WO2003013476A1 - Compositions et procedes servant a empecher la surconsommation d'opioides - Google Patents

Compositions et procedes servant a empecher la surconsommation d'opioides Download PDF

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Publication number
WO2003013476A1
WO2003013476A1 PCT/US2002/024935 US0224935W WO03013476A1 WO 2003013476 A1 WO2003013476 A1 WO 2003013476A1 US 0224935 W US0224935 W US 0224935W WO 03013476 A1 WO03013476 A1 WO 03013476A1
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Prior art keywords
dosage form
oral dosage
controlled release
pharmaceutically acceptable
drug
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PCT/US2002/024935
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English (en)
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WO2003013476B1 (fr
Inventor
Christopher Breder
Robert Colucci
Benjamin Oshlack
Richard Sackler
Curtis Wright
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Euro-Celtique S.A.
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Priority to JP2003518486A priority Critical patent/JP2005500364A/ja
Priority to EP02752708A priority patent/EP1414413A1/fr
Priority to MXPA04001206A priority patent/MXPA04001206A/es
Priority to CA002455420A priority patent/CA2455420A1/fr
Priority to IL16021702A priority patent/IL160217A0/xx
Priority to BR0212020-8A priority patent/BR0212020A/pt
Priority to HU0401344A priority patent/HUP0401344A2/hu
Priority to DE20220917U priority patent/DE20220917U1/de
Priority to KR10-2004-7001877A priority patent/KR20040025741A/ko
Publication of WO2003013476A1 publication Critical patent/WO2003013476A1/fr
Publication of WO2003013476B1 publication Critical patent/WO2003013476B1/fr

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    • 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
    • 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
    • A61K9/14—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • Opioid analgesics are sometimes the subject of abuse.
  • a particular dose of an opioid analgesic is more potent when administered parenterally as compared to the same dose administered orally. Therefore, one popular mode of abuse of oral opioid formulations involves the extraction of the opioid from the dosage form, and the subsequent injection of the opioid (using any "suitable" vehicle for injection) in order to achieve a "high.”
  • some formulations can be tampered with in order to provide the opioid agonist contained therein better available for illicit use. For example, a controlled release opioid agonist formulation can be crushed in order to provide the opioid contained therein available for immediate release upon oral or nasal administration.
  • An opioid formulation can also be abusable by administration of more than the prescribed dose of the drug.
  • Opioid antagonists have been combined with certain opioid agonists in order to deter the parenteral abuse of opioid agonists.
  • the combination of immediate release pentazocine and naloxone has been utilized in tablets available in the United States, commercially available as Talw ⁇ jx from Sanofi-Winthrop.
  • TalwuvNx contains immediate release pentazocine hydrochloride equivalent to 50 mg base and naloxone hydrochloride equivalent to 0.5 mg base.
  • a fixed combination therapy comprising tilidine (50 mg) and naloxone (4 mg) has been available in Germany for the management of pain since 1978 (Valoron ⁇ N, Goedecke).
  • a fixed combination of buprenorphine and naloxone was introduced in 1991 in New Zealand (Temgesic ⁇ Nx, Reckitt & Colman) for the treatnent of pain.
  • Purdue Pharma L.P currently markets sustained-release oxycodone in dosage forms containing 10, 20, 40, and 80 mg oxycodone hydrochloride under the tradename OxyContin.
  • U.S. Patent No. 4,769,372 and 4,785,000 to Kreek describe methods of treating patients suffering from chronic pain or chronic cough without provoking intestinal dysmotility by administering 1 to 2 dosage units comprising from about 1.5 to about 100 mg of opioid analgesic or antitussive and from about 1 to about 18 mg of an opioid antagonist having little to no systemic antagonist activity when administered orally, from 1 to 5 times daily.
  • U.S. Patent No. 6,228,863 to Palermo et al. describes compositions and methods of preventing abuse of opioid dosage forms.
  • WO 99/32119 to Kaiko et al. describes compositions and methods of preventing abuse of opioid dosage forms.
  • U.S. Patent No. 5,472,943 to Crain et al. describes methods of enhancing the analgesic potency of bimodally acting opioid agonists by administering the agonist with an opioid antagonist.
  • U.S. Patent No. 3,980,766 to Shaw et al. is related to drugs which are suitable for therapy in the treatment of narcotic drug addiction by oral use, e.g., methadone, formulated to prevent injection abuse through concentration of the active component in aqueous solution by incorporating in a solid dosage or tablet form of such drug an ingestible solid having thickening properties which cause rapid increase in viscosity upon concentration of an aqueous solution thereof.
  • the oral dosage forms of the present invention comprising an opioid analgesic; and an aversive agent or agents as a component(s) of the dosage form helps to prevent injection, inhalation, and/or oral abuse by decreasing the "attractiveness" of the dosage form to a potential abuser.
  • the dosage form comprises an aversive agent such as a bittering agent to discourage an abuser from tampering with the dosage form and thereafter inhaling or swallowing the tampered dosage form.
  • aversive agent such as a bittering agent to discourage an abuser from tampering with the dosage form and thereafter inhaling or swallowing the tampered dosage form.
  • the bittering agent is released when the dosage form is tampered with and provides an unpleasant taste to the abuser upon inhalation and/or swallowing of the tampered dosage form.
  • the dosage form comprises an aversive agent such as a gelling agent to discourage an abuser from tampering with the dosage form and thereafter inhaling, injecting, and/or swallowing the tampered dosage form.
  • an aversive agent such as a gelling agent to discourage an abuser from tampering with the dosage form and thereafter inhaling, injecting, and/or swallowing the tampered dosage form.
  • the gelling agent is released when the dosage form is tampered with and provides a gel-like quality to the tampered dosage form which slows the absorption of the opioid analgesic such that an abuser is less likely to obtain a rapid "high".
  • the dosage form when the dosage form is tampered with and exposed to a small amount (e.g., less than about 10 ml) of an aqueous liquid (e.g., water), the dosage form will be unsuitable for injection and/or inhalation.
  • an aqueous liquid e.g., water
  • the tampered dosage form preferably becomes thick and viscous, rendering it unsuitable for injection.
  • the term "unsuitable for injection” is defined for purposes of the present invention to mean that one would have substantial difficulty injecting the dosage form (e.g., due to pain upon administration or difficulty pushing the dosage form through a syringe) due to the viscosity imparted on the dosage form, thereby reducing the potential for abuse of the opioid analgesic in the dosage form.
  • the gelling agent is present in such an amount in the dosage form that attempts at evaporation (by the application of heat) to an aqueous mixture of the dosage form in an effort to produce a higher concentration of the therapeutic agent, produces a highly viscous substance unsuitable for injection.
  • Embodiments specifically contemplated include bittering agent; gelling agent; irritant; bittering agent and gelling agent; bittering agent and irritant; gelling agent and irritant; and bittering agent and gelling agent and irritant.
