
US5260331A (en) | 1989-01-02 | 1993-11-09 | John Wyeth & Brother Limited | Composition for treating depression with (S- or O-heteroaryl)alkyl amines |
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 |
US5075341A (en) | 1989-12-01 | 1991-12-24 | The Mclean Hospital Corporation | Treatment for cocaine abuse |
US5086058A (en) | 1990-06-04 | 1992-02-04 | Alko Ltd. | Method for treating alcoholism with nalmefene |
FR2663818B1 (en) | 1990-06-29 | 1993-07-09 | Rhone Poulenc Nutrition Animale | PROCESS FOR THE PREPARATION OF GRANULES OF ACTIVE PRINCIPLES BY EXTRUSION. |
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 |
GB9104854D0 (en) | 1991-03-07 | 1991-04-17 | Reckitt & Colmann Prod Ltd | Sustained release compositions |
NZ242117A (en) * | 1991-03-29 | 1994-11-25 | Lilly Co Eli | 4-phenylpiperidine derivatives and medicaments containing them |
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 |
AU651247B2 (en) | 1991-09-06 | 1994-07-14 | Mcneilab, Inc. | Composition comprising a tramadol material and acetaminophen and its use |
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 |
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 |
US5266331A (en) | 1991-11-27 | 1993-11-30 | Euroceltique, S.A. | Controlled release oxycodone compositions |
US5656295A (en) | 1991-11-27 | 1997-08-12 | Euro-Celtique, 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 |
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 |
US5472712A (en) | 1991-12-24 | 1995-12-05 | Euroceltique, S.A. | Controlled-release formulations coated with aqueous dispersions of ethylcellulose |
US5968551A (en) | 1991-12-24 | 1999-10-19 | Purdue Pharma L.P. | Orally administrable opioid formulations having extended duration of effect |
US5958459A (en) | 1991-12-24 | 1999-09-28 | Purdue Pharma L.P. | Opioid formulations having extended controlled released |
US5580578A (en) * | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
US5286493A (en) | 1992-01-27 | 1994-02-15 | Euroceltique, S.A. | Stabilized controlled release formulations having acrylic polymer coating |
GB9202464D0 (en) * | 1992-02-05 | 1992-03-18 | Danbiosyst Uk | Composition for nasal administration |
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 |
DK0647137T3 (en) | 1992-06-22 | 2008-12-08 | State Of Oregon Through Oregon | 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 |
JP2563100Y2 (en) | 1992-08-05 | 1998-02-18 | 日本精工株式会社 | Seat belt retractor |
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 |
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 |
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 |
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 |
CA2145207A1 (en) | 1992-09-21 | 1994-03-22 | Bo-Yi Qin | Methods for identifying and using low/non-addictive opioid analgesics |
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 |
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 |
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 |
DE4325465B4 (en) | 1993-07-29 | 2004-03-04 | Zenz, Michael, Prof. Dr.med. | Oral pharmaceutical preparation for pain therapy |
US5411965A (en) | 1993-08-23 | 1995-05-02 | Arizona Board Of Regents | Use of delta opioid receptor antagonists to treat cocaine abuse |
GB9319568D0 (en) | 1993-09-22 | 1993-11-10 | Euro Celtique Sa | Pharmaceutical compositions and usages |
HU218673B (en) * | 1993-10-07 | 2000-10-28 | Euroceltique S.A. | Controlled release pharmaceutical composition for orally administration comprising opioid analgesic and process for producing its |
KR100354702B1 (en) | 1993-11-23 | 2002-12-28 | 유로-셀티크 소시에떼 아노뉨 | Manufacturing method and sustained release composition of pharmaceutical composition |
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 |
US5500227A (en) | 1993-11-23 | 1996-03-19 | Euro-Celtique, S.A. | Immediate release tablet cores of insoluble drugs having sustained-release coating |
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 |
US5451408A (en) | 1994-03-23 | 1995-09-19 | Liposome Pain Management, Ltd. | Pain management with liposome-encapsulated analgesic drugs |
US5475995A (en) | 1994-05-16 | 1995-12-19 | Livingston; George G. | Truck spare tire locking rod |
US6077533A (en) | 1994-05-25 | 2000-06-20 | Purdue Pharma L.P. | Powder-layered oral dosage forms |
US5411745A (en) | 1994-05-25 | 1995-05-02 | Euro-Celtique, S.A. | Powder-layered morphine sulfate formulations |
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 |
EP0782445B1 (en) * | 1994-09-19 | 2002-03-13 | Dupont Pharmaceuticals Company | Combination of an opioid antagonist and a selective serotonin reuptake inhibitor for treatment of alcoholism and alcohol dependence |
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 |
ES2244966T3 (en) | 1994-12-12 | 2005-12-16 | Omeros Corporation | IRRIGATION SOLUTION AND ITS USE TO PERIOPERATORY INHIBIT THE PAIN, INFLAMMATION AND SPASM IN A WOUND. |
GB9426102D0 (en) | 1994-12-23 | 1995-02-22 | Merck Sharp & Dohme | Pharmacuetical compositions |
US5834024A (en) | 1995-01-05 | 1998-11-10 | Fh Faulding & Co. Limited | Controlled absorption diltiazem pharmaceutical formulation |
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 |
US5510368A (en) | 1995-05-22 | 1996-04-23 | Merck Frosst Canada, Inc. | N-benzyl-3-indoleacetic acids as antiinflammatory drugs |
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 |
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 |
ES2168610T3 (en) * | 1996-03-12 | 2002-06-16 | Alza Corp | COMPOSITION AND GALENIC FORM CONTAINING AN OPIOID ANTAGONIST. |
JPH11505547A (en) | 1996-03-13 | 1999-05-21 | エール ユニバーシティ | Smoking cessation treatment with naltrexone and related compounds |
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 |
DE19651551C2 (en) | 1996-12-11 | 2000-02-03 | Klinge Co Chem Pharm Fab | Opioid antagonist-containing galenic formulation |
DE19654468C1 (en) | 1996-12-27 | 1998-01-22 | Lohmann Therapie Syst Lts | Flexible dermal or transdermal plaster for drug or cosmetic release |
EP0880352B1 (en) | 1997-02-14 | 1999-11-17 | Gödecke Aktiengesellschaft | Stabilization of naloxone hydrochloride |
DE29719704U1 (en) | 1997-02-14 | 1998-01-22 | Goedecke Ag | Stable preparations of naloxone hydrochloride |
US5780479A (en) | 1997-04-04 | 1998-07-14 | Regents Of The University Of Minnesota | Use of opioid antagonists to treat impulse-control disorders |
US6120806A (en) | 1997-06-25 | 2000-09-19 | Whitmire; David R. | Oral formulations for controlled release of alcohol deterrents |
WO1999001111A1 (en) | 1997-07-02 | 1999-01-14 | Euro-Celtique, S.A. | Stabilized sustained release tramadol formulations |
RS49982B (en) | 1997-09-17 | 2008-09-29 | Euro-Celtique S.A., | Synergistic analgesic combination of opioid analgesic and cyclooxygenase-2 inhibitor |
US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
US5972954A (en) | 1997-11-03 | 1999-10-26 | Arch Development Corporation | Use of methylnaltrexone and related compounds |
ATE210983T1 (en) | 1997-11-03 | 2002-01-15 | Stada Arzneimittel Ag | STABILIZED COMBINATION MEDICINAL PRODUCT CONTAINING NALOXONE AND AN OPIATE ANALGESIC |
BR9813826A (en) * | 1997-12-22 | 2000-10-10 | Euro Celtique Sa | Potential for abusive use of oral administration of analgesic opioids |
US6375957B1 (en) | 1997-12-22 | 2002-04-23 | Euro-Celtique, S.A. | Opioid agonist/opioid antagonist/acetaminophen combinations |
SI2266564T1 (en) | 1997-12-22 | 2013-07-31 | Euro-Celtique S.A. | Pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist |
