I IIIII
`
`1111111111111111111111111111111111111111111111111111111111111
`US008337888B2
`
`c12) United States Patent
`Wright et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,337,888 B2
`*Dec. 25, 2012
`
`(54) PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`
`(75)
`
`Inventors: Curtis Wright, Norwalk, CT (US);
`Benjamin Oshlack, New York, NY
`(US); Christopher Breder, Greenwich,
`CT (US)
`
`(73) Assignee: Purdue Pharma L.P., Stamford, CT
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 13/349,449
`
`(22) Filed:
`
`Jan.12,2012
`
`(65)
`
`Prior Publication Data
`May 3, 2012
`US 2012/0108622 Al
`
`Related U.S. Application Data
`(63) Continuation of application No. 12/653,115, filed on
`Dec. 8, 2009, now abandoned, which is a continuation
`ofapplicationNo. 10/214,412, filedonAug. 6, 2002,
`now abandoned.
`(60) Provisional application No. 60/310,534, filed on Aug.
`6, 2001.
`
`(51)
`
`Int. Cl.
`A61K 9120
`(2006.01)
`(52) U.S. Cl. ........................................ 424/464; 424/465
`(58) Field of Classification Search ........................ None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
`
`Primary Examiner- Robert A Wax
`Assistant Examiner- Olga V Tcherkasskaya
`(74) Attorney, Agent, or Firm- Lowenstein Sandler PC
`
`ABSTRACT
`(57)
`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 phar-
`maceutically 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 administration 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.
`
`24 Claims, No Drawings
`
`KASHIV1004
`IPR of Patent No. 9,492,392
`
`

`

`US 8,337,888 B2
`Page 2
`
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`
`KASHIV1004
`IPR of Patent No. 9,492,392
`
`

`

`US 8,337,888 B2
`Page 3
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`
`KASHIV1004
`IPR of Patent No. 9,492,392
`
`

`

`US 8,337,888 B2
`
`1
`PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`
`RELATED APPLICATIONS
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No. 12/653,115, filed Dec. 8, 2009, which is a
`continuation of U.S. patent application Ser. No. 10/214,412,
`filed Aug. 6, 2002, which claims the benefit of U.S. Provi-
`sional Application No. 60/310,534, filed Aug. 6, 2001. The
`contents of these applications are hereby incorporated by
`reference in their entirety.
`
`2
`U.S. Pat. No. 3,980,766 to Shaw eta!., 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 torr of such drug an ingestible solid having
`thickening properties which cause rapid increase in viscosity
`upon concentration of an aqueous solution thereof.
`However, there still exists a need for a safe and effective
`10 treatment of pain with opioid analgesic dosage forms which
`are less subject to abuse than current therapies.
`All documents cited herein, including the foregoing, art
`incorporated by reference in their entireties for all purposes.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`OBJECTS AND SUMMARY OF THE
`INVENTION
`
`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 20
`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 con- 25
`tained 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 30
`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. In the prior art, the combination of immediate
`release pentazocine and naloxone has been utilized in tablets 35
`available in the United States, commercially available as
`Talwin®Nx from Sanofi-Winthrop. Talwin®Nx 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 40
`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
`in New Zealand (Temgesic®Nx,
`introduced in 1991
`Reckitt & Colman) for the treatment of pain.
`Purdue Pharma EP currently markets sustained-release
`oxycodone in dosage forms containing 10, 20, 40, and 80 mg
`oxycodone hydrochloride under the tradename OxyContin.
`U.S. Pat. Nos. 5,266,331; 5,508,042; 5,549,912 and 5,656,
`295 disclose sustained release oxycodone formulations.
`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 dysmotility by
`administering 1 to 2 dosage units comprising from about 1.5
`to about 100 mg of opioid analgesic or antitussive and from 55
`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. Pat. No. 6,228,863 to Palermo eta!. describes com-
`positions and methods of preventing abuse of opioid dosage 60
`forms.
`WO 99/32119 to Kaiko eta!. describes compositions and
`methods of preventing abuse of opioid dosage forms.
`U.S. Pat. No. 5,472,943 to Crain eta!. describes methods of
`enhancing the analgesic potency of bimodally acting opioid 65
`agonists by administering the agonist with an opioid antago-
`nist.
`
`It is an object of certain embodiments of the 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 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 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 inven-
`tion 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 inven-
`tion to provide a method of treating pain in human patients
`with an oral dosage form of an opioid analgesic while reduc-
`ing the abuse potential of the dosage form.
`It is a further object of certain embodiments of the inven-
`tion to provide a method of manufacturing an oral dosage
`form of an opioid analgesic such that it has less abuse poten-
`tial.
`These objects and others are achieved by the present inven-
`tion, which is directed in part to an oral dosage form com-
`prising an opioid analgesic; and at least one aversive agent for
`reducing the abuse of the opioid analgesic.
`In certain embodiments of the present invention, the oral
`dosage forms of the present invention comprising an opioid
`analgesic; and an aversive agent or agents as a component(s)
`45 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.
`In certain embodiments of the present invention, the dos-
`age form comprises an aversive agent such as a bittering agent
`50 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 provides an unpleasant
`taste to the abuser upon inhalation and/or swallowing of the
`tampered dosage form.
`In certain embodiments of the present invention, the dos-
`age form comprises an aversive agent such as an irritant to
`discourage an abuser from tampering with the dosage form
`and thereafter inhaling, injecting, or swallowing the tampered
`dosage form. Preferably, the irritant is released when the
`dosage form is tampered with and provides 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, the dos-
`age 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 tam-
`
`KASHIV1004
`IPR of Patent No. 9,492,392
`
`

