111111
`
`1111111111111111111111111111111111111111111111111111111111111111111111111111
`US 20030068375Al
`
`(19) United States
`(12) Patent Application Publication
`Wright et al.
`
`(10) Pub. No.: US 2003/0068375 Al
`Apr. 10, 2003
`(43) Pub. Date:
`
`(54) PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`
`(76)
`
`Inventors: Curtis Wright, Norwalk, CT (US);
`Benjamin Oshlack, New York, NY
`(US); Christopher Breder, Greenwich,
`CT (US)
`
`Correspondence Address:
`DAVIDSON, DAVIDSON & KAPPEL, LLC
`485 SEVENTH AVENUE, 14TH FLOOR
`NEW YORK, NY 10018 (US)
`
`(21)
`
`Appl. No.:
`
`10/214,412
`
`(22)
`
`Filed:
`
`Aug. 6, 2002
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/310,534, filed on Aug.
`6, 2001.
`
`Publication Classification
`
`Int. Cl? .......................... A61K 31/485; A61K 9/20
`(51)
`(52) U.S. Cl. ............................................ 424/468; 514/282
`
`(57)
`
`ABSTRACT
`
`Disclosed in certain embodiments is a controlled release oral
`dosage form comprising a therapeutically effective amount
`of a drug susceptible to abuse together with one or more
`pharmaceutically acceptable excipients; the dosage form
`further including a gelling agent in an effective amount to
`impart a viscosity unsuitable for administration selected
`from the group consisting of parenteral and nasal adminis-
`tration to a solubilized mixture formed when the dosage
`form is crushed and mixed with from about 0.5 to about 10
`ml of an aqueous liquid; the dosage form providing a
`therapeutic effect for at least about 12 hours when orally
`administered to a human patient.
`
`KASHIV1017
`IPR of Patent No. 9,492,393
`
`

`

`US 2003/0068375 Al
`
`1
`
`Apr. 10, 2003
`
`PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`[0001] This application claims the benefit of U.S. Provi-
`sional Serial No. 60/310,534, filed Aug. 6, 2001, hereby
`incorporated by reference in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`[0002] Opioid analgesics are sometimes the subject of
`abuse. Typically, 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." Also,
`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.
`[0003] Opioid antagonists have been combined with cer-
`tain opioid agonists in order to deter the parenteral abuse of
`opioid agonists. In the prior art, the combination of imme-
`diate release pentazocine and naloxone has been utilized in
`tablets available in the United States, commercially avail-
`able as Talwin®Nx from Sanofi-Winthrop. Talwin®Nx con-
`tains immediate release pentazocine hydrochloride equiva-
`lent to 50 mg base and naloxone hydrochloride equivalent to
`0.5 mg base. A fixed combination therapy comprising tili-
`dine (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 buprenor-
`phine and naloxone was introduced in 1991 in New Zealand
`(Temgesic®Nx, Reckitt & Colman) for the treatment of
`pain.
`
`[0004] 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.
`[0005] U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912
`and 5,656,295 disclose sustained release oxycodone formu-
`lations.
`
`[0006] U.S. Pat. Nos. 4,769,372 and 4,785,000 to Kreek
`describe methods of treating patients suffering from chronic
`pain or chronic cough without provoking intestinal dysmo-
`tility 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 admin-
`istered orally, from 1 to 5 times daily.
`
`[0007] U.S. Pat. No. 6,228,863 to Palermo et al. describes
`compositions and methods of preventing abuse of opioid
`dosage forms.
`
`[0008] WO 99/32119 to Kaiko et al. describes composi-
`tions and methods of preventing abuse of opioid dosage
`forms.
`
`[0009] U.S. Pat. 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.
`[0010] U.S. Pat. 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, for-
`mulated 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.
`[0011] However, there still exists a need for a safe and
`effective treatment of pain with opioid analgesic dosage
`forms which are less subject to abuse than current therapies.
`[0012] All documents cited herein, including the forego-
`ing, are incorporated by reference in their entireties for all
`purposes.
`
`OBJECTS AND SUMMARY OF THE
`INVENTION
`
`It is an object of certain embodiments of the
`[0013]
`invention to provide an oral dosage form of an opioid
`analgesic which is subject to less parenteral abuse than other
`dosage forms.
`It is an object of certain embodiments of the
`[0014]
`invention to provide an oral dosage form of an opioid
`analgesic which is subject to less intranasal abuse than other
`dosage forms.
`
`It is an object of certain embodiments of the
`[0015]
`invention to provide an oral dosage form of an opioid
`analgesic which is subject to less oral abuse than other
`dosage forms.
`
`It is a further object of certain embodiments of the
`[0016]
`invention to provide an oral dosage form of an opioid
`analgesic which is subject to less diversion than other
`dosage forms.
`
`It is a further object of certain embodiments of the
`[0017]
`invention to provide a method of treating pain in human
`patients with an oral dosage form of an opioid analgesic
`while reducing the abuse potential of the dosage form.
`
`It is a further object of certain embodiments of the
`[0018]
`invention to provide a method of manufacturing an oral
`dosage form of an opioid analgesic such that it has less abuse
`potential.
`
`[0019] These objects and others are achieved by the
`present invention, which is directed in part to an oral dosage
`form comprising an opioid analgesic; and at least one
`aversive agent for reducing the abuse of the opioid analge-
`sic.
`
`In certain embodiments of the present invention,
`[0020]
`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 "attractive-
`ness" of the dosage form to a potential abuser.
`
`KASHIV1017
`IPR of Patent No. 9,492,393
`
`