  • the dosage forms are controlled release oral dosage forms comprising a therapeutically effective amount of an opioid analgesic with one or more of the aversive agents described above such that the dosage form provides effective pain relief for at least about 12 hours, or at least about 24 hours when orally administered to a human patient.
  • the aversive agent present in the dosage form is present in a substantially non-releasable form (i.e., "sequestered") when the dosage form is administered intact as directed.
  • aversive agent is present in the dosage form in a substantially non-releasable form, it is not substantially released in the gastrointestinal tract when the dosage form is orally administered intact.
  • the aversive agent may not be "sequestered” as disclosed above wherein the aversive agent is not released or minimally released from an intact dosage form, but may have a modified or sustained release so as not to dump the aversive agent in a particular section of the gastrointestinal tract, e.g. the stomach, where it may cause an unwanted effect such as excessive irritation.
  • the aversive agent can be combined with an enteric carrier to delay its release or combined with a carrier to provide a sustained release of the aversive agent.
  • the aversive agent will preferably not have any significant side effect (e.g., gastrointestinal side effect) even if all of the aversive agent is immediately released upon oral administration of an intact dosage form as directed.
  • the aversive agent(s) can also be in the dosage form in releasable form and non- releasable fo ⁇ n in any combination.
  • a dosage form can have a bittering agent, irritant, gel or combination thereof in releasable form and non-releasable form as disclosed in U.S. Application entitled "Pharmaceutical Formulations Containing Opioid Agonist, Releasable Antagonist, and Sequestered Antagonist" filed August 6, 2002, the disclosure of which is hereby incorporated by reference in its entirety.
  • aversive agent is defined for purposes of the present invention to mean a bittering agent, an irritant, a gelling agent, or combinations thereof.
  • tampered dosage form is defined for purposes of the present invention to mean that the dosage form has been manipulated by mechanical, thermal, tmd/or chemical means which changes the physical properties of the dosage form, e.g., to liberate the opioid agonist for immediate release if it is in sustained release form, or to make the opioid agonist available for inappropriate use such as administration by an alternate route, e.g., parenterally.
  • the tampering can be, e.g., by means of crushing, shearing, grinding, chewing, dissolution in a solvent, heating, (e.g., greater than about 45° C), or any combination thereof.
  • substantially non-releasable form refers to an aversive agent that is not released or substantially not released at one hour after the intact dosage form containing an opioid agonist and at least one aversive agent is orally administered (i.e., without having been tampered with).
  • the aversive agent in a substantially non-releasable form may be prepared in accordance with the teachings of U.S. Application Serial No. 09/781,081, entitled “Tamper Resistant Oral Opioid Agonist Formulations” filed February 8, 2001, the disclosure of which is hereby incorporated by reference in its entirety, which describes a dosage form comprising an opioid antagonist in a substantially non- releasable form.
  • the amount released after oral administration of the intact dosage form may be measured in- vitro via the dissolution at 1 hour of the dosage form in 900 ml of Simulated Gastric Fluid using a USP Type II (paddle) apparatus at 75 rpm at 37° C.
  • a dosage form is also referred to as comprising a "sequestered aversive agent" depending on the agent or agents which are not released or substantially not released.
  • the substantially non-releasable form of the aversive agent is resistant to laxatives (e.g., mineral oil) used to manage delayed colonic transit and resistant to achlorhydric successions.
  • the aversive agent is not released or not substantially released 4, 8, 12 and/or 24 hours after oral administration.
  • analgesic effectiveness is defined for purposes of the present invention as a satisfactory reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.
  • sustained release is defined for purposes of the present invention as the release of the opioid analgesic from the oral dosage form at such a rate that blood (e.g., plasma) concentrations (levels) are maintained within the therapeutic range but below toxic levels over an extended period of time, e.g., from about 12 to about 24 hours as compared to an immediate release product.
  • blood e.g., plasma
  • concentrations levels
  • the sustained release is sufficient to provide a twice-a-day or a once-a-day formulation.
  • aversive agent particles refers to granules, spheroids, beads or pellets comprising the aversive agent.
  • the aversive agent particles are about 0.2 to about 2 mm in diameter, more preferably about 0.5 to about 2 mm in diameter.
  • parenterally includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, infusion techniques, or other methods of injection known in the art.
  • inhaled includes trans-mucosal, trans-bronchial, and trans- nasal abuse.
  • bittering agent includes a compound used to impart a bitter taste, bitter flavor, etc., to an abuser administering a tampered dosage form of the present invention.
  • the term "irritant” as used herein includes a compound used to impart an irritating or burning sensation to an abuser administering a tampered dosage form of the present invention.
  • the aversive agents of the present invention are preferably for use in connection with oral dosage forms including opioid analgesics, which provide valuable analgesia but which may be abused. This is particularly true for controlled release opioid analgesic products which have a large dose of opioid analgesic intended to be released over a period of time in each dosage unit. Drug abusers typically may take a controlled-release product and crush, shear, grind, chew, dissolve and/or heat, extract or otherwise damage the product so that the full contents of the dosage form become available for immediate absorption by injection, inhalation, and/or oral consumption.
  • the present invention comprises a method for preventing or deterring the abuse of opioid analgesics by the inclusion of at least one aversive agent in the dosage form with the opioid analgesic.
  • the present invention comprises a method for preventing or deterring the abuse of drugs other than opioid analgesics which may also be the subject of abuse, by including at least one of the aversive agents described herein in a dosage form comprising the drug other than an opioid analgesic which is the subj ct of abuse.
  • bittering agents can be employed including, for example and without limitation, natural, artificial and synthetic flavor oils and flavoring aromatics and/or oils, oleoresins and extracts derived from plants, leaves, flowers, fruits, and so forth, and combinations thereof.
  • Nonlimiting representative flavor oils include spearmint oil, peppermint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of bitter almonds, menthol and the like.
  • Useful bittering agents can be artificial, natural and synthetic fruit flavors such as citrus oils including lemon, orange, lime, grapefruit, and fruit essences and so forth.
  • bittering agents include sucrose derivatives (e.g., sucrose octaacetate), chlorosucrose derivatives, quinine sulphate, and the like.
  • sucrose derivatives e.g., sucrose octaacetate
  • chlorosucrose derivatives e.g., quinine sulphate
  • the preferred bittering agent for use in the present invention is Denatonium Benzoate NF-Anhydrous, sold under the name BitrexTM (Macfarlan Smith Limited, Edinburgh, UK).
  • the intake of the tampered dosage form produces a bitter taste upon inhalation or oral administration which in certain embodiments spoils or hinders the pleasure of obtaining a high from the tampered dosage form, and preferably prevents the abuse of the dosage form.
  • a bittering agent may be added to the formulation in an amount of less than about 50% by weight preferably less than about 10% by weight, most preferably less than about 5% by weight of the dosage form, and most preferably in an amount ranging from about 0.1 to 1.0 percent by weight of the dosage form, depending on the particular bittering agent(s) used.
