(12) United States Patent
`Hirsh et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,771,707 B2
`*Aug. 10, 2010
`
`US00777 1707B2
`
`(54) ABUSE-DETERRENT DRUG
`FORMULATIONS
`
`(75) Inventors: Jane C. Hirsh, Wellesley, MA (US);
`Alison B. Fleming, North Attleboro, MA
`(US); Roman V. Rariy, Allston, MA
`(US); Alexander M. Klibanov, Newton,
`MA (US)
`
`(*) Notice:
`
`(73) Assignee: Collegium Pharmaceutical, Inc.,
`Cumberland, RI (US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1058 days.
`This patent is Subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 11/149,867
`
`(22) Filed:
`
`Jun. 10, 2005
`
`(65)
`
`Prior Publication Data
`US 2005/0281748A1
`Dec. 22, 2005
`
`Related U.S. Application Data
`(60) Provisional application No. 60/579,191, filed on Jun
`12, 2004.
`(51) Int. Cl.
`(2006.01)
`A6 IK 49/00
`(2006.01)
`A6 IK 3/44
`(52) U.S. Cl. ...................................... 424/10.1; 514/282
`(58) Field of Classification Search ................. 514/282;
`424/10.1
`See application file for complete search history.
`References Cited
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`
`(Continued)
`FOREIGN PATENT DOCUMENTS
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`(Continued)
`OTHER PUBLICATIONS
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`Cortesi, et al., Sugar Cross-linked gelatin for controlled release:
`microspheres and disksBiomaterials, 19:1641-1649 (1998).
`(Continued)
`Primary Examiner Sreeni Padmanabhan
`Assistant Examiner—Renee Claytor
`(74) Attorney, Agent, or Firm Pabst Patent Group LLP
`
`(57)
`
`ABSTRACT
`
`An abuse-deterrent pharmaceutical composition has been
`developed to reduce the likelihood of improper administra
`tion of drugs, especially drugs such as opiods. In the preferred
`embodiment, the drug is modified to increase its lipophilicity
`by forming a salt between the drug and one or more fatty acids
`wherein the concentration of the one or more fatty acids is one
`to 15 times the molar amount of the active agent, preferably
`two to ten times the molar amount of the active agent. In one
`embodiment the modified drug is homogeneously dispersed
`within microparticles composed of a material that is either
`slowly soluble or not soluble in water. In some embodiments
`the drug containing microparticles or drug particles are
`coated with one or more coating layers, where at least one
`coating is water insoluble and preferably organic solvent
`insoluble. The abuse-deterrent composition prevents the
`immediate release of a Substantial portion of drug, even if the
`physical integrity of the formulation is compromised (for
`example, by chopping with a blade or crushing) and the
`resulting material is placed in water, Snorted, or Swallowed.
`However, when administered as directed, the drug is slowly
`released from the composition as the composition is broken
`down or dissolved gradually within the GI tract by a combi
`nation of enzymatic degradation, Surfactant action of bile
`acids, and mechanical erosion.
`
`30 Claims, 2 Drawing Sheets
`
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`US 7,771,707 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`2/2004 OShlack et al.
`6,696,088 B2
`3, 2004 OShlack et al.
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`4/2004 Kugelmann
`6,723,343 B2
`6, 2004 OShlack et al.
`6,743,442 B2
`7/2005 Yamashita et al.
`6,919,372 B1
`8/2007 Persyn et al.
`7,261,529 B2
`7/2008 Hirsh, et al.
`7,399,488 B2
`6, 2002 Oshlack et al.
`2002fOO81333 A1
`4/2003 Oshlack et al.
`2003, OO64099 A1
`5/2006 Vaghefi et al.
`2006/0104909 A1
`2008/0260819 A1 10/2008 Fleming et al.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`GB
`WO
`WO
`
`O 647 448
`1513166
`WO93/10765
`WO95/20947
`
`4f1995
`6, 1978
`6, 1993
`8, 1995
`
`WO97,14438
`WO
`WOOO, SOOO7
`WO
`WOO1,08661
`WO
`WOO1, 58.447
`WO
`WOO 1/72338
`WO
`WO WO 2004/O75877
`
`4f1997
`8, 2000
`2, 2001
`8, 2001
`10, 2001
`9, 2004
`
`OTHER PUBLICATIONS
`
`Gennaro, ed., Remington. The Science and Practice of Pharmacol
`Ogy, 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000,
`p. 704–706 (2000).