US6248691B1 (en) * | 1998-02-10 | 2001-06-19 | Corning Incorporated | Method of making mesoporous carbon |
DE29923766U1 (en) * | 1998-05-27 | 2001-06-07 | Euro Celtique Sa | Drug delivery system comprising a highly compressed solid drug supply |
DE19859636A1 (en) * | 1998-12-23 | 2000-06-29 | Hexal Ag | Controlled release pharmaceutical composition with tilidine mesylate as active ingredient |
FR2787715B1 (en) | 1998-12-23 | 2002-05-10 | Synthelabo | PHARMACEUTICAL COMPOSITION COMPRISING A HYPNOTIC COMPOUND OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS |
US6312949B1 (en) | 1999-03-26 | 2001-11-06 | The Salk Institute For Biological Studies | Regulation of tyrosine hydroxylase expression |
US6765010B2 (en) | 1999-05-06 | 2004-07-20 | Pain Therapeutics, Inc. | Compositions and methods for enhancing analgesic potency of tramadol and attenuating its adverse side effects |
ATE275402T1 (en) * | 1999-11-01 | 2004-09-15 | John Rhodes | MEDICINAL PRODUCTS FOR THE TREATMENT OF INTESTINAL CONSTITUTION AND irritable colon |
PT1244447E (en) | 1999-11-29 | 2007-02-28 | Adolor Corp | Novel methods and compositions involving opioids and antagonists thereof |
WO2001052851A1 (en) | 2000-01-22 | 2001-07-26 | Albert Shulman | Methods for the treatment of substance abuse |
US6716449B2 (en) * | 2000-02-08 | 2004-04-06 | Euro-Celtique S.A. | Controlled-release compositions containing opioid agonist and antagonist |
SI1299104T1 (en) | 2000-02-08 | 2009-10-31 | Euro Celtique Sa | Tamper-resistant oral opioid agonist formulations |
EP1263438B1 (en) | 2000-03-15 | 2006-05-17 | Wolfgang Sadee | Neutral antagonists and use thereof in treating drug abuse |
CA2408106A1 (en) | 2000-05-05 | 2001-11-15 | Pain Therapeutics, Inc. | Opioid antagonist compositions and dosage forms |
AU2001268353A1 (en) | 2000-06-09 | 2001-12-17 | The Regents Of The University Of California | Method of treating pain using nalbuphine and opioid antagonists |
CA2778114A1 (en) * | 2001-05-11 | 2002-11-21 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
EP1387673B1 (en) * | 2001-05-11 | 2010-12-29 | Endo Pharmaceuticals Inc. | Abuse-resistant controlled-release opioid dosage form |
US6555080B1 (en) * | 2001-07-13 | 2003-04-29 | Chevron U.S.A. Inc. | Using zeolite SSZ-57 for reduction of oxides of nitrogen in a gas stream |
SI1416842T1 (en) | 2001-07-18 | 2009-06-30 | Euro Celtique Sa | Pharmaceutical combinations of oxycodone and naloxone |
DK1414451T3 (en) | 2001-08-06 | 2009-08-10 | Euro Celtique Sa | Opioid agonist formulations with release and sequenced antagonist |
US7842307B2 (en) | 2001-08-06 | 2010-11-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and gelling 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 |
US7332182B2 (en) | 2001-08-06 | 2008-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing opioid agonist, opioid antagonist and irritant |
WO2003013433A2 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Sequestered antagonist formulations |
CN1652752A (en) | 2002-03-14 | 2005-08-10 | 欧罗赛铁克股份有限公司 | Naltrexone hydrochloride compositions |
US7790215B2 (en) | 2002-03-26 | 2010-09-07 | Purdue Pharma Lp | Sustained-release gel coated compositions |
DE20308437U1 (en) | 2002-04-05 | 2003-11-13 | Euro Celtique Sa | Matrix for delayed, consistent and independent release of drugs |
US20030191147A1 (en) | 2002-04-09 | 2003-10-09 | Barry Sherman | Opioid antagonist compositions and dosage forms |
WO2005007135A1 (en) | 2002-08-15 | 2005-01-27 | Euro-Celtique S.A. | Pharmaceutical compositions |
AU2003270778B2 (en) | 2002-09-20 | 2009-10-08 | Alpharma Pharmaceuticals, Llc | Sequestering subunit and related compositions and methods |
AU2003272601B2 (en) * | 2002-09-20 | 2009-05-07 | Alpharma Pharmaceuticals, Llc | Sustained-release opioid formulations and methods of use |
US20050191244A1 (en) | 2002-10-25 | 2005-09-01 | Gruenenthal Gmbh | Abuse-resistant pharmaceutical dosage form |
US20040110781A1 (en) | 2002-12-05 | 2004-06-10 | Harmon Troy M. | Pharmaceutical compositions containing indistinguishable drug components |
US7524515B2 (en) * | 2003-01-10 | 2009-04-28 | Mutual Pharmaceuticals, Inc. | Pharmaceutical safety dosage forms |
WO2004071423A2 (en) | 2003-02-05 | 2004-08-26 | Euro-Celtique S.A. | Methods of administering opioid antagonists and compositions thereof |
US20040202717A1 (en) | 2003-04-08 | 2004-10-14 | Mehta Atul M. | Abuse-resistant oral dosage forms and method of use thereof |
MY135852A (en) | 2003-04-21 | 2008-07-31 | Euro Celtique Sa | Pharmaceutical products |
US20080020028A1 (en) | 2003-08-20 | 2008-01-24 | Euro-Celtique S.A. | Transdermal dosage form comprising an active agent and a salt and a free-base form of an adverse agent |
AU2004277898B2 (en) | 2003-09-25 | 2009-04-02 | Euro-Celtique S.A. | Pharmaceutical combinations of hydrocodone and naltrexone |
US20050245557A1 (en) | 2003-10-15 | 2005-11-03 | Pain Therapeutics, Inc. | Methods and materials useful for the treatment of arthritic conditions, inflammation associated with a chronic condition or chronic pain |
DE10353196A1 (en) * | 2003-11-13 | 2005-06-16 | Röhm GmbH & Co. KG | Multilayer dosage form with a matrix influencing the delivery of a modulatory substance |
DE10353186A1 (en) | 2003-11-13 | 2005-06-16 | Röhm GmbH & Co. KG | Multilayer dosage form containing a modulatory substance in relation to the release of active ingredient |
AU2004296821B2 (en) | 2003-12-05 | 2011-05-12 | Carefusion 303, Inc. | Patient-controlled analgesia with patient monitoring system |
US20050256072A1 (en) * | 2004-02-09 | 2005-11-17 | University Of Massachusetts | Dual functional oligonucleotides for use in repressing mutant gene expression |
HUE032156T2 (en) * | 2006-06-19 | 2017-09-28 | Alpharma Pharmaceuticals Llc | Pharmaceutical compositions |
EP2073797A2 (en) | 2006-10-11 | 2009-07-01 | Alpharma, Inc. | Pharmaceutical compositions |
AU2008296905A1 (en) * | 2007-09-04 | 2009-03-12 | Alpharma Pharmaceuticals, Llc | A multilayer pharmaceutical composition comprising an antagonist in a first layer and an agonist in a second layer |
US8623418B2 (en) * | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
US20100151014A1 (en) * | 2008-12-16 | 2010-06-17 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
WO2009079518A1 (en) | 2007-12-17 | 2009-06-25 | Alpharma Pharmaceuticals. Llc | Pharmaceutical composition |
CA2709950A1 (en) | 2007-12-17 | 2009-07-09 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
EP2224805A4 (en) | 2007-12-17 | 2013-10-16 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
BR112013009267A2 (en) | 2010-10-26 | 2016-07-26 | Alpharma Pharmaceuticals Llc | Formulations and Methods for Mitigating Opioid Overdose-Induced Respiratory Depression |
EP2670400A1 (en) | 2011-02-02 | 2013-12-11 | Alpharma Pharmaceuticals LLC | Pharmaceutical composition comprising opioid agonist and sequestered antagonist |
-
2001
- 2001-02-08 SI SI200130928T patent/SI1299104T1/en unknown
- 2001-02-08 SI SI200131043T patent/SI2283842T1/en unknown
- 2001-02-08 NZ NZ520554A patent/NZ520554A/en not_active IP Right Cessation
- 2001-02-08 EP EP10011790.2A patent/EP2283842B1/en not_active Expired - Lifetime
- 2001-02-08 MX MXPA02007686A patent/MXPA02007686A/en active IP Right Grant
- 2001-02-08 JP JP2001557561A patent/JP2003522146A/en not_active Withdrawn
- 2001-02-08 SI SI200131042T patent/SI2277521T1/en unknown
- 2001-02-08 DK DK12167170.5T patent/DK2517710T3/en active
- 2001-02-08 PT PT100117902T patent/PT2283842E/en unknown