  • a dosage form including a bittering agent preferably discourages improper usage of the tampered dosage form by imparting a disagreeable taste or flavor to the tampered dosage form.
  • various irritants can be employed including, for example and without limitation capsaicin, a capsaicin analog with similar type properties as capsaicin, and the like.
  • capsaicin analogues or derivatives include for example and without limitation, resiniferatoxin, tinyatoxin, heptanoylisobutyHmide, heptanoyl guaiacylamide, other isobutylamides or guaiacylamides, dihydrocapsaicin, homovanillyl octylester, nonanoyl vanillylamide, or other compounds of the class known as vanilloids.
  • Resiniferatoxin is described, for example, in U.S. Pat. No. 5,290,816 (Blumberg), issued Mar. 1, 1994.
  • U.S. Pat. No. 4,812,446 (Brand) issued Mar.
  • an irritant e.g., capsaicin
  • the capsaicin when the dosage form is tampered with, the capsaicin imparts a burning or discomforting quality to the abuser to preferably discourage the inhalation, injection, or oral administration of the tampered dosage form, and preferably to prevent the abuse of the dosage form.
  • Suitable capsaicin compositions include capsaicin (trans 8-methyl-N-vanillyl-6-nonearr ' ' de) or analogues thereof in a concentration between about 0.00125% and 50% by weight, preferably between about 1 and about 7.5% by weight, and most preferably, between about 1 and about 5% by weight of the dosage form.
  • various gelling agents can be employed including, for example and without limitation, sugars or sugar derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives, such as microcrystalline cellulose, sodium caboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose, attapulgites, bentonites, dextrins, alginates, carrageenan, gum tragacanth, gum acacia, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant we
  • the gelling agent is xanthan gum.
  • the gelling agent of the present invention is pectin.
  • the pectin or pectic substances useful for this invention include not only purified or isolated pectates but also crude natural pectin sources, such as apple, citrus or sugar beet residues which have been subjected, when necessary, to esterification or de-esterification, e.g., by alkali or enzymes.
  • the pectins used in this invention are derived from citrus fruits such as lime, lemon, grapefruit, and orange.
  • the gelling agent may be present in a ratio to the opioid agonist of from about 1 : 15 to about 15:1, preferably in a ratio of from about 1:8 to about 8:1, and more preferably from about 1:3 to about 3:1 by weight of the opioid agonist.
  • the substantially non-releasable form of the aversive agent is vulnerable to mechanical, thermal and/or chemical tampering, e.g., tampering by means of crushing, shearing, grinding, chewing and/or dissolution in a solvent in combination with heating (e.g., greater than about 45°C) of the oral dosage form.
  • mechanical, thermal and/or chemical tampering e.g., tampering by means of crushing, shearing, grinding, chewing and/or dissolution in a solvent in combination with heating (e.g., greater than about 45°C) of the oral dosage form.
  • the release of the aversive agent hinders, deters or prevents the administration of the tampered dosage form orally, intranasally, parenterally and/or sublingually.
  • the opioid agonist is selected from the group consisting of hydrocodone, mo ⁇ hine, hydromo ⁇ hone, oxycodone, codeine, levo ⁇ hanol, meperidine, methadone, oxymo ⁇ hone, bupreno ⁇ hine, fentanyl and derivatives thereof, dipipanone, heroin, tramadol, eto ⁇ hine, dihydroeto ⁇ hine, buto ⁇ hanol, levo ⁇ hanol, or salts thereof or mixtures thereof.
  • the opioid agonist is oxycodone or hydrocodone.
  • dosage forms may include analgesic doses from about 2 mg to about 50 mg of hydrocodone bitartrate.
  • the opioid analgesic comprises hydromo ⁇ hone
  • the dosage form may include from about 2 mg to about 64 mg hydromo ⁇ hone hydiochloride.
  • the opioid analgesic comprises mo ⁇ hine
  • the dosage form may include from about 2.5 mg to about 800 mg mo ⁇ hine sulfate, by weight.
  • the opioid analgesic comprises oxycodone
  • the dosage form may include from about 2.5 mg to about 320 mg oxycodone hydrochloride.
  • the dosage form may contain more than one opioid analgesic to provide a therapeutic effect.
  • the dosage form may contain molar equivalent amounts of other salts of the opioids useful in the present invention.
  • Hydrocodone is a semisynthetic narcotic analgesic and antitussive with multiple central nervous system and gastrointestinal actions. Chemically, hydrocodone is 4,5-epoxy- 3-methoxy-17-methylmo ⁇ hinan-6-one, and is also known as dihydrocodeinone. Like other opioids, hydrocodone may be habit forming and may produce drug dependence of the mo ⁇ hine type. In excess doses hydrocodone, like other opium derivatives, will depress respiration.
  • hydrocodone bitartrate is commercially available in the United States only as a fixed combination with non-opiate drugs (i.e., ibuprofen, acetaminophen, aspirin, etc.) for relief of moderate or moderately severe pain.
  • non-opiate drugs i.e., ibuprofen, acetaminophen, aspirin, etc.
  • a common dosage form of hydrocodone is in combination with acetaminophen, and is commercially available, e.g., as Lortab® in the U.S. from UCB Pharma, Inc. as 2.5/500 mg, 5/500 mg, 7.5/500 mg and 10/500 mg hydrocodone/acetaminophen tablets. Tablets are also available in the ratio of 7.5mg hydrocodone bitartrate and 650mg acetaminophen; and 7.5mg hydrocodone bitartrate and 750mg acetaminophen. Hydrocodone in combination with aspirin is given in an oral dosage form to adults generally in 1-2 tablets every 4-6 hours as needed to alleviate pain.
  • the tablet form is 5mg hydrocodone bitartrate and 224mg aspirin with 32mg caffeine; or 5mg hydrocodone bitartrate and 500mg aspirin.
  • a relatively new formulation comprises hydrocodone bitartrate and ibuprofen.
  • Vicoprofen® commercielly available in the U.S. from Knoll Laboratories, is a tablet containing 7.5 mg hydrocodone bitartrate and 200 mg ibuprofen.
  • the present invention is contemplated to encompass all such formulations, with the inclusion of one or more aversive agents as described herein.
  • Oxycodone chemically known as 4,5-expoxy-14-hydroxy-3-methoxy-17- methylmo ⁇ hinan-6-one, is an opioid agonist whose principal therapeutic action is analgesia.
  • Other therapeutic effects of oxycodone include anxiolysis, euphoria and feelings of relaxation.
  • the precise mechanism of its analgesic action is not known, but specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and play a role in the analgesic effects of this drug.
  • Oxycodone is commercially available in the United States, e.g., as Oxycontin® from Purdue Pharma L.P. as controlled-release tablets for oral administration containing 10 mg, 20 mg, 40 mg or 80 mg oxycodone hydrochloride, and as OxylRTM, also from Purdue Pharma L.P., as immediate-release capsules containing 5 mg oxycodone hydrochloride.