`

`US 2003/0068375 Al
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`2
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`Apr. 10, 2003
`
`In certain embodiments of the present invention,
`[0021]
`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. Preferably, the bittering agent is
`released when the dosage form is tampered with and pro-
`vides an unpleasant taste to the abuser upon inhalation
`and/or swallowing of the tampered dosage form.
`In certain embodiments of the present invention,
`[0022]
`the dosage form comprises an aversive agent such as an
`irritant to discourage an abuser from tampering with the
`dosage form and thereafter inhaling, injecting, or swallow-
`ing the tampered dosage form. Preferably, the irritant is
`released when the dosage form is tampered with and pro-
`vides a burning or irritating effect to the abuser upon
`inhalation, injection, and/or swallowing of the tampered
`dosage form.
`In certain embodiments of the present invention,
`[0023]
`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. Preferably, the gel-
`ling 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". In certain
`preferred embodiments, 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. Upon the
`addition of the aqueous liquid, the tampered dosage form
`preferably becomes thick and viscous, rendering it unsuit-
`able 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. In certain embodiments, the gelling agent is present in
`such an amount in the dosage form that attempts at evapo-
`ration (by the application of heat) to an aqueous mixture of
`the dosage form in an effort to produce a higher concentra-
`tion of the therapeutic agent, produces a highly viscous
`substance unsuitable for injection.
`[0024] When nasally inhaling the tampered dosage form,
`the gelling agent can become gel like upon administration to
`the nasal passages due to the moisture of the mucous
`membranes. This also makes such formulations aversive to
`nasal administration, as the gel will stick to the nasal passage
`and minimize absorption of the abusable substance. In
`certain embodiments of the present invention, the dosage
`form comprises a combination of any or all of the afore-
`mentioned aversive agents (e.g., a bittering agent, an irritant,
`and/or a gelling agent) to discourage an abuser from tam-
`pering with the dosage form and thereafter inhaling, inject-
`ing, and/or swallowing the tampered dosage form.
`[0025] 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.
`In certain preferred embodiments, the dosage
`[0026]
`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.
`In certain embodiments of the present invention the
`[0027]
`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. Prefer-
`ably, because the aversive agent is present in the dosage
`form in a substantially non-releasable form, it is not sub-
`stantially released in the gastrointestinal tract when the
`dosage form is orally administered intact.
`In other embodiments, the aversive agent may not
`[0028]
`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. However, it is
`contemplated in the present invention that 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.
`[0029] The aversive agent(s) can also be in the dosage
`form in releasable form and non-releasable form in any
`combination. For example, a dosage form can have a bit-
`tering agent, irritant, gel or combination thereof in releasable
`form and non-releasable form as disclosed in U.S. Applica-
`tion entitled "Pharmaceutical Formulations Containing
`Opioid Agonist, Releasable Antagonist, and Sequestered
`Antagonist" filed Aug. 6, 2002, the disclosure of which is
`hereby incorporated by reference in its entirety.
`[0030] The term "aversive agent" is defined for purposes
`of the present invention to mean a bittering agent, an irritant,
`a gelling agent, or combinations thereof.
`[0031] The term "tampered dosage form" is defined for
`purposes of the present invention to mean that the dosage
`form has been manipulated by mechanical, thermal, and/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.
`[0032] The term "substantially non-releasable form" for
`purposes of the present invention 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 Ser. No.
`09/781,081, entitled "Tamper Resistant Oral Opioid Agonist
`Formulations" filed Feb. 8, 2001, the disclosure of which is
`
`KASHIV1017
`IPR of Patent No. 9,492,393
`
`