`Abuse and Mental Health Services Administration, "Results from the
`2004 National Survey on Drug Use and Health: National Findings.”
`pp. 1-310 (2005).
`Nakmura, et al., “Development of an oral Sustained release drug
`delivery system utilizing pH-dependent Swelling of carboxyvinyl
`polymer, J. Control. Rel., 111:309-319 (2006).
`* cited by examiner
`
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`Collegium v. Purdue, PGR2018-00048
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`

`

`U.S. Patent
`
`Aug. 10, 2010
`
`Sheet 1 of 2
`
`US 7,771,707 B2
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`Collegium v. Purdue, PGR2018—00048
`
`Purdue 2020
`
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`
`58832526505
`
`Purdue 2020
`Collegium v. Purdue, PGR2018-00048
`
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`

`

`U.S. Patent
`
`Aug. 10, 2010
`
`Sheet 2 of 2
`
`US 7,771,707 B2
`
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`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 7,771,707 B2
`
`1.
`ABUSE-DETERRENT DRUG
`FORMULATIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority under 35 U.S.C. S 119 to
`U.S. Provisional Application No. 60/579,191, filed Jun. 12.
`2004 entitled “Abuse-Deterrent Drug Formulations'.
`FIELD OF THE INVENTION
`
`10
`
`The present invention is generally in the field of pharma
`ceutical compositions, specifically compositions designed to
`reduce the potential for improper administration of drugs that
`are subject to abuse.
`
`15
`
`BACKGROUND OF THE INVENTION
`
`C1a.
`
`2
`DEA's Office of Diversion Control reported 700 OxyCon
`tin. RTM thefts in the U.S. between January 2000 and June
`2001. Some of these reported cases have been associated with
`serious consequences including death.
`Oxycodone is a controlled substance in Schedule II of the
`Controlled Substances Act (CSA), which is administered by
`the Drug Enforcement Administration (DEA). Despite the
`fact that Schedule II provides the maximum amount of con
`trol possible under the CSA for approved drug products, in
`practice, it is difficult for law enforcement agencies to control
`the diversion or misuse of legitimate prescriptions. Although
`abuse, misuse, and diversion are potential problems for all
`opioids, including Oxycodone, opioids are a very important
`part of the medical arsenal for the management of pain when
`used appropriately under the careful supervision of a physi
`Currently available formulations for such drugs are
`designed for oral administration but do not include mecha
`nisms to prevent or retard improper methods of administra
`tion such as chewing, injection and Snorting. This represents
`a serious problem given the large number of legitimate pre
`scriptions written in the U.S.; for example, the medical use of
`opioids within the U.S. increased 400% from 1996 to 2000.
`The problems with abuse are significant and longstanding.
`and efforts to design new abuse-resistant or abuse-deterrent
`formulations have been largely unsuccessful. U.S. Pat. Nos.
`3,980,766, 4,070,494 and 6,309.668 describe formulations
`designed to prevent the injection of compositions meant for
`oral administration. U.S. Pat. No. 3,980,766 describes the
`incorporation of an ingestible solid which causes a rapid
`increase in viscosity upon concentration of an aqueous solu
`tion thereof. U.S. Pat. No. 4,070,494 describes the incorpo
`ration of a non-toxic, water gelable material in an amount
`sufficient to render the drug resistant to aqueous extraction.
`U.S. Pat. No. 6,309,668 describes a tablet for oral adminis
`tration containing two or more layers comprising one or more
`drugs and one or more gelling agents within separate layers of
`the tablet. The resulting tablet forms a gel when combined
`with the volume of water necessary to dissolve the drug; this
`formulation thus reduces the extractability of the drug from
`the tablet. It should be noted that although these compositions
`preclude abuse by injection, this approach fails to prevent
`abuse by crushing and Swallowing or Snorting the formula
`tion, which are commonly reported methods of abuse associ
`ated with OxyContin.RTM.
`U.S. Pat. Nos. 3,773.955 and 3,966,940 describe formula
`tions containing a combination of opioid agonists and antago
`nists, in which the antagonist does not block the therapeutic
`effect when the admixture is administered orally, but which
`does not produce analgesia, euphoria or physical dependence
`when administered parenterally by an abuser. U.S. Pat. No.