  • the present invention is contemplated to encompass all such formulations, with the inclusion of one or more aversive agents as described herein.
  • agents other than opioid analgesics which are subject to abuse may be used in accordance with the present invention in place of the opioid analgesics in the dosage form.
  • agents include, for example and without limitation, tranquilizers, CNS depressants, CNS stimulants, sedative hypnotics and the like.
  • barbiturates such as phenobarbital, secobarbital, pentobarbital, butabarbital, talbutal, aprobarbital, mephobarbital, butalbital, pharmaceutically acceptable salts thereof, and the like; benzodiazepines such as diazepam, chlordiazepoxide, alprazolam, triazolam, estazolam, clonazepam, flunitrazepam, pharmaceutically acceptable salts thereof, and the like; stimulants such as gamma-hydroxybutyrate, dextroamphetamine, methylphenidate, sibutramine, methylenedioxymethamphetamine, pharmaceutically acceptable salts thereof, and the like; and other agents such as marinol, meprobamate, carisoprodol, pharmaceutically acceptable salts thereof and the like.
  • an aversive agent in a substantially non-releasable form may be prepared by combining the aversive agent with one or more of a pharmaceutically acceptable hydrophobic material.
  • aversive agent particles may be coated with coating that substantially prevents the release of the aversive agent, the coating comprising the hydrophobic materials(s).
  • Another example would be an aversive agent that is dispersed in a matrix that renders the aversive agent substantially non-releasable, the matrix comprising the hydrophobic materials(s).
  • the pharmaceutically acceptable hydrophobic material comprises a cellulose polymer selected from the group consisting of ethylcellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, celluk se acetate butyrate, cellulose acetate phthalate and cellulose triacetate.
  • ethylcellulose is one that has an ethoxy content of 44 to 55%.
  • Ethylcellulose may be used in the form of an alcoholic solution.
  • the hydrophobic material comprises polylactic acid, polyglycolic acid or a co-polymer of the polylactic and polyglycolic acid.
  • Additional cellulose polymers useful for preparing an aversive agent in a substantially non-releasable form include acetaldehyde dimethyl cellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, and cellulose acetate dimethylaminocellulose acetate.
  • Acrylic polymers useful for preparation of the aversive agent in a substantially non- releasable form include, but are not limited to, acrylic resins comprising c- polymers synthesized from acrylic and methacrylic acid esters (e.g., the copolymer of acrylic acid lower alkyl ester and methacrylic acid lower alkyl ester) containing about 0.02 to 0.03 mole of a tri (lower alkyl) ammonium group per mole of the acrylic and methacrylic monomers used.
  • An example of a suitable acrylic resin is a polymer manufactured by Rohm Pharma GmbH and sold under the Eudragit " RS trademark. Eudragit RS30D is preferred.
  • Eudragit 3 RS is a water insoluble copolymer of ethyl acrylate (EA), methyl methacrylate (MM) and trimethylammoniumethyl methacrylate chloride (TAM) in which the molar ratio of TAM to the remaining components (EA and MM) is 1 :40.
  • Acrylic resins such as Eudragit RS may be used in the form of an aqueous suspension.
  • the coating composition may be applied onto the aversive agent particles by spraying it onto the particles using any suitable spray equipment known in the art.
  • a Wuster fluidized-bed system may be used in which an air jet, injected from underneath, fluidizes the coated material and effects drying while the insoluble polymer coating is sprayed on.
  • the thickness of the coating will depend on the characteristics of the particular coating composition being used. However, it is well within the ability of one skilled in the art to dete ⁇ nine by routine experimentation the optimum thickness of a particular coating required for a particular dosage form of the present invention.
  • the pharmaceutically acceptable hydrophobic material useful for preparing an aversive agent in a substantially non-releasable form includes a biodegradable polymer comprising a poly(lactic/glycolic acid) ("PLGA"), a polylactide, a polyglycolide, a polyanhydride, a polyorthoester, polycaprolactones, polyphosphazenes, pc ysaccharides, proteinaceous polymers, polyesthers, polydioxanone, polygluconate, polylactic-acid- polyethylene oxide copolymers, poly(hydroxybutyrate), polyphosphoesther or mixtures or blends of any of these.
  • PLGA poly(lactic/glycolic acid)
  • biodegradable polymer comprises a poly(lactic/glycolic acid), a copolymer of lactic and glycolic acid, having molecular weight of about 2,000 to about 500,000 daltons.
  • the ratio of lactic acid to glycolic acid is from about 100:0 to about 25:75, with the ratio of lactic acid to glycolic acid of 65:35 being preferred.
  • Poly(lactic/glycolic acid) may be prepared by the procedure set forth in U.S. Patent No. 4,293,539 (Ludwig et al.), the disclosure of which is hereby inco ⁇ orated by reference in its entirety.
  • Ludwig prepares the copolymer 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 by-products.
  • Poly(lactic/glycolic acid) is then recovered by filtering the molten reaction mixture in an organic solvent such as dichloromethane or acetone and then filtering to remove the catalyst.
  • the aversive agent in a substantially non-releasable form may be combined with an opioid agonist, along with conventional excipients known in the art, to prepare the oral dosage form of the present invention. It is contemplated that a bittering agent or capsaicin would be the most likely aversive agent to be included in a sequestered formulation.
  • the polymers and other ingredients above may also be utilized to formulate the aversive agents to slow release or delay release as disclosed above.
  • the oral dosage form is a capsule or a tablet.
  • the aversive agent and opioid agonist may be combined with one or more inert, non-toxic pharmaceutical excipients which are suitable for the manufacture of tablets.
  • excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the oral dosage form of the present invention may be formulated to provide immediate release of the opioid agonist contained therein. In other embodiments of the invention, however, the oral dosage form provides sustained-release of the opioid agonist.
  • the oral dosage forms providing sustaine ⁇ release of the opioid agonist may be prepared by admixing the aversive agent in a substantially non- releasable form with the opioid agonist and desirable pharmaceutical excipients to provide a tablet, and then coating the tablet with a sustained-release tablet coating.
  • sustained release opioid agonist tablets may be prepared by admixing the substantially non-releasable form of an aversive agent with an aversive agent in a matrix that provides the tablets with sustained-releasing properties.
  • the opioid analgesic formulation in combination with one or more aversive agents can be formulated as an immediate release formulation or controlled release oral formulation in any suitable tablet, coated tablet or multiparticulate formulation known to those skilled in the art.
  • the controlled release dosage form may include a controlled release material which is inco ⁇ orated into a matrix along with the opioid analgesic.
  • the aversive agent may be separate from the matrix, or inco ⁇ orated into the matrix.
  • the controlled release dosage form may optionally comprise particles containing or comprising the opioid analgesic, wherein the particles have diameter from about 0.1 mm to about 2.5 mm, preferably from about 0.5 mm to about 2 mm.