- 2001-02-08 OA OA1200200241A patent/OA12215A/en unknown
- 2001-02-08 EA EA200200840A patent/EA004876B1/en not_active IP Right Cessation
- 2001-02-08 ES ES10011789.4T patent/ES2540103T3/en not_active Expired - Lifetime
- 2001-02-08 CZ CZ20022706A patent/CZ299991B6/en not_active IP Right Cessation
- 2001-02-08 ES ES10011790.2T patent/ES2539945T3/en not_active Expired - Lifetime
- 2001-02-08 PT PT90060245T patent/PT2092936E/en unknown
- 2001-02-08 HU HU0204229A patent/HU229705B1/en unknown
- 2001-02-08 JP JP2001557557A patent/JP2003522144A/en active Pending
- 2001-02-08 US US09/781,081 patent/US6696088B2/en not_active Expired - Lifetime
- 2001-02-08 EP EP09006024A patent/EP2092936B1/en not_active Expired - Lifetime
- 2001-02-08 HU HU0204163A patent/HUP0204163A2/en unknown
- 2001-02-08 CN CN01807725A patent/CN1423559A/en active Pending
- 2001-02-08 KR KR1020027010121A patent/KR20020071032A/en not_active Application Discontinuation
- 2001-02-08 DK DK01909086T patent/DK1299104T3/en active
- 2001-02-08 DE DE60138706T patent/DE60138706D1/en not_active Expired - Lifetime
- 2001-02-08 PT PT01909087T patent/PT1255547E/en unknown
- 2001-02-08 BR BR0108379-1A patent/BR0108379A/en not_active Application Discontinuation
- 2001-02-08 SI SI200131041T patent/SI2517710T1/en unknown
- 2001-02-08 EP EP12167170.5A patent/EP2517710B1/en not_active Expired - Lifetime
- 2001-02-08 AU AU36877/01A patent/AU776904B2/en not_active Expired
- 2001-02-08 CN CNB018065694A patent/CN100563656C/en not_active Expired - Lifetime
- 2001-02-08 CA CA002400567A patent/CA2400567C/en not_active Expired - Lifetime
- 2001-02-08 AP APAP/P/2002/002617A patent/AP1665A/en active
- 2001-02-08 ME MEP-2008-483A patent/ME00398B/en unknown
- 2001-02-08 SK SK1134-2002A patent/SK287107B6/en not_active IP Right Cessation
- 2001-02-08 EE EEP200200437A patent/EE05171B1/en unknown
- 2001-02-08 WO PCT/US2001/004346 patent/WO2001058451A1/en active Search and Examination
- 2001-02-08 PT PT100117894T patent/PT2277521E/en unknown
- 2001-02-08 EP EP15160341.2A patent/EP3130338A1/en not_active Withdrawn
- 2001-02-08 CN CN2009102080743A patent/CN101703777B/en not_active Expired - Lifetime
- 2001-02-08 ES ES09006024T patent/ES2415407T3/en not_active Expired - Lifetime
- 2001-02-08 RS YUP-589/02A patent/RS50407B/en unknown
- 2001-02-08 DK DK10011790.2T patent/DK2283842T3/en active
- 2001-02-08 KR KR1020027010211A patent/KR100552038B1/en active IP Right Grant
- 2001-02-08 ES ES12167170.5T patent/ES2539904T3/en not_active Expired - Lifetime
- 2001-02-08 AU AU36876/01A patent/AU776666B2/en not_active Expired
- 2001-02-08 SI SI200131021T patent/SI2092936T1/en unknown
- 2001-02-08 MX MXPA02007690A patent/MXPA02007690A/en unknown
- 2001-02-08 PT PT01909086T patent/PT1299104E/en unknown
- 2001-02-08 DK DK10011789.4T patent/DK2277521T3/en active
- 2001-02-08 AT AT01909086T patent/ATE431145T1/en active
- 2001-02-08 PT PT121671705T patent/PT2517710E/en unknown
- 2001-02-08 PL PL385885A patent/PL210845B1/en unknown
- 2001-02-08 GE GE4855A patent/GEP20053614B/en unknown
- 2001-02-08 EP EP01909086A patent/EP1299104B1/en not_active Expired - Lifetime
- 2001-02-08 IL IL15105701A patent/IL151057A0/en active IP Right Grant
- 2001-02-08 BR BRPI0108380-5 patent/BRPI0108380B8/en not_active IP Right Cessation
- 2001-02-08 WO PCT/US2001/004347 patent/WO2001058447A1/en active Search and Examination
- 2001-02-08 ES ES01909086T patent/ES2326730T3/en not_active Expired - Lifetime
- 2001-02-08 DK DK09006024.5T patent/DK2092936T3/en active
- 2001-02-08 EP EP10011789.4A patent/EP2277521B1/en not_active Revoked
- 2001-04-17 TW TW090102735A patent/TWI292317B/en not_active IP Right Cessation
- 2001-08-02 UA UA2002097179A patent/UA79069C2/en unknown
-
2002
- 2002-08-01 IL IL151057A patent/IL151057A/en unknown
- 2002-08-07 NO NO20023728A patent/NO324717B1/en not_active IP Right Cessation
- 2002-08-07 NO NO20023729A patent/NO20023729L/en not_active Application Discontinuation
- 2002-08-08 BG BG106986A patent/BG65828B1/en unknown
-
2003
- 2003-03-28 HK HK03102267.9A patent/HK1051487A1/en unknown
- 2003-09-29 HK HK03107027.9A patent/HK1056822A1/en not_active IP Right Cessation
- 2003-10-21 US US10/689,866 patent/US7842311B2/en not_active Expired - Lifetime
- 2003-11-04 US US10/700,906 patent/US7682632B2/en active Active
- 2003-11-04 US US10/701,041 patent/US7658939B2/en not_active Expired - Lifetime
- 2003-11-04 US US10/700,893 patent/US7718192B2/en active Active
- 2003-11-04 US US10/700,861 patent/US7842309B2/en not_active Expired - Lifetime
-
2007
- 2007-02-15 IL IL181356A patent/IL181356A/en active IP Right Grant
- 2007-10-10 JP JP2007264445A patent/JP2008019280A/en active Pending
-
2009
- 2009-02-04 JP JP2009023739A patent/JP5351538B2/en not_active Expired - Lifetime
- 2009-08-04 CY CY20091100824T patent/CY1109270T1/en unknown
-
2010
- 2010-02-24 HK HK10101944.3A patent/HK1135907A1/en not_active IP Right Cessation
- 2010-03-25 IL IL204761A patent/IL204761A/en active IP Right Grant
- 2010-10-21 US US12/909,614 patent/US8236351B2/en not_active Expired - Lifetime
-
2011
- 2011-09-13 IL IL215132A patent/IL215132A0/en unknown
-
2012
- 2012-02-16 JP JP2012032017A patent/JP5676504B2/en not_active Expired - Lifetime
- 2012-06-20 JP JP2012138857A patent/JP2012176993A/en active Pending
- 2012-07-09 US US13/544,333 patent/US8357399B2/en not_active Expired - Lifetime
- 2012-12-18 US US13/718,879 patent/US8586088B2/en not_active Expired - Fee Related
-
2013
- 2013-06-18 CY CY20131100491T patent/CY1114063T1/en unknown
- 2013-10-04 US US14/045,961 patent/US8936812B2/en not_active Expired - Fee Related
-
2014
- 2014-05-01 JP JP2014094376A patent/JP2014169306A/en active Pending
- 2014-10-31 JP JP2014222704A patent/JP6063427B2/en not_active Expired - Lifetime
- 2014-12-10 US US14/565,904 patent/US9456989B2/en not_active Expired - Lifetime
-
2015
- 2015-03-23 US US14/665,670 patent/US9278073B2/en not_active Expired - Fee Related
-
2016
- 2016-08-24 US US15/245,338 patent/US9801828B2/en not_active Expired - Fee Related
- 2016-10-04 JP JP2016196329A patent/JP2016222730A/en active Pending
- 2016-10-25 JP JP2016208382A patent/JP6403742B2/en not_active Expired - Lifetime
-
2017
- 2017-09-26 US US15/715,425 patent/US10350173B2/en not_active Expired - Fee Related
-
2019
- 2019-06-05 US US16/432,719 patent/US10588865B2/en not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0205282A2 (en) * | 1985-06-11 | 1986-12-17 | Euroceltique S.A. | Oral pharmaceutical composition |
US4861598A (en) * | 1986-07-18 | 1989-08-29 | Euroceltique, S.A. | Controlled release bases for pharmaceuticals |
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 |
US5767125A (en) * | 1992-09-21 | 1998-06-16 | 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 |
US5942241A (en) * | 1995-06-09 | 1999-08-24 | Euro-Celtique, S.A. | Formulations and methods for providing prolonged local anesthesia |
US5998434A (en) * | 1995-12-06 | 1999-12-07 | Eli Lilly And Company | Composition for treating pain |
US5968547A (en) * | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
Cited By (312)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9283221B2 (en) | 2001-05-11 | 2016-03-15 | 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 |
US8969369B2 (en) | 2001-05-11 | 2015-03-03 | 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 |
US9161937B2 (en) | 2001-05-11 | 2015-10-20 | 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 |
WO2002092059A1 (en) * | 2001-05-11 | 2002-11-21 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