`

`US 2003/0068375 Al
`
`3
`
`Apr. 10, 2003
`
`hereby incorporated by reference in its entirety, which
`describes a dosage form comprising an opioid antagonist in
`a substantially non-releasable form. For purposes of the
`present invention, the amount released after oral adminis-
`tration 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 Gastic Fluid using a USP Type II (paddle) appa-
`ratus at 75 rpm at 37° C. Such 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. In certain preferred embodiments of the inven-
`tion, 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
`states. Preferably, the aversive agent is not released or not
`substantially released 4, 8, 12 and/or 24 hours after oral
`administration.
`[0033] The phrase "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.
`[0034] The term "sustained release" is defined for pur-
`poses 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. Pref-
`erably the sustained release is sufficient to provide a twice-
`a-day or a once-a-day formulation.
`[0035] The term "particles" of aversive agent, as used
`herein, refers to granules, spheroids, beads or pellets com-
`prising the aversive agent. In certain preferred embodiments,
`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.
`[0036] The term "parenterally" as used herein includes
`subcutaneous injections, intravenous injections, intramuscu-
`lar injections, intrasternal injections, infusion techniques, or
`other methods of injection known in the art.
`[0037] The term "inhaled" as used herein includes trans-
`mucosal, trans-bronchial, and trans-nasal abuse.
`[0038] The term "bittering agent" as used herein includes
`a compound used to impart a bitter taste, bitter flavor, etc.,
`to an abuser administering a tampered dosage form of the
`present invention.
`[0039] The term "irritant" as used herein includes a com-
`pound used to impart an irritating or burning sensation to an
`abuser administering a tampered dosage form of the present
`invention.
`[0040] The term "gelling agent" as used herein includes a
`compound or composition used to impart-gel-like or thick-
`ening quality to a tampered dosage form upon the addition
`of moisture or liquid.
`
`DETAILED DESCRIPTION OF 1HE
`INVENTION
`[0041] The aversive agents of the present invention are
`preferably for use in connection with oral dosage forms
`including opioid analgesics, which provide valuable anal-
`
`gesia 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 injec-
`tion, inhalation, and/or oral consumption.
`In certain embodiments, the present invention com-
`[0042]
`prises 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.
`In certain alternative embodiments, the present
`[0043]
`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 compris-
`ing the drug other than an opioid analgesic which is the
`subject of abuse.
`In certain embodiments of the present invention
`[0044]
`wherein the dosage form includes an aversive agent com-
`prising a bittering agent, various 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 spear-
`mint 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. Additional
`bittering agents include sucrose derivatives (e.g., sucrose
`octaacetate ), chlorosucrose derivatives, quinine sulphate,
`and the like. The preferred bittering agent for use in the
`present invention is Denatonium Benzoate NF-Anhydrous,
`sold under the name Bitrex® (Macfarlan Smith Limited,
`Edinburgh, UK).
`[0045] With the inclusion of a bittering agent in the
`formulation, the intake of the tampered dosage form pro-
`duces 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.
`[0046] 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 tam-
`pered dosage form by imparting a disagreeable taste or
`flavor to the tampered dosage form.
`In certain embodiments of the present invention
`[0047]
`wherein the dosage form includes an aversive agent com-
`prising an irritant, various irritants can be employed includ-
`ing, for example and without limitation capsaicin, a capsai-
`cin analog with similar type properties as capsaicin, and the
`like. Some capsaicin analogues or derivatives include for
`
`KASHIV1017
`IPR of Patent No. 9,492,393
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`