  • the aversive agent may be inco ⁇ orated into these particles, or may be inco ⁇ orated into a tablet or capsule containing these particles.
  • the particles are film coated with a material that permits release of the opioid analgesic at a controlled rate in an environment of use.
  • the film coat is chosen so as to achieve, in combination with the other stated properties, a desired in- vitro release rate.
  • the controlled 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 of the present invention comprise normal release matrixes containing the opioid analgesic and the aversive agent.
  • a hydrophobic material is used to coat inert pharmaceutical beads such as nu pariel 18/20 beads comprising an opioid analgesic, and a plurality of the resultant solid controlled release beads may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media.
  • the one or more aversive agents may also be coated onto the beads comprising the opioid analgesic, may be prepared as separate beads and then combined in a dosage form including the controlled release beads comprising an opioid analgesic, or the one or more aversive agents may be mixed in the dosage form with the controlled release beads comprising the opioid analgesic.
  • the beads In prefe ⁇ ed embodiments where the opioid analgesic and the aversive agent are mixed in a capsule as different beads, the beads have an exact or similar appearance in order to deter an abuser from manually separating the beads prior to abuse in order to avoid the aversive substance.
  • the aversive agent is preferably not included as a distinct layer which can be easier to separate from the active agent, although the present invention does encompass these embodiments.
  • the controlled release bead formulations of the present invention slowly release the opioid analgesic, 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 a 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 +he thickness of the retardant coating.
  • the resultant coated substrate in this example beads, may then be optionally overcoated with a ba ⁇ ier agent, to separate the opioid analgesic from the hydrophobic controlled release coating.
  • a suitable barrier agent is one which comprises hydroxypronylmethylcellulose.
  • any film-former known in the art may be used. It is preferred that the ba ⁇ ier agent does not affect the dissolution rate of the final product.
  • Plasticized hydrophobic material may be applied onto the substrate comprising the opioid analgesic by spraying using any suitable spray equipment known in the art.
  • a Wurster fluidized— bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on.
  • a further overcoat of a film-former such as Opadry ® is optionally applied to the beads.
  • This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads.
  • the matrix also may include a binder.
  • the binder preferably contributes to the sustained-release of the opioid analgesic or pharmaceutically acceptable salt thereof from the sustained-release matrix.
  • an additional hydrophobic binder material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, carnauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive. In certain preferred embodiments, a combination of two or more hydrophobic binder materials are included in the matrix formulations.
  • Prefe ⁇ ed hydrophobic binder materials which may be used in accordance with the present invention include digestible, long chain (C 8 -Cso, especially C ⁇ 2 -C 0 ), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Hydrocarbons having a melting point of between 25° and 90°C are prefe ⁇ ed. Of the long- chain hydrocarbon binder materials, fatty (aliphatic) alcohols are prefe ⁇ ed in certain embodiments.
  • the oral dosage form may contain up to 80% (by weight) of at least one digestible, long chain hydrocarbon.
  • a wax-like substar-e is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to about 100°C.
  • the dosage form comprises a sustained release matrix comprising an opioid analgesic; one or more aversive agents; and at least one water soluble hydroxyalkyl cellulose, at least one C ⁇ 2 -C 36 , preferably C ⁇ 4 -C 22 , aliphatic alcohol and, optionally, at least one polyalkylene glycol.
  • the hydroxyalkyl cellulose is preferably a hydroxy (Ci to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose.
  • the amount of the at least one hydroxyalkyl cellulose in the present oral dosage form may be determined, inter alia, by the precise rate of opioid analgesic release required.
  • the aliphatic 'alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly prefe ⁇ ed embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol.
  • the amount of the aliphatic alcohol in the present oral dosage form may be determined, as above, by the precise rate of opioid analgesic release required. It may also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between about 20% and about 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably constitutes between about 20% and about 50% (by wt) of the total dosage form.
  • 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 analgesic from the formulation.
  • a ratio of the hydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol of between 1:1 and 1:4 is preferred, with a ratio of between 1:2 and 1:3 being particularly prefe ⁇ ed.
  • the polyalkylene glycol may be, for example, polypropylene glycol, or polyethylene glycol which is prefe ⁇ ed.
  • the average molecular weight of the at least one polyalkylene glycol is preferably between 1,000 and 15,000, especially between 1,500 and 12,000.
  • Another suitable sustained-release matrix comprises an alkylcellulose (especially ethylcellulose), a C 12 to C 36 aliphatic alcohol and, optionally, a polyalkylene glycol.
  • a sustained-release matrix can also be prepared by, e.g., melt-granulation or melt- extrusion techniques.
  • melt-granulation techniques involve melting a normally solid hydrophobic binder material, e.g., a wax, and inco ⁇ orating a powdered drug therein.
  • a sustained release dosage form it may be necessary to inco ⁇ orate a hydrophobic sustained-release material, e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic binder material.
  • sustained-release formulations prepared via melt-granulation techniques are found, e.g., in U.S. Patent No. 4,861,598.
  • the preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the opioid analgesic and at least one aversive agent, together with a sustained release material and preferably a binder 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, e.g., using a twin-screw extruder, to form strands.
  • the extrudate is preferably cooled and cut into multiparticulates by any means known in the art.
  • the matrix multiparticulates are then divided into unit doses.
  • the extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides sustained release of the opioid analgesic or pharmaceutically acceptable salt thereof for a time period of at least abou- 12 hours.
  • the one or more aversive agents may be added to a dosage form including multiparticulates comprising opioid analgesic (without the one or more aversive agents).
  • a melt extruded matrix multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice.
  • the terms "melt-extruded matrix multiparticulate(s)” and “melt-extruded matrix multiparticulate system(s)” and “melt-extruded matrix 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 sustained release material as described herein.
  • the melt-extruded matrix multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm.
  • the melt-extruded matrix multiparticulates can be any geometrical shape within this size range.
  • the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step.
  • oral dosage forms are prepared that include an effective amount of melt-extruded matrix multiparticulates within a capsule.
  • a plurality of the melt-extruded matrix multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective sustained release dose when ingested and contacted by gastrointestinal fluid.
  • the sustained-release matrix multiparticulate systems, tablets, or capsules can be coated with a sustained release coating such as the sustained release coatings described herein.
  • a sustained release coating such as the sustained release coatings described herein.
  • Such coatings preferably include a sufficient amount of hydrophobic and/or hydrophilic sustained-release material to obtain a weight gain level from about 2 to about 25 percent, although the overcoat may be greater depending upon, e.g., the desired release rate.
  • the coating can optionally contain one or more of the aversive agents.
  • an optional second overcoat can be applied as to minimize the perception of the aversive agent when a dosage form of the present invention is administered intact.
  • the dosage forms of the present invention may further include combinations of melt- extruded matrix multiparticulates containing an opioid analgesic; onu or more aversive agents; or mixtures thereof. Furthermore, the dosage forms can also include an amount of an immediate release opioid analgesic for prompt therapeutic effect.