US9283216B2 (en) | 2001-05-11 | 2016-03-15 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
AU2002303718B2 (en) * | 2001-05-11 | 2008-02-28 | Endo Pharmaceuticals, Inc. | Abuse-resistant opioid dosage form |
US9358230B1 (en) | 2001-05-11 | 2016-06-07 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
US9480685B2 (en) | 2001-05-11 | 2016-11-01 | Purdue Pharma L.P. | Abuse-resistant controlled-release opioid dosage form |
WO2002092060A1 (en) * | 2001-05-11 | 2002-11-21 | Endo Pharmaceuticals, Inc. | 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 |
US8309122B2 (en) | 2001-07-06 | 2012-11-13 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US8329216B2 (en) | 2001-07-06 | 2012-12-11 | Endo Pharmaceuticals Inc. | Oxymorphone controlled release formulations |
US9693961B2 (en) | 2001-08-06 | 2017-07-04 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9517207B2 (en) | 2001-08-06 | 2016-12-13 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
USRE45822E1 (en) | 2001-08-06 | 2015-12-22 | Purdue Pharma L.P. | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US9867783B2 (en) | 2001-08-06 | 2018-01-16 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9308170B2 (en) | 2001-08-06 | 2016-04-12 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9308171B2 (en) | 2001-08-06 | 2016-04-12 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
WO2003013433A3 (en) * | 2001-08-06 | 2004-04-15 | Euro Celtique Sa | Sequestered antagonist formulations |
US9387173B2 (en) | 2001-08-06 | 2016-07-12 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US11135171B2 (en) | 2001-08-06 | 2021-10-05 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9387174B2 (en) | 2001-08-06 | 2016-07-12 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US8389007B2 (en) | 2001-08-06 | 2013-03-05 | Purdue Pharma L.P. | Pharmaceutical composition containing gelling agent |
US9861582B2 (en) | 2001-08-06 | 2018-01-09 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9867784B2 (en) | 2001-08-06 | 2018-01-16 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10537526B2 (en) | 2001-08-06 | 2020-01-21 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
WO2003013433A2 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Sequestered antagonist formulations |
US9044435B2 (en) | 2001-08-06 | 2015-06-02 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9872836B2 (en) | 2001-08-06 | 2018-01-23 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9060976B2 (en) | 2001-08-06 | 2015-06-23 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9040084B2 (en) | 2001-08-06 | 2015-05-26 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9861583B2 (en) | 2001-08-06 | 2018-01-09 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10064825B2 (en) | 2001-08-06 | 2018-09-04 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10500160B2 (en) | 2001-08-06 | 2019-12-10 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9877924B2 (en) | 2001-08-06 | 2018-01-30 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10064824B2 (en) | 2001-08-06 | 2018-09-04 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US8871265B2 (en) | 2001-08-06 | 2014-10-28 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10206881B2 (en) | 2001-08-06 | 2019-02-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10130586B2 (en) | 2001-08-06 | 2018-11-20 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9757341B2 (en) | 2001-08-06 | 2017-09-12 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US10076497B2 (en) | 2001-08-06 | 2018-09-18 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9034376B2 (en) | 2001-08-06 | 2015-05-19 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US9968559B2 (en) | 2001-08-06 | 2018-05-15 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
US8999961B2 (en) | 2001-08-06 | 2015-04-07 | Purdue Pharma, L.P. | Pharmaceutical formulation containing gelling agent |
US10071057B2 (en) | 2001-08-06 | 2018-09-11 | Purdue Pharma L.P. | Pharmaceutical formulation containing gelling agent |
JP2009167214A (en) * | 2001-10-18 | 2009-07-30 | Nektar Therapeutics Al Corp | Polymer conjugates of opioid antagonists |
JP4814488B2 (en) * | 2001-10-18 | 2011-11-16 | ネクター セラピューティックス | Polymer conjugate opioid antagonist |
JP2005506351A (en) * | 2001-10-18 | 2005-03-03 | ネクター セラピューティックス エイエル,コーポレイション | Polymer conjugate opioid antagonist |
US8349307B2 (en) | 2001-10-18 | 2013-01-08 | Nektar Therapeutics | Polymer conjugates of opioid antagonists |
US20060177381A1 (en) * | 2002-02-15 | 2006-08-10 | Howard Brooks-Korn | Opiopathies |
WO2003070191A3 (en) * | 2002-02-19 | 2004-09-10 | Euro Celtique Sa | Tamper-resistant transdermal opioid delivery devices |
WO2003070191A2 (en) * | 2002-02-19 | 2003-08-28 | Euro-Celtique, S.A. | Tamper-resistant transdermal opioid delivery devices |
EP2319540A1 (en) * | 2002-02-22 | 2011-05-11 | Shire LLC | Sustained release pharmaceutical compounds to prevent abuse of controlled substances |
US7666876B2 (en) | 2002-03-19 | 2010-02-23 | Vernalis (R&D) Limited | Buprenorphine formulations for intranasal delivery |
JP4728580B2 (en) * | 2002-03-19 | 2011-07-20 | ヴァーナリス アールアンドディー リミテッド | Formulation |
WO2003080183A1 (en) * | 2002-03-19 | 2003-10-02 | Euro-Celtique S.A. | Pharmaceutical combination of the cox-2 inhibitor etodolac and opioids |
JP2005526094A (en) * | 2002-03-19 | 2005-09-02 | イオニクス ファーマシューティカルズ リミテッド | Formulation |
US7790215B2 (en) | 2002-03-26 | 2010-09-07 | Purdue Pharma Lp | Sustained-release gel coated compositions |
JP2006508021A (en) * | 2002-03-26 | 2006-03-09 | ユーロ−セルティーク エス.エイ. | Sustained release gel coating composition |
JP2011201912A (en) * | 2002-03-26 | 2011-10-13 | Euro-Celtique Sa | Sustained-release gel coated composition |
JP4790219B2 (en) * | 2002-03-26 | 2011-10-12 | ユーロ−セルティーク エス.エイ. | Sustained release gel coating composition |
EP2425823A1 (en) * | 2002-04-05 | 2012-03-07 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
EP1639997A1 (en) * | 2002-04-05 | 2006-03-29 | Euro-Celtique S.A. | Matrix for sustained, invariant and independant release of active compounds |
EP2425825A1 (en) * | 2002-04-05 | 2012-03-07 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
EP1639996A1 (en) * | 2002-04-05 | 2006-03-29 | Euro-Celtique S.A. | Matrix for sustained, invariant and independant release of active compounds |
CN102813654A (en) * | 2002-04-05 | 2012-12-12 | 欧洲凯尔蒂克公司 | Matrix for sustained, invariant and independent release of active compounds |
EP2425824A1 (en) * | 2002-04-05 | 2012-03-07 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
EP2425825B1 (en) | 2002-04-05 | 2016-11-16 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
US9555000B2 (en) | 2002-04-05 | 2017-01-31 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
EP2319496A1 (en) * | 2002-04-05 | 2011-05-11 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
EP3241548A1 (en) * | 2002-04-05 | 2017-11-08 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
EP2425821A1 (en) * | 2002-04-05 | 2012-03-07 | Euro-Celtique S.A. | 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 |
EP1492505B1 (en) * | 2002-04-05 | 2015-06-03 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
EP2425821B1 (en) | 2002-04-05 | 2017-05-10 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
CN107669681A (en) * | 2002-04-05 | 2018-02-09 | 欧洲凯尔蒂克公司 | Pharmaceutical preparation containing dihydrohydroxycodeinone and naloxone |
EP2308475A1 (en) * | 2002-04-05 | 2011-04-13 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