`4,457.933 describes a method for decreasing both the oral and
`parenteral abuse potential of strong analgesic agents by com
`bining an analgesic dose of the analgesic agent with an
`antagonist in specific, relatively narrow ratios. U.S. Pat. Nos.
`6,277,384, 6,375,957 and 6.475,494 describe oral dosage
`forms including a combination of an orally active opioid
`agonist and an orally active opioid antagonist in a ratio that,
`when delivered orally, is analgesically effective but that is
`aversive in a physically dependent subject. While such a
`formulation may be successful in deterring abuse, it also has
`the potential to produce adverse effects in legitimate patients.
`It is therefore an object of the present invention to provide
`a pharmaceutical composition that significantly reduces the
`potential for improper administration or use of drugs but
`which, when administered as directed, is capable of deliver
`ing a therapeutically effective dose.
`
`25
`
`Oxycodone, morphine, and other opioid analgesics are
`therapeutically useful and effective medications, e.g., as pain
`killers, when administered orally. Unfortunately, they also
`pose a severe threat for willful abuse due to their ability to
`alter mood and/or cause a sense of euphoria. Currently avail
`able sustained release formulations of such drugs, which con
`tain a relatively large amount of drug intended to be released
`from the formulation over an extended period of time, are
`particularly attractive to abusers since the sustained release
`coating can be destroyed by crushing or grinding the formu
`lation. The crushed material no longer controls the release of
`drug. Depending on the drug, abusers can then (1) Snort the
`material, (2) swallow the material or (3) dissolve the material
`in water and subsequently inject it intravenously. The dose of
`drug contained in the formulation is thus absorbed immedi
`ately through the nasal or GI mucosa (for Snorting or Swal
`lowing, respectively) or is administered systemically in a
`bolus via the circulatory system (for IV injection). These
`abuse methods result in the rapid bioavailability of relatively
`high doses of drug, giving the abuser a "high”. Since rela
`tively simple methods (crushing, grinding, chewing and/or
`dissolution in water) can be used to transform such formula
`tions into an abusable form, they provide virtually no deter
`rent to a potential abuser.
`For example, the FDA recently strengthened the warnings
`and precautions sections in the labeling of OxyContin. RTM
`(oxycodone HCl controlled-release) tablets, a narcotic drug
`approved for the treatment of moderate to severe pain,
`because of continuing reports of abuse and diversion. Oxy
`Contin.RTM contains oxycodone HCl (available in 10, 20, 40
`and 80 mg strengths), an opioid agonist with an addiction
`potential similar to that of morphine. Opioid agonists are
`substances that act by attaching to specific proteins called
`opioid receptors, which are found in the brain, spinal cord,
`and gastrointestinal tract. When these drugs attach to certain
`opioid receptors in the brain and spinal cord they can effec
`tively block the transmission of pain messages to the brain.
`OxyContin. RTM is supplied in a controlled-release dosage
`form and is intended to provide up to 12 hours of relief from
`moderate to severe pain. The warning specifically states that
`the tablet must be taken whole and only by mouth. When the
`tablet is chewed or crushed and its contents are swallowed,
`snorted into the nostrils or dissolved and subsequently
`injected intravenously, the controlled release mechanism is
`destroyed and a potentially lethal dose of oxycodone
`becomes bioavailable.
`65
`In recent years, there have been numerous reports of Oxy
`codone diversion and abuse in several states. For example,
`
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`US 7,771,707 B2
`
`3
`BRIEF SUMMARY OF THE INVENTION
`
`An abuse-deterrent pharmaceutical composition has been
`developed to reduce the likelihood of improper administra
`tion of drugs, especially drugs such as opioids. In the pre
`ferred embodiment, the drug is modified to increase its lipo
`philicity by forming a salt between the drug and one or more
`fatty acids or amines, wherein the concentration of the one or
`more fatty acids or amines is one to fifteen times the molar
`amount of the active agent, preferably two to ten times the
`molar amount of the active agent. In one embodiment the
`modified drug is homogeneously dispersed within micropar
`ticles composed of a material that is either slowly soluble or
`insoluble in water. In some embodiments the drug containing
`microparticles or drug particles are coated with one or more
`coating layers. The abuse-deterrent composition prevents the
`immediate release of a Substantial portion of drug, even if the
`physical integrity of the formulation is compromised (for
`example, by chopping with a blade or crushing) and the
`resulting material is placed in water, Snorted, or Swallowed.