  • the immediate release opioid analgesic may be inco ⁇ orated, e.g., as separate multiparticulates within a gelatin capsule, or may be coated on the surface of, e.g., melt extruded matrix multiparticulates.
  • melt-extruded formulations are prepared without the inclusion of the opioid analgesic; one or more aversive agents; or mixtures thereof; which is added thereafter to the extrudate.
  • Such formulations typically will have the opioid analgesic; one or more aversive agents; or mixtures thereof blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation.
  • Such formulations may be advantageous, for example, when the opioid analgesic; one or more aversive agents; or mixtures thereof included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/or the retardant material.
  • Typical melt-extrusion production systems suitable for use in accordance with the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and a meter.
  • the production system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length of the extruder.
  • the production system will include an extruder such as a twin-screw extruder which consists of two counter- rotating intermeshing screws enclosed within a cylinder or barrel having ..n aperture or die at the exit thereof.
  • the feed materials enter through a feed hopper and are moved through the ba ⁇ el by the screws and are forced through the die into strands which are thereafter conveyed such as by a continuous movable belt to allow for cooling and being directed to a pelletizer or other suitable device to render the extruded ropes into the matrix multiparticulate system.
  • the pelletizer can consist of rollers, fixed knife, rotating cutter and the like. Suitable instruments and systems are available from distributors such as C.W. Brabender Instruments, Inc. of South hackensack, New Jersey. Other suitable apparatus will be apparent to those of ordinary skill in the art.
  • a further aspect of the invention is related to the preparation of melt-extruded matrix multiparticulates as set forth above in a manner which controls the amount of air included in the extruded product.
  • the amount of air included in the extrudate By controlling the amount of air included in the extrudate, the release rate of the opioid analgesic, one or more aversive agents, or mixtures thereof may be altered.
  • melt-extruded product is prepared using a Wemer-Pfleiderer twin screw extruder.
  • a spheronizing agent is added to a granulate or matrix multiparticulate and then spheronized to produce sustained release spheroids.
  • the spheroids are then optionally overcoated with a sustained release coating by methods such as those described above.
  • Spheronizing agents which may be used to prepare the matrix multiparticulate formulations of the present invention include any art-known spheronizing agent.
  • Cellulose derivatives are prefe ⁇ ed, and microcrystalline cellulose is especially preferred.
  • a suitable microcrystalline cellulose is, for example, the material sold as Avicel PH 101 (TradeMark, FMC Co ⁇ oration).
  • the spheronizing agent is preferably included as about 1 to about 99% of the matrix multiparticulate by weight.
  • 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 hydroxy propyl cellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate copolymer, or ethyl cellulose.
  • a sustained release coating is applied to the sustained release spheroids, granules, or matrix multiparticulates.
  • the sustained-release coating may include a water insoluble material such as (a) a wax, either alone or in admixrare with a fatty alcohol; or (b) shellac or zein.
  • the coating is preferably derived from an aqueous dispersion of the hydrophobic sustained release material.
  • the sustained release spheroids, granules, or matrix multiparticulates comprising the opioid analgesic, one or more aversive agents, and sustained release carrier with a sufficient amount of the aqueous dispersion of, e.g., alkylcellulose or acrylic polymer, to obtain a weight gain level from about 2 to about 50%, e.g., about 2 to about 25%, in order to obtain a sustained-release formulation.
  • the overcoat may be lesser or greater depending upon, e.g., the desired release rate, the inclusion of plasticizer in the aqueous dispersion and the manner of inco ⁇ oration of the same.
  • Cellulosic materials and polymers are sustained release materials well suited for coating the sustained release spheroids, granules, or matrix multiparticulates according to the invention.
  • one prefe ⁇ ed 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.
  • Aquacoat® FMC Co ⁇ ., Philadelphia, Pennsylvania, U.S.A.
  • Aquacoat® 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.
  • th. sustained release material comprising the sustained-release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, 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 copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, poly(acrylic acid), poly(meth
  • methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention.
  • methacrylic acid copolymer or polymeric methacrylates commercially available as Eudragit ® from Rohm GMBH and Co. Kg Darmstadt, Ge ⁇ nany.
  • Eudragit E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media.
  • Eudragit L is a methacrylic acid copolymer which 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; however, dosage forms coated with Eudragit L and RS are pH- independent.
  • the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available from Rohm under the Tradenames Eudragit® RL30D and Eudragit® RS30D, respectively.
  • 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® RL30D and 1:40 in Eudragit® RS30D.
  • the mean molecular weight is about 150,000.
  • RL high permeability
  • RS low permeability
  • Eudragit® RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and pe ⁇ neable in aqueous solutions and digestive fluids.
  • the uncoated/coated sustained release spheroids, granules, or matrix multiparticulates containing the opioid analgesic; and one or more aversive agents; are cured until an endpoint is reached at which the sustained release spheroids, granules, or matrix multiparticulates provide a stable dissolution of the opioid.
  • the caring endpoint may be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing to the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions of, e.g., at least one month at a temperature of 40°C and a relative humidity of 75%. Cured formulations are described in detail in U.S. Patent Nos.
  • sustained-release formulations and coatings which may be used in accordance with the present invention include those described in U.S. Patent Nos. 5,324,351; 5,356,467; and 5,472,712.
  • Sustained release dosage forms according to the present invention may also be prepared as osmotic dosage formulations.
  • the osmotic dosage forms preferably include a bilayer core comprising a drug layer (containing the opioid analgesic and optionally one or more aversive agents) and a delivery or push layer (which may contain the one or more aversive agents), wherein the bilayer core is surrounded by a semipermeable wall and optionally having at least one passageway disposed therein.
  • Representative compounds for forming a passageway include erodible poly(glycolic) acid, or poly(lactic) acid in the wall; a gelatinous filament; a water-removable poly(vinyl alcohol); leachable compounds such as fluid-removable pore-forming polysaccharides, acids, salts or oxides.
  • a passageway can be formed by leaching a compound from the wall, such as sorbitol, sucrose, lactose, maltose, or fructose, to form a sustained-release dimensional pore-passageway.
  • the passageway can have any shape, such as round, triangular, square and elliptical, for assisting in the sustained metered release of opioid analgesic from the dosage form.
  • the dosage form can be manufactured with one or more passageways in spaced-apart relation on one or more surfaces of + ';e dosage form.
  • a passageway and equipment for forming a passageway are described in U.S. Patent Nos. 3,845,770; 3,916,899; 4,063,064 and 4,088,864.
  • Passageways comprising sustained-release dimensions sized, shaped and adapted as a releasing-pore formed by aqueous leaching to provide a releasing-pore of a sustained-release rate are described in U.S. Patent Nos. 4,200,098 and 4,285,987.