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`
`example and without limitation, resiniferatoxin, tinyatoxin,
`heptanoylisobutylamide, heptanoyl guaiacylamide, other
`isobutylamides or guaiacylamides, dihydrocapsaicin, homo-
`vanillyl octylester, nonanoyl vanillylamide, or other com-
`pounds of the class known as vanilloids. Resiniferatoxin is
`described, for example, in U.S. Pat. No. 5,290,816 (Blum-
`berg), issued Mar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand),
`issued Mar. 14, 1989, describes capsaicin analogs and meth-
`ods for their preparation. Further, U.S. Pat. No. 4,424,205
`(LaHann et al.), issued Jan. 3, 1984, cite Newman, "Natural
`and Synthetic Pepper-Flavored Substances" published in
`1954 as listing pungency of capsaicin-like analogs. Ton et
`al., British Journal of Pharmacology, 10, pp. 175-182 (1955)
`discuss pharmacological actions of capsaicin and its ana-
`logs.
`[0048] With the inclusion of an irritant (e.g., capsaicin) in
`the dosage form, 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 pref-
`erably to prevent the abuse of the dosage form. Suitable
`capsaicin compositions include capsaicin (trans 8-methyl-
`N-vanillyl-6-noneamide) or analogues thereof in a concen-
`tration between about 0.00125% and 50% by weight, pref-
`erably between about 1 and about 7.5% by weight, and most
`preferably, between about 1 and about 5% by weight of the
`dosage form.
`In certain embodiments of the present invention
`[0049]
`wherein the dosage form includes an aversive agent com-
`prising a gelling agent, 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 deriva-
`tives, such as microcrystalline cellulose, sodium caboxym-
`ethyl cellulose, methylcellulose, ethyl cellulose, hydroxy-
`ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl
`methylcellulose, attapulgites, bentonites, dextrins, alginates,
`carrageenan, gum tragacanth, gum acacia, guar gum, xan-
`than gum, pectin, gelatin, kaolin, lecithin, magnesium alu-
`minum silicate, the carbomers and carbopols, polyvinylpyr-
`rolidone, polyethylene glycol, polyethylene oxide, polyvinyl
`alcohol, silicon dioxide, surfactants, mixed surfactant/wet-
`ting agent systems, emulsifiers, other polymeric materials,
`and mixtures thereof, etc. In certain preferred embodiments,
`the gelling agent is xanthan gum. In other preferred embodi-
`ments, 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.
`Preferably, the pectins used in this invention are derived
`from citrus fruits such as lime, lemon, grapefruit, and
`orange.
`[0050] With the inclusion of a gelling agent in the dosage
`form, when the dosage form is tampered with, the gelling
`agent preferably imparts a gel-like quality to the tampered
`dosage form which preferably spoils or hinders the pleasure
`of obtaining a rapid high from the tampered dosage form due
`to the gel like consistency in contact with the mucous
`membrane, and in certain embodiments, prevents the abuse
`of the dosage form by minimizing absorption, e.g. in the
`nasal passages. A gelling agent may be added to the formu-
`
`lation in a ratio of gelling agent to opioid agonist of from
`about 1:40 to about 40:1 by weight, preferably from about
`1:1 to about 30:1 by weight, and more preferably from about
`2:1 to about 10:1 by weight of the opioid agonist. In certain
`alternative embodiments, 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.
`In certain other embodiments, the dosage form
`[0051]
`forms a viscous gel after the dosage form is tampered with,
`dissolved in an aqueous liquid (from about 0.5 to about 10
`ml and preferably from 1 to about 5 ml), causing the
`resulting mixture to have a viscosity of at least about 10 cP.
`Most preferably, the resulting mixture will have a viscosity
`of at least about 60 cP.
`In certain other embodiments, the dosage form
`[0052]
`forms a viscous gel after the dosage form is tampered with,
`dissolved in an aqueous liquid (from about 0.5 to about 10
`ml and preferably from 1 to about 5 ml) and then heated
`(e.g., greater than about 45° C.), causing the resulting
`mixture to have a viscosity of at least about 10 cP. Most
`preferably, the resulting mixture will have a viscosity of at
`least about 60 cP.
`In certain embodiments, the dosage form may
`[0053]
`include one or more of the aforementioned aversive agents.
`For safety reasons, the amount of the bittering agent, irritant,
`or gelling agent in a formulation of the present invention
`should not be toxic to humans.
`the aversive agent
`In certain embodiments,
`[0054]
`included in the dosage form may be in a substantially
`non-releasable form. Where the aversive agent is in a
`substanitially non-releasable form, the substantially non-
`releasable form of the aversive agent comprises an aversive
`agent that is formulated with one or more pharmaceutically
`acceptable hydrophobic materials, such that the aversive
`agent is not released or substantially not released during its
`transit through the gastrointestinal tract when administered
`orally as intended, without having been tampered with.
`In certain embodiments of the present invention,
`[0055]
`the substantially non-releasable form of the aversive agent is
`vulnerable to mechanical, thermal and/or chemical tamper-
`ing, e.g., tampering by means of crushing, shearing, grind-
`ing, chewing and/or dissolution in a solvent in combination
`with heating (e.g., greater than about 45° C.) of the oral
`dosage form. When the dosage form is tampered with, the
`integrity of the substantially non-releasable form of the
`aversive agent will be compromised, and the aversive agent
`will be made available to be released. In certain embodi-
`ments, when the dosage form is chewed, crushed or dis-
`solved and heated in a solvent, the release of the aversive
`agent hinders, deters or prevents the administration of the
`tampered dosage form orally, intranasally, parenterally and/
`or sublingually.
`[0056] The opioid agonists useful in the present invention
`include, but are not limited to, alfentanil, allylprodine,
`alphaprodine, anileridine, benzylmorphine, bezitramide,
`buprenorphine, butorphanol, clonitazene, codeine, desomor-
`phine, dextromoramide, dezocine, diampromide, diamor-
`phone, dihydrocodeine, dihydromorphine, dimenoxadol,
`dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate,
`
`KASHIV1017
`IPR of Patent No. 9,492,393
`
`