`However, when administered as directed, the drug is slowly
`released from the composition as the composition is broken
`down or dissolved gradually within the GI tract by a combi
`nation of enzymatic degradation, Surfactant action of bile
`acids, and mechanical erosion.
`
`10
`
`15
`
`25
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is an illustration of the testing procedures for deter
`mining abuse resistance of the formulations.
`FIG. 2 is a graph showing the percentage of oxycodone
`released in Oral Abuse Testing as a function of composition.
`
`30
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`35
`
`I. Definitions
`
`4
`coated with one or more coating layers. Microparticles and
`coated microparticles have a size range of 10 to 3000 microns
`in diameter.
`
`II. Compositions
`
`The currently available Sustained release dosage forms
`containing narcotic analgesics and other drugs are subject to
`misuse, in part, because mechanical destruction of the dosage
`form exposes the encapsulated drug and allows for immediate
`dissolution of the drug into aqueous media. Two properties of
`the dosage form that contribute to this outcome are (1) the
`ease with which drug is exposed to the extraction media and
`(2) the high water solubility of the drug salt form.
`In the composition disclosed herein, one or both of these
`properties are altered in order to achieve an abuse-deterrent
`composition. Specifically, in the preferred embodiment, the
`drug is modified to increase its lipophilicity and, in additional
`preferred embodiments, is then homogeneously dispersed
`within a material that is either slowly soluble or not soluble in
`water and Subsequently formulated into microparticles. The
`drug may be present in the form of discrete particles or may be
`partially or fully dispersed in the carrier material on a molecu
`lar level.
`The abuse deterrent composition preferably comprises a
`drug modified to increase its lipophilicity. In other preferred
`embodiments, the drug is homogenously dispersed within
`microparticles composed of a material that is either slowly
`soluble in water or water insoluble. The compositions slow
`the release of drug if the dosage form is chopped or crushed
`and the resulting material is placed in water, Snorted, or Swal
`lowed since most of the drug will remain associated with or
`entrapped within portions of the core material of the micro
`particles. In some embodiments the drug containing micro
`particles or individual drug particles are coated with one or
`more coating layers, where at least one coating is water
`insoluble and preferably organic solvent insoluble, but enzy
`matically degradable. The components of the resulting coated
`microparticles are not mutually soluble in water, organic Sol
`vents, or any combination thereof. Such that no one solvent or
`enzyme solution is capable of dissolving the formulation in
`its entirety in vitro. It follows that extraction of the drug from
`the formulation cannot be carried out in one step. However,
`when administered as directed, the drug is slowly released
`from the formulation since it is eroded within the environ
`ment of the gastrointestinal tract.
`A. Drugs to be Formulated
`There are many drugs that it is desirable to deliver using the
`compositions described herein. The Controlled Substances
`Act (CSA), Title II of the Comprehensive Drug Abuse Pre
`vention and Control Act of 1970, places all substances that are
`regulated under existing federal law into one offive schedules
`based upon the Substance's medicinal value, harmfulness,
`and potential for abuse or addiction. Drugs that are preferred
`include those classified as Schedule II, III, IV and V drugs.
`Drugs that are most preferable include those, like oxycodone,
`that are currently formulated as sustained or controlled
`release compositions, where drug release is intended to occur
`over a prolonged period of time through the gastrointestinal
`tract, and immediate or burst release, for example, by inhala
`tion or injection, is undesirable. As used herein, drugs prone
`to abuse refer to controlled substance specified as schedule II,
`II, IV and V drugs.
`The terms “drug”, “active agent, and “pharmacologically
`active agent” are used interchangeably herein to refer to a
`chemical compound that induces a desired pharmacological,
`physiological effect. The terms also encompass pharmaceu
`
`40
`
`"Composition” as used herein refers to the drug dosage
`unit for administration to a patient. It may also be used in
`reference solely to the active ingredient, or to the formulation
`containing the active ingredient.
`Abuse-deterrent composition” or “abuse-deterrentformu
`lation” are used interchangeably herein to refer to composi
`tions that reduce the potential for improper administration of
`45
`drugs but that deliver a therapeutically effective dose when
`administered as directed. Improper administration includes
`tampering with the dosage form and/or administering the
`drug by any route other than instructed.