EP2308474A1 (en) * | 2002-04-05 | 2011-04-13 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
EP2311438A1 (en) * | 2002-04-05 | 2011-04-20 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
US10420762B2 (en) | 2002-04-05 | 2019-09-24 | Purdue Pharma L.P. | Pharmaceutical preparation containing oxycodone and naloxone |
US8846091B2 (en) | 2002-04-05 | 2014-09-30 | Euro-Celtique S.A. | 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 |
EP2425824B1 (en) | 2002-04-05 | 2017-05-10 | Euro-Celtique S.A. | Pharmaceutical preparation containing oxycodone and naloxone |
US9655855B2 (en) | 2002-04-05 | 2017-05-23 | Purdue Pharma L.P. | Matrix for sustained, invariant and independent release of active compounds |
US10525053B2 (en) | 2002-07-05 | 2020-01-07 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
US9044398B2 (en) | 2002-07-05 | 2015-06-02 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
US9248195B2 (en) | 2002-07-05 | 2016-02-02 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
US10004729B2 (en) | 2002-07-05 | 2018-06-26 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US9682075B2 (en) | 2002-07-05 | 2017-06-20 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
EP1594467A1 (en) * | 2002-07-05 | 2005-11-16 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
WO2004004693A1 (en) | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
US9592200B2 (en) | 2002-07-05 | 2017-03-14 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
JP4694207B2 (en) * | 2002-07-05 | 2011-06-08 | コルジウム ファーマシューティカル, インコーポレイテッド | Abuse deterrent pharmaceutical compositions for opioids and other drugs |
US8557291B2 (en) | 2002-07-05 | 2013-10-15 | Collegium Pharmaceutical, Inc. | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
EP1594467A4 (en) * | 2002-07-05 | 2008-10-22 | Collegium Pharmaceutical Inc | Abuse-deterrent pharmaceutical compositions of opioids and other drugs |
JP2006500426A (en) * | 2002-07-05 | 2006-01-05 | コルジェジウム ファーマシューティカル | Abuse-deterrent pharmaceutical compositions for opioids and other drugs |
US8840928B2 (en) | 2002-07-05 | 2014-09-23 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
WO2004006929A1 (en) * | 2002-07-11 | 2004-01-22 | Taiho Pharmaceutical Co., Ltd. | Composition for nasal absorption |
US8679533B2 (en) | 2002-07-25 | 2014-03-25 | Pharmacia Corporation | Pramipexole once-daily dosage form |
DE10237056A1 (en) * | 2002-08-09 | 2004-03-04 | Grünenthal GmbH | Transdermal therapeutic systems containing buprenorphine, useful in treating pain or urinary incontinence, also containing mu-, kappa- or delta-opioid receptor antagonist to reduce abuse potential |
EP1894562A1 (en) * | 2002-08-15 | 2008-03-05 | Euro-Celtique S.A. | Pharmaceutical compositions |
EP1542658A1 (en) * | 2002-08-15 | 2005-06-22 | Euro-Celtique S.A. | Pharmaceutical compositions |
EP1542658A4 (en) * | 2002-08-15 | 2006-04-05 | Euro Celtique Sa | Pharmaceutical compositions |
EP2422773A3 (en) * | 2002-09-20 | 2012-04-18 | Alpharma, Inc. | Sequestering subunit and related compositions and methods |
US8685444B2 (en) | 2002-09-20 | 2014-04-01 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and methods |
EP1551372A1 (en) * | 2002-09-20 | 2005-07-13 | Alpharma, Inc. | Sequestering subunit and related compositions and metohds |
US8685443B2 (en) | 2002-09-20 | 2014-04-01 | Alpharma Pharmaceuticals Llc | Sequestering subunit and related compositions and methods |
EP2422772A3 (en) * | 2002-09-20 | 2012-04-18 | Alpharma, Inc. | Sequestering subunit and related compositions and methods |
AU2009251081B2 (en) * | 2002-09-20 | 2012-07-12 | Alpharma Pharmaceuticals, Llc | Sequestering subunit and related compositions and methods |
EP1551372A4 (en) * | 2002-09-20 | 2007-08-01 | Alpharma Inc | Sequestering subunit and related compositions and metohds |
EP2422775A3 (en) * | 2002-09-20 | 2012-04-18 | Alpharma, Inc. | Sequestering subunit and related compositions and methods |
US8623412B2 (en) | 2002-09-23 | 2014-01-07 | Elan Pharma International Limited | Abuse-resistant pharmaceutical compositions |
WO2004052346A1 (en) * | 2002-12-05 | 2004-06-24 | Eurand, Inc. | Pharmaceutical compositions containing indistinguishable drug components |
US8889176B2 (en) | 2003-01-10 | 2014-11-18 | Depomed, Inc. | Method of managing or treating pain |
US9078814B2 (en) | 2003-01-10 | 2015-07-14 | Depomed, Inc. | Intranasal spray device containing pharmaceutical composition |
US9814705B2 (en) | 2003-01-10 | 2017-11-14 | Depomed, Inc. | Intranasal spray device containing pharmaceutical composition |
EP1444977A1 (en) * | 2003-02-07 | 2004-08-11 | Novosis AG | Transdermal therapeutic delivery system with a butenolide |
EP3175846A1 (en) * | 2003-04-08 | 2017-06-07 | Elite Laboratories, Inc. | Abuse-resistant oral dosage forms and method of use thereof |
JP2006524249A (en) * | 2003-04-21 | 2006-10-26 | ユーロ−セルティーク エス.エイ. | Pharmaceutical products |
JP2011157384A (en) * | 2003-04-21 | 2011-08-18 | Euro-Celtique Sa | Tamper resistant dosage form comprising co-extruded adverse agent particle and method for making the same |
EP2258347A3 (en) * | 2003-04-21 | 2012-05-23 | Euro-Celtique S.A. | Tamper-resistant products for opioid delivery |
US10092519B2 (en) | 2003-04-21 | 2018-10-09 | Purdue Pharma L.P. | Pharmaceutical products |
EP2179724A3 (en) * | 2003-04-21 | 2010-10-27 | Euro-Celtique S.A. | Tamper-resistant products for opioid delivery |
JP2006524261A (en) * | 2003-04-21 | 2006-10-26 | ユーロ−セルティーク エス.エイ. | Anti-modified dosage form containing coextrusion adverse agent particles and process for producing the same |
EP1615615A4 (en) * | 2003-04-21 | 2007-03-07 | Euro Celtique Sa | Pharmaceutical products |
EP1615615A2 (en) * | 2003-04-21 | 2006-01-18 | Euro-Celtique S.A. | Pharmaceutical products |
US9149436B2 (en) | 2003-04-21 | 2015-10-06 | Purdue Pharma L.P. | Pharmaceutical product comprising a sequestered agent |
EP2269579A3 (en) * | 2003-04-21 | 2012-05-30 | Euro-Celtique S.A. | Tamper-resistant products for opioid delivery |
JP2012067113A (en) * | 2003-04-21 | 2012-04-05 | Euro-Celtique Sa | Pharmaceutical product |
US10238647B2 (en) | 2003-04-29 | 2019-03-26 | Nalpropion Pharmaceuticals, Inc. | Compositions for affecting weight loss |
EP1889621A1 (en) * | 2003-06-27 | 2008-02-20 | Euro-Celtique S.A. | Multiparticulates |
EA013424B1 (en) * | 2003-06-27 | 2010-04-30 | Эро-Селтик С.А. | Multiparticulates |
JP2007520429A (en) * | 2003-06-27 | 2007-07-26 | ユーロ−セルティーク エス.エイ. | Multi particles |
WO2005000310A1 (en) * | 2003-06-27 | 2005-01-06 | Euro-Celtique S.A. | Multiparticulates |
JP2013209387A (en) * | 2003-06-27 | 2013-10-10 | Euro-Celtique Sa | Multiparticulate |
KR101116518B1 (en) * | 2003-06-27 | 2012-03-13 | 유로-셀티큐 에스.에이. | Multiparticulates |
AU2004251481B2 (en) * | 2003-06-27 | 2010-01-28 | Euro-Celtique S.A. | Multiparticulates |
WO2005037318A3 (en) * | 2003-10-15 | 2005-06-09 | Pain Therapeutics Inc | Treatment of arthritic conditions, chronic inflammation or pain |
WO2005037318A2 (en) * | 2003-10-15 | 2005-04-28 | Pain Therapeutics, Inc. | Treatment of arthritic conditions, chronic inflammation or pain |
US8920836B2 (en) | 2004-02-12 | 2014-12-30 | Euro-Celtique S.A. | Particulates |
EP1718258A4 (en) * | 2004-02-23 | 2007-08-15 | Euro Celtique Sa | Abuse resistance opioid transdermal delivery device |
EP2074989A1 (en) * | 2004-02-23 | 2009-07-01 | Euro-Celtique S.A. | Abuse resistance opioid transdermal delivery device |