`

`US 2003/0068375 Al
`
`5
`
`Apr. 10, 2003
`
`dipipanone, eptazocine, ethoheptazine, ethylmethylthiam-
`butene, ethylmorphine, etonitazene, etorphine, dihydroetor-
`phine, fentanyl and derivatives, heroin, hydrocodone, hydro-
`morphone, hydroxypethidine, isomethadone, ketobemidone,
`levorphanol, levophenacylmorphan, lofentanil, meperidine,
`meptazinol, metazocine, methadone, metopon, morphine,
`myrophine,
`narceine,
`nicomorphine,
`norlevorphanol,
`normethadone, nalorphine, nalbuphene, normorphine, nor-
`pipanone, opium, oxycodone, oxymorphone, papaveretum,
`pentazocine, phenadoxone, phenomorphan, phenazocine,
`phenoperidine, piminodine, piritramide, propheptazine,
`promedol, properidine, propoxyphene, sufentanil, tilidine,
`tramadol, mixtures of any of the foregoing, salts of any of
`the foregoing, and the like. In certain embodiments, the
`amount of the opioid agonist in the claimed opioid compo-
`sition may be about 75 ng to about 750 mg.
`In certain preferred embodiments, the opioid ago-
`[0057]
`nist is selected from the group consisting of hydrocodone,
`morphine, hydromorphone, oxycodone, codeine, levorpha-
`nol, meperidine, methadone, oxymorphone, buprenorphine,
`fentanyl and derivatives thereof, dipipanone, heroin, trama-
`dol, etorphine, dihydroetorphine, butorphanol, levorphanol,
`or salts thereof or mixtures thereof. In certain preferred
`embodiments, the opioid agonist is oxycodone or hydroc-
`odone.
`In embodiments in which the opioid analgesic
`[0058]
`comprises hydrocodone, dosage forms may include analge-
`sic doses from about 2 mg to about 50 mg of hydrocodone
`bitartrate. In embodiments in which the opioid analgesic
`comprises hydromorphone the dosage form may include
`from about 2 mg to about 64 mg hydromorphone hydro-
`chloride. In embodiments in which the opioid analgesic
`comprises morphine, the dosage form may include from
`about 2.5 mg to about 800 mg morphine sulfate, by weight.
`In embodiments in which 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. Alternatively, the dosage form may con-
`tain molar equivalent amounts of other salts of the opioids
`useful in the present invention.
`[0059] 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-methylmorphinan-6-one, and is also
`known as dihydrocodeinone. Like other opioids, hydroc-
`odone may be habit forming and may produce drug depen-
`dence of the morphine type. In excess doses hydrocodone,
`like other opium derivatives, will depress respiration.
`[0060] Oral hydrocodone is also available in Europe (Bel-
`gium, Germany, Greece, Italy, Luxembourg, Norway and
`Switzerland) as an antitussive agent. A parenteral formula-
`tion is also available in Germany as an antitussive agent. For
`use as an analgesic, hydrocodone bitartrate is commercially
`available in the United States only as a fixed combination
`with non-opiate drugs (i.e., ibuprofen, acetaminophen, aspi-
`rin, etc.) for relief of moderate or moderately severe pain.
`[0061] 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 avail-
`
`able in the ratio of 7.5 mg hydrocodone bitartrate and 650
`mg acetaminophen; and 7.5 mg hydrocodone bitartrate and
`750 mg 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 5 mg hydrocodone bitartrate and 224 mg
`aspirin with 32 mg caffeine; or 5 mg hydrocodone bitartrate
`and 500 mg aspirin. A relatively new formulation comprises
`hydrocodone bitartrate and ibuprofen. Vicoprofen®, com-
`mercially available in the U.S. from Knoll Laboratories, is