`"Drug”, “active agent, and “pharmacologically active
`agent” are used interchangeably herein to refer to a chemical
`compound that induces a desired pharmacological and/or
`physiological effect. The terms also encompass pharmaceu
`tically acceptable derivatives of those active agents specifi
`cally mentioned herein, including, but not limited to, salts,
`Solvates, hydrates, complexes with one or more molecules,
`prodrugs, active metabolites, lipophilic derivatives, analogs,
`and the like.
`“Lipophilic derivative' and “lipophililic drug derivative'.
`as used herein, refer to derivatives of the drug that are less
`soluble in water than the most soluble salt of the drug. The
`most soluble salt is selected from either alkaline metal salts
`(for acidic drugs) or acid addition salts of (for basic drugs).
`“Microparticle' as used herein refers to a composition
`comprising a drug dispersed within a carrier material.
`“Coated microparticle' as used herein refers to a composition
`comprising a drug containing microparticle or a drug particle
`
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`5
`tically acceptable derivatives of those active agents specifi
`cally mentioned herein, including, but not limited to, salts,
`Solvates, hydrates, complexes with one or more molecules,
`prodrugs, active metabolites, lipophilic derivatives, analogs,
`and the like. When the terms “active agent”, “pharmacologi
`cally active agent” and "drug” are used, or when a particular
`drug, Such as oxycodone, is identified, it is to be understood as
`including the active agent per seas well as pharmaceutically
`acceptable salts, Solvates, hydrates, complexes with one or
`more molecules, prodrugs, active metabolites, and lipophilic
`derivatives and analogs.
`Examples of preferred drugs include, 1-phenylcyclohexy
`lamine, 1-piperidinocyclohexanecarbonitrile, alfentanil,
`alphacetylmethadol, alphaprodine, alprazolam, amobarbital,
`amphetamine, anilleridine, apomorphine, aprobarbital, bar
`bital, barbituric acid derivative, bemidone, benzoylecgonine,
`benzphetamine, betacetylmethadol, betaprodine, bezitra
`mide, bromazepam, buprenorphine, butabarbital, butalbital,
`butorphanol, camazepam, cathine, chloral, chlordiazepoxide,
`clobazam, clonazepam, cloraZepate, clotiazepam, clox
`aZolam, cocaine, codeine, chlorphentermine, delorazepam,
`dexfenfluramine, dextromoramide, dextropropoxyphen,
`dezocine, diazepam, diethylpropion, difenoxin, dihydroco
`deine, dihydromorphine, dioxaphentyl butyrate, dipanone,
`diphenoxylate, diprenorphine, ecgonine, enadoline, eptaZo
`cine, estaZolam, ethoheptazine, ethyl loflazepate, ethylmor
`phine, etorphine, femproponex, fencamfamin, fenfluramine,
`fentanyl, fludiazepam, flunitrazepam, flurazepam, glutethim
`ide, halazepam, haloxazolam, hexalgon, hydrocodone,
`hydromorphone, isomethadone, hydrocodone, ketamine,
`ketazolam, ketobemidone, levanone, levoalphacetylmeth
`adol, levomethadone, levomethadyl acetate, levomethor
`phan, levorphanol, lofentanil, loperamide, loprazolam,
`lorazepam, lormetazepam, lysergic acid, lysergic acid amide,
`mazindol, medazepam, mefenorex, meperidine, meptazinol,
`metazocine, methadone, methamphetamine, methohexital,
`methotrimeprazine,
`methyldihydromorphinone, meth
`ylphenidate, methylphenobarbital, metopon, morphine,
`nabilone, nalbuphine, nalbupine, nalorphine, narceline, nefo
`pam, nicomorphine, nimetazepam, nitrazepam, nordiaz
`epam, normethadone, normorphine, oxazepam, oxazolam,
`oxycodone, oxymorphone, pentazocine, pentobarbital, phen
`adoxone, phenazocine, phencyclidine, phendimetrazine,
`phenmetrazine, pheneridine, piminodine, prodilidine, prope
`ridine, propoxyphene, racemethorphan, racemorphan,
`racemoramide, remifentanil, secobarbital, Sufentanil, talb
`utal, thebaine, thiamylal, thiopental, tramadol, trimeperidine,
`and vinbarbital.