EP2351555A3 (en) * | 2004-02-23 | 2011-11-30 | Euro-Celtique S.A. | Abuse resistance opioid transdermal delivery device |
EP1718258A2 (en) * | 2004-02-23 | 2006-11-08 | Euro-Celtique S.A. | Abuse resistant opioid transdermal delivery device containing opioid antagonist microspheres |
WO2005107726A3 (en) * | 2004-04-27 | 2006-08-24 | Pain Therapeutics Inc | Method for the treatment of back pain |
WO2005107726A2 (en) * | 2004-04-27 | 2005-11-17 | Pain Therapeutics, Inc. | Method for the treatment of back pain |
US9763883B2 (en) | 2004-06-12 | 2017-09-19 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
US7771707B2 (en) | 2004-06-12 | 2010-08-10 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
US10525052B2 (en) | 2004-06-12 | 2020-01-07 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
US8758813B2 (en) | 2004-06-12 | 2014-06-24 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
US8449909B2 (en) | 2004-06-12 | 2013-05-28 | Collegium Pharmaceutical, Inc. | Abuse-deterrent drug formulations |
EP2269582A3 (en) * | 2004-08-31 | 2011-01-26 | Euro-Celtique S.A. | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
EA017435B1 (en) * | 2004-08-31 | 2012-12-28 | Эро-Селтик С.А. | Multiparticulates, method of manufacturing and use thereof |
WO2006024881A3 (en) * | 2004-08-31 | 2006-05-26 | Euro Celtique Sa | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
JP2013129663A (en) * | 2004-08-31 | 2013-07-04 | Euro-Celtique Sa | Multiparticulates |
WO2006024881A2 (en) * | 2004-08-31 | 2006-03-09 | Euro-Celtique S.A. | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
JP2008511604A (en) * | 2004-08-31 | 2008-04-17 | ユーロ−セルティック エス. ア. | Multi particles |
JP2016029091A (en) * | 2004-08-31 | 2016-03-03 | ユーロ−セルティック エス. ア. | Multiparticulates |
CN103462904A (en) * | 2004-08-31 | 2013-12-25 | 欧洲凯尔蒂克公司 | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
US9259872B2 (en) | 2004-08-31 | 2016-02-16 | Euro-Celtique S.A. | Multiparticulates |
GB2418854B (en) * | 2004-08-31 | 2009-12-23 | Euro Celtique Sa | Multiparticulates |
AU2005278919B2 (en) * | 2004-08-31 | 2011-04-07 | Euro-Celtique S.A. | Multiparticulates of preferably an opioid, and method of manufacturing using extrusion |
EP1771160A2 (en) * | 2005-01-28 | 2007-04-11 | Euroceltique S.A. | Alcohol resistant dosage forms |
EP2319499A1 (en) | 2005-01-28 | 2011-05-11 | Euro-Celtique S.A. | Alcohol resistant dosage forms |
US10258235B2 (en) | 2005-02-28 | 2019-04-16 | Purdue Pharma L.P. | Method and device for the assessment of bowel function |
WO2006124890A1 (en) * | 2005-05-13 | 2006-11-23 | Alpharma, Inc. | Morphine sulphate formulations |
WO2006124898A1 (en) * | 2005-05-13 | 2006-11-23 | Alpharma, Inc. | Morphine sulfate formulations |
WO2007016563A3 (en) * | 2005-08-01 | 2007-06-28 | Alpharma Inc | Alcohol resistant pharmaceutical formulations |
WO2007016563A2 (en) * | 2005-08-01 | 2007-02-08 | Alpharma Inc. | Alcohol resistant pharmaceutical formulations |
US9457005B2 (en) | 2005-11-22 | 2016-10-04 | Orexigen Therapeutics, Inc. | Compositions and methods for increasing insulin sensitivity |
WO2007070632A3 (en) * | 2005-12-13 | 2007-10-11 | Biodelivery Sciences Internati | Abuse resistant transmucosal drug delivery device |
US20200155543A1 (en) * | 2005-12-13 | 2020-05-21 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
WO2007070632A2 (en) * | 2005-12-13 | 2007-06-21 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
AU2006326377B2 (en) * | 2005-12-13 | 2010-10-07 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
US9522188B2 (en) | 2005-12-13 | 2016-12-20 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
US20210000819A1 (en) * | 2005-12-13 | 2021-01-07 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
US20180098986A1 (en) * | 2005-12-13 | 2018-04-12 | Biodelivery Sciences International, Inc. | Abuse resistant transmucosal drug delivery device |
EP1810714A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of a combination of heroin and naloxon for drug substitution |
EP1810678A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Use of morphine and naloxone for drug substitution |
WO2007082935A1 (en) * | 2006-01-19 | 2007-07-26 | Phoenux Ag | Use of a combination of morphine and at least one opiate antagonist for treatment of opiate dependency and for prevention of non-oral opiate abuse in opiate addicts |
US10507205B2 (en) | 2006-01-19 | 2019-12-17 | Purdue Pharmaceutical Products L.P. | Methods of treating opiate dependency and preventing non-oral opiate abuse among opiate addicts |
EA014539B1 (en) * | 2006-01-19 | 2010-12-30 | Фенукс Аг | Use of a combination of morphine and at least one opiate antagonists for treatment of opiate dependency and for prevention of non-oral opiate abuse in opiate addicts |
US9107837B2 (en) | 2006-06-05 | 2015-08-18 | Orexigen Therapeutics, Inc. | Sustained release formulation of naltrexone |
US8158156B2 (en) | 2006-06-19 | 2012-04-17 | Alpharma Pharmaceuticals, Llc | Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist |
US8877247B2 (en) | 2006-06-19 | 2014-11-04 | Alpharma Pharmaceuticals Llc | Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist |
US8846104B2 (en) | 2006-06-19 | 2014-09-30 | Alpharma Pharmaceuticals Llc | Pharmaceutical compositions for the deterrence and/or prevention of abuse |
US7682634B2 (en) | 2006-06-19 | 2010-03-23 | Alpharma Pharmaceuticals, Llc | Pharmaceutical compositions |
US7682633B2 (en) | 2006-06-19 | 2010-03-23 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
AU2011205222B2 (en) * | 2006-07-21 | 2014-02-27 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
WO2008011194A3 (en) * | 2006-07-21 | 2008-05-15 | Biodelivery Sciences Int Inc | Transmucosal delivery devices with enhanced uptake |
US9597288B2 (en) | 2006-07-21 | 2017-03-21 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
EP3067044A1 (en) * | 2006-07-21 | 2016-09-14 | BioDelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
WO2008011595A3 (en) * | 2006-07-21 | 2008-11-13 | Lab Internat Srl | Hydrophobic abuse deterrent delivery system |
NO340668B1 (en) * | 2006-07-21 | 2017-05-29 | Biodelivery Sciences Int Inc | Bioerodible drug delivery device for use in medicine and mucoadhesive drug delivery device. |
WO2008011595A2 (en) * | 2006-07-21 | 2008-01-24 | Lab International Srl | Hydrophobic abuse deterrent delivery system |
WO2008011194A2 (en) * | 2006-07-21 | 2008-01-24 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
AU2007275581B2 (en) * | 2006-07-21 | 2011-09-08 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
US9655843B2 (en) | 2006-07-21 | 2017-05-23 | Biodelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
EP3566692A1 (en) * | 2006-07-21 | 2019-11-13 | BioDelivery Sciences International, Inc. | Transmucosal delivery devices with enhanced uptake |
RU2504377C2 (en) * | 2006-07-21 | 2014-01-20 | БайоДеливери Сайенсиз Интэнэшнл, Инк. | Method for transmucosal drug delivery, agent for transmucosal drug delivery (versions) and method for pain management |
WO2008063301A3 (en) * | 2006-10-11 | 2008-09-04 | Alpharma Inc | Pharmaceutical compositions |
WO2008063301A2 (en) * | 2006-10-11 | 2008-05-29 | Alpharma, Inc. | Pharmaceutical compositions |
US9125868B2 (en) | 2006-11-09 | 2015-09-08 | Orexigen Therapeutics, Inc. | Methods for administering weight loss medications |
US9308202B2 (en) | 2006-11-21 | 2016-04-12 | Purdue Pharma L.P. | Transdermal therapeutic system for administering the active substance buprenorphine |