`

`US 8,337,888 B2
`
`3
`pered dosage form. Preferably, 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". In certain preferred embodi-
`ments, 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 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 15
`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 analge-
`sic in the dosage form. In certain embodiments, 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.
`When nasally inhaling the tampered dosage form, the gel-
`ling 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 admin-
`istration, as the gel will stick to the nasal passage and mini-
`mize absorption of the abusable substance. In certain embodi- 30
`ments of the present invention, the dosage form comprises a
`combination of any or all of the aforementioned aversive
`agents (e.g., a bittering agent, an irritant, and/or a gelling
`agent) to discourage an abuser from tampering with the dos-
`age form and thereafter inhaling, injecting, and/or swallow- 35
`ing the tampered dosage form.
`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 forms are
`controlled release oral dosage forms comprising a therapeu-
`tically 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 45
`hours, or at least about 24 hours when orally administered to
`a human patient.
`In certain embodiments of the present invention the aver-
`sive agent present in the dosage form is present in a substan-
`tially non-releasable form (i.e., "sequestered") when the dos- 50
`age form is administered intact as directed. Preferably,
`because the 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.
`In other embodiments, 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 60
`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 65
`the present invention that the aversive agent will preferably
`not have any significant side effect (e.g., gastrointestinal side
`
`4
`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 form in any combination.
`For example, a dosage form can have a bittering agent, irri-
`tant, 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
`10 Aug. 6, 2002, the disclosure of which is hereby incorporated
`by reference in its entirety.
`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.
`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
`20 in sustained release form, or to make the opioid agonist avail-
`able for inappropriate use such as administration by an alter-
`nate 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
`25 combination thereof.
`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 hereby incorporated
`by reference in its entirety, which describes a dosage form
`comprising an opioid antagonist in a substantially non-releas-
`able form. For purposes of the present invention, the amount
`released after oral administration of the intact dosage form
`40 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. 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 invention, the substantially non-releas-
`able form of the aversive agent is resistant to laxatives (e.g.,
`mineral oil) used to manage delayed colonic transit and resis-
`tant to achlorhydric states. Preferably, the aversive agent is
`not released or not substantially released 4, 8, 12 and/or 24
`hours after oral administration.
`The phrase "analgesic effectiveness" is defined for pur-
`poses of the present invention as a satisfactory reduction in or
`elimination of pain, along with a tolerable level of side
`55 effects, as determined by the human patient.
`The term "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. Preferably the sustained release is
`sufficient to provide a twice-a-day or a once-a-day formula-
`tion.
`The term "particles" of aversive agent, as used herein,
`refers to granules, spheroids, beads or pellets comprising the
`aversive agent. In certain preferred embodiments, the aver-
`
`KASHIV1004
`IPR of Patent No. 9,492,392
`
`