  • polymer hydrogels include but are not limited to a maltodextrin polymer comprising the formula (C 6 H ⁇ 2 0 5 ) n ⁇ 0, wherein n is 3 to 7,500, and the maltodextrin polymer comprises a 500 to 1,250,000 number-average molecular weight; a poly(alkylene oxide) represented by, e.g., a poly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to 750,000 weight-average molecular weight, and more specifically represented by a poly(ethylene oxide) of at least one of 100,000, 200,000, 300,000 or 400,000 weight-average molecular weights; an alkali carboxyalkylcellulose, wherein the alkali is sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000 weight-average molecular weight; and a copolymer of ethylene-acrylic acid, including methacrylic and ethacrylic acid of 10,000 to
  • the polyalkylene oxide may be a member selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene oxide having a 1,000,000 average molecular weight, polyethylene oxide comprising a 5,000,000 average molecular weight, polyethylene oxide comprising a 7,000,000 average molecular weight, cross-linked polymethylene oxide possessing a 1,000,000 average molecular weight, and polypropylene oxide of 1,200,000 average molecular weight.
  • Typical osmopolymer carboxyalkylcellulose comprises a member selected from the group consisting of alkali carboxyalkylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium carboxyethylcellulose, lithium carboxymethylcellulose, sodium carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose, carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcellulose and carboxymethylhydroxypropylcellulose.
  • the osmopolymers used for the displacement layer exhibit an osmotic pressure gradient across the semipermeable wall.
  • the osmopolymers imbibe fluid into dosage form, thereby swelling and expanding as an osmotic hydrogel (also known as osmogel), whereby they push the contents of the drug layer from the osmotic dosage form.
  • osmopolymers used for the displacement layer exhibit an osmotic pressure gradient across the semipermeable wall.
  • the push layer may optionally include a hydroxypropylalkylcellulose possessing a 9,000 to 450,000 number-average molecular weight.
  • the hydroxypropylalkylcellulose is represented by a member selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropyl isopropyl cellulose, hydroxypropylbutylcellulose, and hydroxypropylpen ylcellulose.
  • the push layer may also optionally comprise an antioxidant to inhibit the oxidation of ingredients.
  • antioxidants include but are not limited to a member selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol, and propylgallate.
  • the semipermeable wall comprises a member selected from the group consisting of a cellulose ester polymer, a cellulose ether polymer and a cellulose ester-ether polymer.
  • Representative wall polymers comprise a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkenylates, and mono-, di- and tricellulose alkinylates.
  • the poly(cellulose) used for the present invention comprises a number-average molecular weight of 20,000 to 7,500,000.
  • transde ⁇ nal formulations of bupreno ⁇ hine reported in the literature. See, for example, U.S. Patent No. 5,240,711 (Hille et al), U.S. Patent No. 5,225,199 (Hidaka et al), U.S. Patent No. 5,069,909 (Sharma et al), U.S. Patent No. 4,806,341 (Chien et al), and U.S. Patent No. 5,026,556 (Drust et al), all of which are hereby inco ⁇ orated by reference.
  • These transdermal devices can also be reformulated with the aversive agents as disclosed herein.
  • compositions for the transdermal delivery of bupreno ⁇ hine comprise bupreno ⁇ hine in a ca ⁇ ier of a polar solvent material selected from the group consisting of C3-C4 diols, C3-
  • the transdermal 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 permeable 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% bupreno ⁇ hine, 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.
  • transdermal delivery system used in the present invention may also be that described in PCT/US01/04347 to Oshlack et al.
  • the present invention is contemplated to encompass all transdermal formulations, e.g., the technologies described above, with the inclusion of an aversive agent, such that the dosage form deters abuse of the opioid therein.
  • the suppository base chosen should be compatible with the agent(s) of the present invention. Further, the suppository base is preferably non-toxic and nonirritating to mucous membranes, melts or dissolves in rectal 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 C12 to C 18 .
  • a wax may be used to form the proper shape for administration via the rectal 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 Henkel, 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.
  • Novata TM types AB, AB, B, BC, BD, BBC, E, BCF, C, D and 299
  • Witepsol TM types H5, H12, H15, H175, H185, H19, H32, H35, H39, H42, W25, W31, W35, W45, S55, S58, E75, E76 and E85
  • suppository bases may be substituted in whole or in part for the above-mentioned mono-, di- and triglycerides.
  • the amount of base in the suppository is determined by the size (i.e. actual weight) of the dosage form, the amount of base (e.g., alginate) and drug used.
  • the amount of suppository base is from about 20 percent to about 90 percent by weight of the total weight of the suppository.
  • the amount of base in the suppository is from about 65 percent to about 80 percent, by weight of the total weight of the suppository.
  • the dosage forms of the present invention may also include a surfactant.
  • surfactants useful in accordance with the present invention include for example, ionic and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, including but not limited to castor oil derivatives, cholesterol, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polysorbates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene compounds, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium laurylsulfate, cholic acid or derivatives thereof, ethoxylated alcohols, ethoxylated esters, ethoxylated amides, polyoxypropylene compounds, propoxylated alcohols, ethoxylated/propoxylated block polymers, propoxylated esters, alkanol
  • Mixed surfactant wetting agents useful in accordance with the present invention include, for example, sodium lauryl sulfate/polyethylene glycol (PEG) 6000 and sodium lauryl sulfate/PEG 6000/stearic acid, etc.
  • one or more opioid analgesic is included and a further non-opioid drug is also included.
  • non-opioid drugs 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; cyclooxygenase-II inhibitors ("COX-II inhibitors"); and/or glycine receptor antagonists.
  • NSAIDS non-steroidal anti-inflammatory drugs
  • NMDA N-methyl-D-aspartate
  • COX-II inhibitors cyclooxygenase-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 analgesic, such as an NSAID or a COX-2 inhibitor.
  • an additional non- opioid analgesic 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, 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 GMi or GTi b a phenothiazine such as trifluoperazine or a naphthalenesulfonamide such as N-(6- aminohexyl)-5-chloro-l-naphthalenesulfonamide.
  • narcotic analgesics such as mo ⁇ hine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,83° (both to Mayer, et al.), and to treat chronic pain in U.S. Pat. No. 5,502,058 (Mayer, et al.), all of which are hereby inco ⁇ orated by reference.
  • the 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 chenical 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; 5,474,995; 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 (prodrug 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 drug can be included which provides a desired effect other than analgesia, e.g., antitussive, expectorant, decongestant, antihistamine drugs, local anesthetics, and the like.
  • the invention disclosed herein is meant to encompass the use of any pharmaceutically acceptable salts thereof of the disclosed opioid analgesics.
  • 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 triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like; organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like; amino acid salts such
  • opioid analgesics disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other slereoisomeric fo ⁇ ns.
  • the present invention is also meant to encompass the use of any such possible forms as well as their racemic and resolved forms and mixtures thereof.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers.
  • the use of all tautomers are intended to be encompassed by the present invention as well.
