111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US0090343 76B2
`
`c12) United States Patent
`Wright et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,034,376 B2
`*May 19, 2015
`
`(54) PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`
`(71) Applicants:Purdue Pharma L.P., Stamford, CT
`(US); The P.F. Laboratories, Inc.,
`Totowa, NJ (US); Purdue
`Pharmaceuticals L.P., Wilson, NC (US)
`
`(72)
`
`Inventors: Curtis Wright, Rockport, MA (US);
`Benjamin Oshlack, Boca Raton, FL
`(US); Christopher Breder, Bethesda,
`MD (US)
`
`(73) Assignees: Purdue Pharma L.P., Stamford, CT
`(US); The P.F. Laboratories, Inc.,
`Totowa, NJ (US); Purdue
`Pharmaceuticals L.P., Wilson, NC (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.: 14/460,134
`
`(22) Filed:
`
`Aug. 14, 2014
`
`(65)
`
`Prior Publication Data
`US 2014/0357657 Al
`Dec. 4, 2014
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`Related U.S. Application Data
`Continuation of application No. 14/255,502, filed on
`Apr. 17, 2014, now Pat. No. 8,871,265, which is a
`continuation of application No. 13/726,324, filed on
`Dec. 24, 2012, which is a continuation of application
`No. 13/349,449, filed on Jan. 12, 2012, now Pat. No.
`8,337,888, which is a continuation of application No.
`12/653,115, filed on Dec. 8, 2009, now abandoned,
`which is a continuation of application No. 10/214,412,
`filed on Aug. 6, 2002.
`Provisional application No. 60/310,534, filed on Aug.
`6, 2001.
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K9/20
`A61K 311167
`A61K9/00
`A61K 311439
`A61K 311485
`A61K 47138
`A61K 47136
`A61K 47110
`A61K 45106
`A61K 311192
`A61K9/16
`A61K 47126
`U.S. Cl.
`CPC ............. A61K 311167 (2013.01); A61K 912013
`(2013.01); A61K 91205 (2013.01); A61K
`912054 (2013.01); A61K 910002 (2013.01);
`A61K 311439 (2013.01); A61K 311485
`
`(2013.01); A61K 47138 (2013.01); A61K 47136
`(2013.01); A61K 47110 (2013.01); A61K 45106
`(2013.01); A61K 311192 (2013.01); A61K
`911652 (2013.01); A61K 47126 (2013.01)
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
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`
`(Continued)
`
`Primary Examiner- Robert A Wax
`Assistant Examiner- Olga V Tcherkasskaya
`(74) Attorney, Agent, or Firm- Lowenstein Sandler LLP
`
`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.
`
`19 Claims, No Drawings
`
`KASHIV1008
`IPR of Patent No. 9,492,392
`
`

`

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`KASHIV1008
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`

`US 9,034,376 B2
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`KASHIV1008
`IPR of Patent No. 9,492,392
`
`

`

`US 9,034,376 B2
`Page 4
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`KASHIV1008
`IPR of Patent No. 9,492,392
`
`

`

`1
`PHARMACEUTICAL FORMULATION
`CONTAINING GELLING AGENT
`
`RELATED APPLICATIONS
`
`This application is a continuation of U.S. patent applica-
`tion Ser. No. 14/255,502, filed Apr. 17, 2014, which is a
`continuation of U.S. patent application Ser. No. 13/726,324,
`filed Dec. 24, 2012, which is a continuation of U.S. patent
`application Ser. No. 13/349,449, filed Jan. 12, 2012, now
`issued as U.S. Pat. No. 8,337,888, which is a continuation of
`U.S. patent application 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
`ofU.S. Provisional Application No. 60/310,534, filedAug. 6,
`2001. The contents of these applications are hereby incorpo-
`rated by reference in their entirety.
`
`BACKGROUND OF THE INVENTION
`
`US 9,034,376 B2
`
`2
`U.S. Pat. No. 5,472,943 to Crain eta!. describes methods of
`enhancing the analgesic potency of bimodally acting opioid
`agonists by administering the agonist with an opioid antago-
`nist.
`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
`10 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.
`However, there still exists a need for a safe and effective
`treatment of pain with opioid analgesic dosage forms which
`15 are less subject to abuse than current therapies.
`All documents cited herein, including the foregoing, are
`incorporated by reference in their entireties for all purposes.
`
`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 25
`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-
`tained therein better available for illicit use. For example, a 30
`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. In the prior art, the combination of immediate
`release pentazocine and naloxone has been utilized in tablets
`available in the United States, commercially available as 40
`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
`mg) and naloxone ( 4 mg) has been available in Germany for 45
`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 treatment of pain.
`Purdue Pharma EP currently markets sustained-release 50
`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 55
`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 60
`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
`forms.
`WO 99/32119 to Kaiko eta!. describes compositions and
`methods of preventing abuse of opioid dosage forms.
`
`20
`
`OBJECTS AND SUMMARY OF THE
`INVENTION
`
`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-
`35 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)
`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
`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
`65 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.
`
`KASHIV1008
`IPR of Patent No. 9,492,392
`
`