`

`5
`sive agent particles are about 0.2 to about 2 mm in diameter,
`more preferably about 0.5 to about 2 mm in diameter.
`The term "parenterally" as used herein includes subcuta-
`neous injections, intravenous injections, intramuscular injec-
`tions, intrastemal injections, infusion techniques, or other
`methods of injection known in the art.
`The term "inhaled" as used herein includes trans-mucosal,
`trans-bronchial, and trans-nasal abuse.
`The term "bittering agent" as used herein includes a com-
`pound 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 inven-
`tion.
`The term "gelling agent" as used herein includes a com-
`pound or composition used to impart gel-like or thickening
`quality to a tampered dosage form upon the addition of mois-
`ture or liquid.
`
`DETAILED DESCRIPTION OF THE 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.
`In certain embodiments, the present invention comprises a
`method for preventing or deterring the abuse of opioid anal-
`gesics by the inclusion of at least one aversive agent in the
`dosage form with the opioid analgesic.
`In certain alternative embodiments, 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 45
`other than an opioid analgesic which is the subject of abuse.
`In certain embodiments of the present invention wherein
`the dosage form includes an aversive agent comprising a
`bittering agent, various bittering agents can be employed
`including, for example and without limitation, natural, artifi- 50
`cia! and synthetic flavor oils and flavoring aromatics and/or
`oils, oleoresins and extracts derived from plants, leaves, flow-
`ers, fruits, and so forth, and combinations thereof. Nonlimit-
`ing representative flavor oils include spearmint oil, pepper-
`mint oil, eucalyptus oil, oil of nutmeg, allspice, mace, oil of 55
`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 60
`derivatives, quinine sulphate, and the like. The preferred bit-
`tering agent for use in the present invention is Denatonium
`Benzoate NF-Anhydrous, sold under the name Bitrex™
`(Macfarlan Smith Limited, Edinburgh, UK).
`With the inclusion of a bittering agent in the formulation, 65
`the intake of the tampered dosage form produces a bitter taste
`upon inhalation or oral administration which in certain
`
`US 8,337,888 B2
`
`6
`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 ofless 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
`10 dosage form including a bittering agent preferably discour-
`ages improper usage of the tampered dosage form by impart-
`ing a disagreeable taste or flavor to the tampered dosage form.
`In certain embodiments of the present invention wherein
`the dosage form includes an aversive agent comprising an
`15 irritant, various irritants can be employed including, for
`example and without limitation capsaicin, a capsaicin analog
`with similar type properties as capsaicin, and the like. Some
`capsaicin analogues or derivatives include for example and
`without limitation, resiniferatoxin, tinyatoxin, heptanoyl-
`20 isobutylamide, heptanoyl guaiacylamide, other isobutyla-
`mides 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
`25 Mar. 1, 1994. U.S. Pat. No. 4,812,446 (Brand), issued Mar.
`14, 1989, describes capsaicin analogs and methods for their
`preparation. Further, U.S. Pat. No. 4,424,205 (LaHann eta!.),
`issued Jan. 3, 1984, cite Newman, "Natural and Synthetic
`Pepper-Flavored Substances" published in 1954 as listing
`30 pungency of capsaicin-like analogs. Ton eta!., British Journal
`of Pharmacology, 10, pp. 175-182 (1955) discuss pharmaco-
`logical actions of capsaicin and its analogs.
`With the inclusion of an irritant (e.g., capsaicin) in the
`dosage form, when the dosage form is tampered with, the
`35 capsaicin imparts a