`In addition to the compounds above, the following sched
`uled drugs may be incorporated into the composition: allo
`barbitone, alprazolam, amylobarbitone, aprobarbital, bar
`bital,
`barbitone,
`benZphetamine,
`brallobarbital,
`bromazepam, brotizolam, buspirone, butalbital, butobarbi
`tone, butorphanol, camazepam, captodiame, carbromal,
`carfentanil, carpipramine, cathine, chloral, chloral betaine,
`chloral hydrate, chloralose, chlordiazepoxide, chlorhexadol,
`chlormethiazole edisylate, chlormeZanone, cinolazepam,
`clobazam, potassium cloraZepate, clotiazepam, cloxazolam,
`cyclobarbitone, delorazepam, dexfenfluramine, diazepam,
`diethylpropion, difebarbamate, difenoxin, enciprazine, esta
`Zolam, ethyl loflazepate, etizolam, febarbamate, fencam
`famin, fenfluramine, fenproporex, fluianisone, fludiazepam,
`flunitraam, flunitrazepam, flurazepam, flutoprazepam,
`gepirone, glutethimide, halazepam, haloxazolam, hexobarbi
`tone, ibomal, ipsapirone, ketazolam, loprazolam mesylate,
`lorazepam,
`lormetazepam,
`mazindol,
`mebutamate,
`medazepam, mefenorex, mephobarbital, meprobamate,
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`US 7,771,707 B2
`
`6
`metaclazepam, methaqualone, methohexital, methylpen
`tynol, methylphenobarbital, midazolam, milaZolam, mor
`phine, nimetazepam, nitrazepam, nordiazepam, oxazepam,
`oxazolam, paraldehyde, pemoline, pentabarbitone, pentaZo
`cine, pentobarbital, phencyclidine, phenobarbital, phendime
`trazine, phenmetrazine, phenprobamate, phentermine, phen
`yacetone, pinazepam, pipradol, prazepam, proxibarbal,
`quazepam, quinalbaritone, secobarbital, secbutobarbitone,
`Sibutramine, temazepam, tetrazepam, triazolam, triclofos,
`Zalepan, Zaleplon, Zolazepam, Zolpidem, and Zopiclone. In a
`preferred embodiment, the pharmaceutically active agent is
`oxycodone. Certain compounds described herein may existin
`particular geometric or stereoisomeric forms. The composi
`tions disclosed herein contemplate all Such compounds,
`including cis- and trans-isomers, R- and S-enantiomers, dias
`tereomers, (D)-isomers, (L)-isomers, the racemic mixtures
`thereof, compounds of different spatial conformations, and
`other mixtures thereof Additional asymmetric carbon atoms
`may be present in a Substituent Such as an alkyl group.
`As used herein, “pharmaceutically acceptable salts' refer
`to derivatives of the disclosed compounds wherein the parent
`compound is modified by making acid or base salts thereof.
`Examples of pharmaceutically acceptable salts include, but
`are not limited to, mineral or organic acid salts of basic
`residues such as amines; alkali or organic salts of acidic
`residues such as carboxylic acids; and the like. The pharma
`ceutically acceptable salts include the conventional non-toxic
`salts or the quaternary ammonium salts of the parent com
`pound formed, for example, from non-toxic inorganic or
`organic acids. For example, Such conventional non-toxic salts
`include those derived from inorganic acids such as hydro
`chloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric
`and the like; and the salts prepared from organic acids such as
`acetic, propionic, Succinic, glycolic, Stearic, lactic, malic,
`tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phe
`nylacetic, glutamic, benzoic, Salicylic, Sulfanilic, 2-acetoxy
`benzoic, fumaric, tolunesulfonic, methanesulfonic, ethane
`disulfonic, oxalic, and isethionic.
`The pharmaceutically acceptable salts of the compounds
`can be synthesized from the parent compound, which con
`tains a basic oracidic moiety, by conventional chemical meth
`ods. Generally, such salts can be prepared by reacting the free
`acid or base forms of these compounds with a stoichiometric
`amount of the appropriate base or acid in water or in an
`organic solvent, or in a mixture of the two: generally, non
`aqueous media like ether, ethyl acetate, ethanol, isopropanol,
`oracetonitrile are preferred. Lists of suitable salts are found in
`Remington’s Pharmaceutical Sciences, 20th ed., Lippincott
`Williams & Wilkins, Baltimore, Md., 2000, p. 704, the dis
`closure of which is hereby incorporated by reference.