`

`US 9,034,376 B2
`
`4
`3
`In certain embodiments of the present invention, the dos-
`release of the aversive agent. However, it is contemplated in
`age form comprises an aversive agent such as a gelling agent
`the present invention that the aversive agent will preferably
`to discourage an abuser from tampering with the dosage form
`not have any significant side effect (e.g., gastrointestinal side
`effect) even if all of the aversive agent is immediately released
`and thereafter inhaling, injecting, and/or swallowing the tam-
`upon oral administration of an intact dosage form as directed.
`pered dosage form. Preferably, the gelling agent is released
`The aversive agent(s) can also be in the dosage form in
`when the dosage form is tampered with and provides a gel-
`releasable form and non-releasable form in any combination.
`like quality to the tampered dosage form which slows the
`absorption of the opioid analgesic such that an abuser is less
`For example, a dosage form can have a bittering agent, irri-
`likely to obtain a rapid "high". In certain preferred embodi-
`tant, gel or combination thereof in releasable form and non-
`ments, when the dosage form is tampered with and exposed to 10 releasable form as disclosed in U.S. application entitled
`a small amount (e.g., less than about 10 ml) of an aqueous
`"Pharmaceutical Formulations Containing Opioid Agonist,
`liquid (e.g., water), the dosage form will be unsuitable for
`Releasable Antagonist, and Sequestered Antagonist" filed
`Aug. 6, 2002, the disclosure of which is hereby incorporated
`injection and/or inhalation. Upon the addition of the aqueous
`by reference in its entirety.
`liquid, the tampered dosage form preferably becomes thick
`The term "aversive agent" is defined for purposes of the
`and viscous, rendering it unsuitable for injection. The term 15
`"unsuitable for injection" is defined for purposes of the
`present invention to mean a bittering agent, an irritant, a
`present invention to mean that one would have substantial
`gelling agent, or combinations thereof.
`difficulty injecting the dosage form (e.g., due to pain upon
`The term "tampered dosage form" is defined for purposes
`administration or difficulty pushing the dosage form through
`of the present invention to mean that the dosage form has been
`a syringe) due to the viscosity imparted on the dosage form,
`20 manipulated by mechanical, thermal, and/or chemical means
`thereby reducing the potential for abuse of the opioid analge-
`which changes the physical properties of the dosage form,
`sic in the dosage form. In certain embodiments, the gelling
`e.g., to liberate the opioid agonist for immediate release if it is
`in sustained release form, or to make the opioid agonist avail-
`agent is present in such an amount in the dosage form that
`attempts at evaporation (by the application of heat) to an
`able for inappropriate use such as administration by an alter-
`aqueous mixture of the dosage form in an effort to produce a
`25 nate route, e.g., parenterally. The tampering can be, e.g., by
`higher concentration of the therapeutic agent, produces a
`means of crushing, shearing, grinding, chewing, dissolution
`in a solvent, heating, (e.g., greater than about 45° C.), or any
`highly viscous substance unsuitable for injection.
`When nasally inhaling the tampered dosage form, the gel-
`combination thereof.
`The term "substantially non-releasable form" for purposes
`ling agent can become gel like upon administration to the
`nasal passages due to the moisture of the mucous membranes. 30
`of the present invention refers to an aversive agent that is not
`This also makes such formulations aversive to nasal admin-
`released or substantially not released at one hour after the
`intact dosage form containing an opioid agonist and at least
`istration, as the gel will stick to the nasal passage and mini-
`mize absorption of the abusable substance. In certain embodi-
`one aversive agent is orally administered (i.e., without having
`ments of the present invention, the dosage form comprises a
`been tampered with). The aversive agent in a substantially
`combination of any or all of the aforementioned aversive 35
`non-releasable form may be prepared in accordance with the
`teachings of U.S. application Ser. No. 09/781,081, entitled
`agents (e.g., a bittering agent, an irritant, and/or a gelling
`"Tamper Resistant Oral Opioid Agonist Formulations" filed
`agent) to discourage an abuser from tampering with the dos-
`age form and thereafter inhaling, injecting, and/or swallow-
`Feb. 8, 2001, the disclosure of which is hereby incorporated
`ing the tampered dosage form.
`by reference in its entirety, which describes a dosage form
`Embodiments specifically contemplated include bittering 40
`comprising an opioid antagonist in a substantially non-releas-
`agent; gelling agent; irritant; bittering agent and gelling
`able form. For purposes of the present invention, the amount
`released after oral administration of the intact dosage form
`agent; bittering agent and irritant; gelling agent and irritant;
`may be measured in-vitro via the dissolution at 1 hour of the
`and bittering agent and gelling agent and irritant.
`dosage form in 900 ml of Simulated Gastric Fluid using a
`In certain preferred embodiments, the dosage forms are
`USP Type II (paddle) apparatus at 75 rpm at 37.degree. C.
`controlled release oral dosage forms comprising a therapeu- 45
`tically effective amount of an opioid analgesic with one or
`Such a dosage form is also referred to as comprising a
`more of the aversive agents described above such that the
`"sequestered aversive agent" depending on the agent or
`agents which are not released or substantially not released. In
`dosage form provides effective pain relief for at least about 12
`hours, or at least about 24 hours when orally administered to
`certain preferred embodiments of the invention, the substan-
`a human patient.
`50 tially non-releasable form of the aversive agent is resistant to
`In certain embodiments of the present invention the aver-
`laxatives (e.g., mineral oil) used to manage delayed colonic
`sive agent pre