US8912211B2 (en) * | 2007-03-01 | 2014-12-16 | Rb Pharmaceuticals Limited | Medicinal compositions comprising buprenorphine and naltrexone |
GB2447014A (en) * | 2007-03-01 | 2008-09-03 | Reckitt Benckiser Healthcare | Analgesic composition comprising a specific ratio of buprenorphine and naltrexone |
US10888521B2 (en) | 2007-03-02 | 2021-01-12 | Farnam Companies, Inc. | Sustained release compositions using wax-like materials |
AU2008223091B2 (en) * | 2007-03-02 | 2014-04-24 | Farnam Companies, Inc. | Sustained release pellets comprising wax-like material |
WO2008109462A2 (en) * | 2007-03-02 | 2008-09-12 | Farnam Companies, Inc. | Sustained release pellets comprising wax-like material |
WO2008109462A3 (en) * | 2007-03-02 | 2008-12-24 | Farnam Co Inc | Sustained release pellets comprising wax-like material |
US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
US9700552B2 (en) | 2008-02-28 | 2017-07-11 | Syntropharma Limited | Pharmaceutical compositions for treatment of addiction |
WO2009106831A2 (en) * | 2008-02-28 | 2009-09-03 | Syntropharma Limited | Pharmaceutical composition |
WO2009106831A3 (en) * | 2008-02-28 | 2009-10-29 | Syntropharma Limited | Pharmaceutical composition comprising naltrexone |
US10729686B2 (en) | 2008-02-28 | 2020-08-04 | Libero Pharma Limited | Pharmaceutical compositions |
US11324741B2 (en) | 2008-05-30 | 2022-05-10 | Nalpropion Pharmaceuticals Llc | Methods for treating visceral fat conditions |
EP2352494B1 (en) * | 2008-10-30 | 2019-10-09 | Grünenthal GmbH | Novel and potent tapentadol dosage forms |
US9642801B2 (en) | 2008-10-30 | 2017-05-09 | Gruenenthal Gmbh | And potent tapentadol dosage forms |
EP2448406A4 (en) * | 2009-02-26 | 2013-06-26 | Relmada Therapeutics Inc | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
EP2448406A1 (en) * | 2009-02-26 | 2012-05-09 | Relmada Therapeutics, Inc. | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
EP3045043A1 (en) * | 2009-02-26 | 2016-07-20 | Relmada Therapeutics, Inc. | Extended release oral pharmaceutical compositions of 3-hydroxy-n-methylmorphinan and method of use |
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 |
WO2010121600A3 (en) * | 2009-04-22 | 2011-10-27 | Lars Holger Hermann | Particulate pharmaceutical composition having an opioid and an opioid antagonist |
US9814679B2 (en) | 2009-06-05 | 2017-11-14 | Euro-Celtique S.A. | Tamper resistant dosage form comprising a matrix and melt-extruded particulates comprising a drug |
US10668060B2 (en) | 2009-12-10 | 2020-06-02 | Collegium Pharmaceutical, Inc. | Tamper-resistant pharmaceutical compositions of opioids and other drugs |
US9248123B2 (en) | 2010-01-11 | 2016-02-02 | Orexigen Therapeutics, Inc. | Methods of providing weight loss therapy in patients with major depression |
US10322121B2 (en) | 2010-01-11 | 2019-06-18 | Nalpropion Pharmaceuticals, Inc. | Methods of providing weight loss therapy in patients with major depression |
US9277748B2 (en) | 2010-03-12 | 2016-03-08 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Agonist/antagonist compositions and methods of use |
WO2011112956A1 (en) * | 2010-03-12 | 2011-09-15 | Government Of The Usa, As Represented By The Sec., Dept. Of Health And Human Services | Agonist/antagonist compositions and methods of use |
CN103002881A (en) * | 2010-05-10 | 2013-03-27 | 欧洲凯尔特公司 | Combination of active loaded granules with additional actives |
US9993433B2 (en) | 2010-05-10 | 2018-06-12 | Euro-Celtique S.A. | Manufacturing of active-free granules and tablets comprising the same |
US9901540B2 (en) | 2010-05-10 | 2018-02-27 | Euro-Celtique S.A. | Combination of active loaded granules with additional actives |
US9700508B2 (en) | 2010-05-10 | 2017-07-11 | Euro-Celtique S.A. | Pharmaceutical compositions comprising hydromorphone and naloxone |
WO2011141490A1 (en) * | 2010-05-10 | 2011-11-17 | Euro-Celtique S.A. | Combination of active loaded granules with additional actives |
AU2011252041B2 (en) * | 2010-05-10 | 2014-04-03 | Euro-Celtique S.A. | Combination of active loaded granules with additional actives |
WO2012052169A3 (en) * | 2010-10-21 | 2012-07-26 | Phoeme Gmbh | Particulate pharmaceutical composition containing an opioid and an opioid antagonist |
US9861584B2 (en) | 2010-12-22 | 2018-01-09 | Purdue Pharma L.P. | Tamper resistant controlled release dosage forms |
US9393206B2 (en) | 2010-12-22 | 2016-07-19 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US11911512B2 (en) | 2010-12-22 | 2024-02-27 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US10966932B2 (en) | 2010-12-22 | 2021-04-06 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US11590082B2 (en) | 2010-12-22 | 2023-02-28 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US9572779B2 (en) | 2010-12-22 | 2017-02-21 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US9872837B2 (en) | 2010-12-22 | 2018-01-23 | Purdue Pharma L.P. | Tamper resistant controlled release dosage forms |
US9744136B2 (en) | 2010-12-22 | 2017-08-29 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US9750703B2 (en) | 2010-12-22 | 2017-09-05 | Purdue Pharma L.P. | Encased tamper resistant controlled release dosage forms |
US9895317B2 (en) | 2010-12-23 | 2018-02-20 | Purdue Pharma L.P. | Tamper resistant solid oral dosage forms |
US9707180B2 (en) | 2010-12-23 | 2017-07-18 | Purdue Pharma L.P. | Methods of preparing tamper resistant solid oral dosage forms |
US9233073B2 (en) | 2010-12-23 | 2016-01-12 | Purdue Pharma L.P. | Tamper resistant solid oral dosage forms |
JP2016040268A (en) * | 2010-12-28 | 2016-03-24 | ユーロ−セルティーク エス.エイ. | Combination of opioid agonist and an opioid antagonist in treatment of parkinson's disease |
EA025747B1 (en) * | 2010-12-28 | 2017-01-30 | Эро-Селтик С.А. | Combination of an opioid receptor agonist and an opioid receptor antagonist in the treatment of parkinson's disease |
JP2014501268A (en) * | 2010-12-28 | 2014-01-20 | ユーロ−セルティーク エス.エイ. | Combination of opioid agonists and opioid antagonists in the treatment of Parkinson's disease |
WO2012089738A1 (en) * | 2010-12-28 | 2012-07-05 | Euro-Celtique S.A. | A combination of an opioid agonist and an opioid antagonist in the treatment of parkinson's disease |
AU2011351447B2 (en) * | 2010-12-28 | 2016-02-25 | Mundipharma Pty Limited | A combination of an opioid agonist and an opioid antagonist in the treatment of Parkinson's disease |
US9549903B2 (en) | 2011-12-12 | 2017-01-24 | Purdue Pharma L.P. | Transdermal delivery system comprising buprenorphine |
US9901539B2 (en) | 2011-12-21 | 2018-02-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
WO2013096811A2 (en) | 2011-12-21 | 2013-06-27 | Biodelivery Sciences International, Inc. | Transmucosal drug delivery devices for use in chronic pain relief |
EP2793870A4 (en) * | 2011-12-21 | 2016-02-17 | Biodelivery Sciences Int Inc | Transmucosal drug delivery devices for use in chronic pain relief |
WO2013153145A1 (en) * | 2012-04-12 | 2013-10-17 | Lts Lohmann Therapie-Systeme Ag | Oral film containing opiate enteric-release beads |
US9763879B2 (en) | 2012-04-12 | 2017-09-19 | Lts Lohmann Therapie-Systeme Ag | Oral film containing opiate enteric-release beads |
US9633575B2 (en) | 2012-06-06 | 2017-04-25 | Orexigen Therapeutics, Inc. | Methods of treating overweight and obesity |
US10403170B2 (en) | 2012-06-06 | 2019-09-03 | Nalpropion Pharmaceuticals, Inc. | Methods of treating overweight and obesity |
US9579389B2 (en) | 2013-02-05 | 2017-02-28 | Purdue Pharma L.P. | Methods of preparing tamper resistant pharmaceutical formulations |