`Optionally, the composition described herein can further
`include a drug having no appreciable abuse potential.
`In preferred embodiments, the solubility characteristics of
`a drug are altered prior to incorporation into the formulation.
`Modification of the drug to produce a more lipophilic deriva
`tive serves to reduce the water solubility of the drug and thus
`reduces the aqueous extractability. Furthermore, if the drug is
`made more lipophilic, it can be solubilized in a fatty sub
`stance or wax like mixture, rather than physically dispersed in
`a particulate form. Solubilization of drug enhances the abuse
`deterrent properties of microparticles formulated from the
`mixture as it is difficult to extract drug from an intimately
`dispersed composition.
`Some of the methods that can be used to alter the drugs
`lipophilicity are outlined below. It is understood that two or
`more approaches can be combined to achieve a desired solu
`bility profile.
`
`Purdue 2020
`Collegium v. Purdue, PGR2018-00048
`
`

`

`US 7,771,707 B2
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`B. Lipophilic Drug Formulations
`In one embodiment, drug is made more lipophilic by elimi
`nating or reducing the overall charge of the drug molecule.
`For example, for a basic drug, a water soluble salt (such as
`hydrochloride, sulfate, or maleate) can be converted to a free
`base using techniques known in the art. Correspondingly, in
`the case of an acidic drug, a water soluble salt (such sodium,
`potassium, or the like) can be converted to a free acid.
`In another embodiment, the drugs lipophilicity is
`increased by forming a salt between a drug molecule and one
`or more charged lipophilic compounds. In this case the lipo
`philicity of the resulting salt can be manipulated by varying
`the lipophilicity of the counter-ion. In general lipophilic
`(fatty) acids oramines with chain lengths between Cs-Co are
`suitable lipophilic counter-ion candidates. Suitable (fatty)
`acids and amines include, but are not limited to, pentanoic
`acid, hexanoic (caproic) acid, heptanoic acid, octanoic (ca
`prylic) acid, nonanoic acid, decanoic (capric) acid, unde
`canoic acid, dodecanoic (lauric) acid, tridecanoic acid, tet
`radecanoic (myristic) acid, pentadecanoic acid, hexadecanoic
`(palmitic) acid, heptadecanoic (margaric) acid, octadecanoic
`(Stearic) acid, nonadecanoic acid, eicosanoic (arachidic) acid,
`heneicosanoic acid, docosanoic (behenic) acid, tricosanoic
`acid, tetracosanoic (lignoceric) acid, pentacosanoic acid,
`hexacosanoic acid, heptacosanoic acid, octacosanoic acid,
`nonacosanoic acid, triacontanoic acid, linoleic acid, oleic
`acid, octyl amine, lauryl amine, Stearyl amine, palmityl
`amine, linoleylamine, and oleylamine and mixtures thereof.
`In a preferred embodiment, the fatty acid is myristic acid or a
`mixture of stearic and palmitic acid. The fatty acid oramine is
`present in an amount from about one to about fifteen times the
`molar amount of the pharmaceutically active agent, prefer
`ably two to ten times the molar of amount of the pharmaceu
`tically acceptable agent.
`The formation of a salt composed of a pharmaceutically
`active agent and a fatty acid oramine can be accomplished by
`a melt process, with or without the use of a solvent. One or
`more fatty acids or amines are heated above their melting
`point and the pharmaceutically active agent, in free base or
`acid form, is added to the molten fatty acid or amine either
`directly or after dissolution of the active agent in an appro
`priate solvent, such as methylene chloride. The lipophilic
`compound is present in excess (on a molar basis) relative to
`the pharmaceutically active agent. The lipophilic compound
`45
`is present, preferably, in an amount one to fifteen times the
`molar amount of the pharmaceutically active agent, more
`preferably, two to ten times the molar amount of the pharma
`ceutically active agent. The mass of fatty acid or amine
`required to dissolve the active agent is a function of the chain
`length of the fatty acid or amine. For example, oxycodone
`base can be dissolved in a molten mixture of Stearic and
`plamitic acids at a ratio of 1:5, by weight, or in molten myris
`tic acid at a ratio of 1:4, by weight. The factors determining
`the amount offatty acid or amine required to dissolve a given
`amount of base include but are not limited to base strength,
`acid strength, Steric hindrance of the portions of the acid
`and/or base molecule involved in salt formation, and the
`ability