  • the oral dosage forms of the present invention may be in the form of tablets, troches, lozenges, powders or granules, hard or soft capsules, microparticles (e.g., microcapsules, microspheres and the like), buccal tablets, etc.
  • the present invention provides for a method of preventing abuse of an oral controlled release dosage form of an opioid analgesic comprising preparing the dosage forms as described above. In certain embodiments, the present invention provides for a method of preventing diversion of an oral controlled release dosage form of an opioid analgesic comprising preparing the dosage forms as described above.
  • the present invention provides for a method of treating pain while at the same time reducing the risk of abuse by administering to a human patient the dosage forms described above.
  • a 20 mg oxycodone formulation is prepared containing xanthan gum as the aversive agent
  • xanthan gum is added to the oxycodone formulation during the granulation process.
  • Other gelling agents such as curdlan, ca ⁇ ageenan, alginates, pectin, gelatin, furcelleran, agar, guar gum, locust bean gum, tara gum, tragacanth, acacia, glucomannans, karaya, starch and starch derivatives, egg white powder, lacto albumin, soy protein, Jargel, gellan gum, welan gum, rhamsan gum, and the like, could also be used as gelling agents.
  • Milling Pass the cooled granulation through a mill.
  • a 40 mg oxycodone formulation was prepared containing .”.anthan gum as the aversive agent
  • Example 2 To determine the effect of varying amount of xanthan gum on the gelling property and dissolution rate of an oxycodone tablet, three levels of xanthan gum were added to 40 mg oxycodone granulation and compressed into tablets. Oxycodone recovery from water extraction of the tablet and the drug release rate was determined.
  • the oxycodone granulation formulation of Example 2 is listed in Table 2 below.
  • Examples 2A to 2C were prepared adding different amounts (3mg. 5mg, and 9mg) of xanthan gum to a 125 mg oxycodone granulation of Example 2.
  • Dispersion Disperse Eudragit and Triacetin in an aqueous med'- to form an
  • Granulation Spray the Eudragit/Triacetin dispersion onto the Oxycodone HC1,
  • Milling Discharge the granulation and pass through a mill.
  • Lubrication Lubricate the granulation with talc and magnesium stearate using a mixer.
  • THICK (lOcP to 60cP): Although a syringe can be filled with this solution, it was hard to do.
  • Cooling Cool the waxed granulation in a fluid bed dryer.
  • Blending Blend the milled waxed granulation, Talc and Magnesium Stearate.
  • Compression Compress the resultant granulation using a tablet press.
  • Example 5 controlled release tablets containing a opioid agonist (mo ⁇ hine sulfate) and gelling agent (hydroxyethyl cellulose) are prepared.
  • the controlled release tablets comprise granulates comprising the opioid agonist and the gelling agent 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.
  • 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.
  • a controlled release tablet having the formula listed below is prepared by wet granulating oxycodone hydrochloride (25.00 gm) with lactose monohydrate (417.5 gm), and hydroxyethyl cellulose (100.00 gm). The granules are sieved through a 12 mesh screen. The granules are then dried in a fluid bed dryer at 50° C and sieved through a 16 mesh screen.
  • Granulation Spray the Eudragit/Triacetin dispersion onto the Oxycodone HCl,
  • Waxing Melt the stearyl alcohol and add to the milled granulation using a mixer. Allow to cool.
  • Compression Compress the granulation into tablets using a tablet press.
  • Solution Preparation Dissolve the denatonium benzoate in Purified Water. Once dissolved, add the Opadry White and continue mixing until a homogeneous dispersion is yielded.
  • Example 11 a substantially non-releasable form of a bittering agent (denatonium benzoate) is prepared as denatonium benzoate containing granulates.
  • the granulates are comprised of denatonium benzoate dispersed in a matrix that renders the denatonium benzoate substantially non-releasable.
  • the formula for Example 11 is listed in Table 11 below.
  • Granulation Place the denatonium benzoate, and Dicalcium Phosphate in a fluid bed coating machine and granulate by spraying the above solution.
  • Example 12 a substantially non-releasable form of a bittering agent (denatonium benzoate) is prepared as denatonium benzoate extruded pellets.
  • the formula for Example 12 is listed in Table 12 below.
  • Lubrication Lubricate the granulation with talc and magnesium stearate using a mixer.
  • Compression Compress the granulation into tablets using a tablet press.
  • a sustained release hydrocodone formulation is prepared having the formula in Table 14 below.
  • One or more aversive agents as described herein can be inco ⁇ orated into a capsule with the hydrocodone pellets, into the hydrocodone pellets, or on the hydrocodone pellets by one skilled in the art.
  • the one or more aversive agents may be in releasable, non-releasable, or substantially non-releasable form or a combination thereof.
  • pellets comprising the aversive agent(s) are inco ⁇ orated into the capsule they are indistinguishable from the hydrocodone pellets.

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Abstract

Procédés et compositions servant à empêcher la surconsommation ou la consommation illicite de formes galéniques contenant un analgésique opioïde ou un autre médicament pouvant faire l'objet d'un abus ou d'une surconsommation, ainsi qu'au moins une quantité efficace d'un agent dissuasif servant à empêcher l'utilisation frauduleuse de ladite forme galénique et sa consommation par les voies intraveineuses, nasales et/ou orales.
PCT/US2002/024935 2001-08-06 2002-08-06 Compositions et procedes servant a empecher la surconsommation d'opioides WO2003013476A1 (fr)

Priority Applications (9)

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JP2003518486A JP2005500364A (ja) 2001-08-06 2002-08-06 オピオイドの乱用を防止する組成物と方法
EP02752708A EP1414413A1 (fr) 2001-08-06 2002-08-06 Compositions et procedes servant a empecher la surconsommation d'opioides
MXPA04001206A MXPA04001206A (es) 2001-08-06 2002-08-06 Composiciones y metodos para prevenir el abuso de opioides.
CA002455420A CA2455420A1 (fr) 2001-08-06 2002-08-06 Compositions et procedes servant a empecher la surconsommation d'opioides
IL16021702A IL160217A0 (en) 2001-08-06 2002-08-06 Compositions and methods to prevent abuse of opioids
BR0212020-8A BR0212020A (pt) 2001-08-06 2002-08-06 Formas de dosagem, métodos para impedir o abuso de uma forma de dosagem, métodos para impedir o desvio de uma forma de dosagem, métodos para o tratamento de dor e método de preparação de uma forma de dosagem
HU0401344A HUP0401344A2 (hu) 2001-08-06 2002-08-06 Gyógyszerkészítmények opioidokkal való visszaélés megakadályozására, és eljárás előállításukra
DE20220917U DE20220917U1 (de) 2001-08-06 2002-08-06 Zusammensetzungen zur Verhinderung des Missbrauchs von Opioiden
KR10-2004-7001877A KR20040025741A (ko) 2001-08-06 2002-08-06 오피오이드 남용을 방지하기 위한 조성물 및 방법

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