US9545448B2 (en) | 2013-02-05 | 2017-01-17 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9655971B2 (en) | 2013-02-05 | 2017-05-23 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9662399B2 (en) | 2013-02-05 | 2017-05-30 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US11576974B2 (en) | 2013-02-05 | 2023-02-14 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10792364B2 (en) | 2013-02-05 | 2020-10-06 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10478504B2 (en) | 2013-02-05 | 2019-11-19 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9149533B2 (en) | 2013-02-05 | 2015-10-06 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US9616030B2 (en) | 2013-03-15 | 2017-04-11 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10751287B2 (en) | 2013-03-15 | 2020-08-25 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10195152B2 (en) | 2013-03-15 | 2019-02-05 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10517832B2 (en) | 2013-03-15 | 2019-12-31 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US11529345B2 (en) | 2013-06-04 | 2022-12-20 | Lts Lohmann Therapie-Systeme Ag | Buprenorphine transdermal delivery system |
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 |
US10258616B2 (en) | 2013-11-13 | 2019-04-16 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
US9814710B2 (en) | 2013-11-13 | 2017-11-14 | Euro-Celtique S.A. | Hydromorphone and naloxone for treatment of pain and opioid bowel dysfunction syndrome |
US9801875B2 (en) | 2013-12-06 | 2017-10-31 | Orexigen Therapeutics, Inc. | Compositions and methods for weight loss in at risk patient populations |
US8969371B1 (en) | 2013-12-06 | 2015-03-03 | Orexigen Therapeutics, Inc. | Compositions and methods for weight loss in at risk patient populations |
US9119850B2 (en) | 2013-12-06 | 2015-09-01 | Orexigen Therapeutics, Inc. | Compositions and methods for weight loss in at risk patient populations |
US10231962B2 (en) | 2013-12-06 | 2019-03-19 | Nalpropion Pharmaceuticals, Inc. | Compositions and methods for reducing major adverse cardiovascular events |
US10231964B2 (en) | 2013-12-06 | 2019-03-19 | Nalpropion Pharmaceuticals, Inc. | Compositions and methods for weight loss in at risk patient populations |
US9480644B2 (en) | 2014-03-14 | 2016-11-01 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US9775838B2 (en) | 2014-03-14 | 2017-10-03 | Adapt Pharma Limited | Nasal drug products and methods of their use |
US9211253B2 (en) | 2014-03-14 | 2015-12-15 | Lightlake Therapeutics Inc. | Nasal drug products and methods of their use |
US10085937B2 (en) | 2014-03-14 | 2018-10-02 | Adapt Pharma Limited | Nasal drug products and methods of their use |
US9629965B2 (en) | 2014-03-14 | 2017-04-25 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US9468747B2 (en) | 2014-03-14 | 2016-10-18 | Opiant Pharmaceuticals, Inc. | Nasal drug products and methods of their use |
US9707226B2 (en) | 2014-03-14 | 2017-07-18 | Adapt Pharma Limited | Nasal drug products and methods of their use |
US9561177B2 (en) | 2014-03-14 | 2017-02-07 | Adapt Pharma Limited | Nasal drug products and methods of their use |
US10493027B2 (en) | 2014-08-07 | 2019-12-03 | Mucodel Pharma Llc | Chemically stable compositions of a pharmaceutical active agent in a multi- chambered delivery system for mucosal delivery |
EP3177270A4 (en) * | 2014-08-07 | 2018-01-24 | Mucodel Pharma LLC | Chemically stable and oromucosally absorbable gel compositions of a pharmaceutical active agent in a multi-chambered delivery system |
WO2016091805A3 (en) * | 2014-12-08 | 2016-12-15 | Develco Pharma Schweiz Ag | Naloxone monopreparation and multi-layer tablet |
US10406300B2 (en) | 2015-02-06 | 2019-09-10 | Vapomed Limited | Dual chamber inhaler for sequentially administering multiple drugs |
US10406299B2 (en) | 2015-02-06 | 2019-09-10 | Vapomed Limited | Pharmaceutical composition and device for treating pain |
WO2016124788A1 (en) | 2015-02-06 | 2016-08-11 | Jacques Seguin | Pharmaceutical composition and device for treating pain |
US11077055B2 (en) | 2015-04-29 | 2021-08-03 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
WO2017044789A1 (en) * | 2015-09-09 | 2017-03-16 | Micell Technologies, Inc. | Biopharma application of micell technology |
CN108135852A (en) * | 2015-09-09 | 2018-06-08 | 脉胜医疗技术公司 | The bio-pharmaceutical application of micellar technology |
US10835488B2 (en) | 2016-06-16 | 2020-11-17 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
US9737530B1 (en) | 2016-06-23 | 2017-08-22 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
US10646485B2 (en) | 2016-06-23 | 2020-05-12 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
US9968598B2 (en) | 2016-06-23 | 2018-05-15 | Collegium Pharmaceutical, Inc. | Process of making stable abuse-deterrent oral formulations |
US10188644B2 (en) | 2016-06-23 | 2019-01-29 | Collegium Pharmaceutical, Inc | Process of making stable abuse-deterrent oral formulations |
WO2018208241A1 (en) * | 2017-05-10 | 2018-11-15 | İlko Ilaç Sanayi Ve Ticaret Anonim Şirketi | Formulation and optimization of controlled release tablets of morphine sulphate |
WO2021019506A1 (en) * | 2019-07-31 | 2021-02-04 | Vetagro International S.R.L. | Multiparticulate microparticle controlled release formulation comprising combination of amino acids and phytocompound |
EP3936112A1 (en) * | 2020-07-07 | 2022-01-12 | Occlugel | Hydrophilic degradable microspheres for delivering buprenorphine |
WO2022008100A1 (en) * | 2020-07-07 | 2022-01-13 | Occlugel | Hydrophilic degradable microspheres for delivering buprenorphine |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6716449B2 (en) | Controlled-release compositions containing opioid agonist and antagonist | |
AU776904B2 (en) | Controlled-release compositions containing opioid agonist and antagonist | |
US8815287B2 (en) | Opiod agonist formulations with releasable and sequestered antagonist | |
EP1255547B1 (en) | Controlled-release compositions containing opioid agonist and antagonist |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 36877/01 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 520553 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: IN/PCT/2002/00757/DE Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 151058 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020027010121 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: P-588/02 Country of ref document: YU Ref document number: 2400578 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2001 557557 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2002/007690 Country of ref document: MX Ref document number: 2001909087 Country of ref document: EP Ref document number: PV2002-2707 Country of ref document: CZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 200200839 Country of ref document: EA |
|
WWP | Wipo information: published in national office |
Ref document number: 1020027010121 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 018077250 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2001909087 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: PV2002-2707 Country of ref document: CZ |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1020027010121 Country of ref document: KR |
|
WWR | Wipo information: refused in national office |
Ref document number: PV2002-2707 Country of ref document: CZ |
|
WWG | Wipo information: grant in national office |
Ref document number: 36877/01 Country of ref document: AU |
|
DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) |