(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`7 November 2002 (07.11.2002)
`
`(I0) International Publication Number
`
`PCT
`
`W0 ()2/087558 A1
`
`(51) International Patent Classification’: A6lK 31/135,
`3 l/445, A6 1P 25/30
`
`SOMMA, Russell [US/US]; 5 Shady Lane, Sparta, NJ
`07871 (US).
`
`(21) International Application Number:
`
`PCT/EP02/04722
`
`(22) International Filing Date:
`
`29 April 2002 (29.04.2002)
`
`(25) Filing Language:
`
`P
`
`2
`( 6)
`
`L
`
`anguage
`
`.
`.
`l
`"b mam"
`_
`_
`(30) Priority Data:
`60/287,509
`09/942.808
`
`z
`
`English
`
`.
`E 1 h
`Hg 15
`
`30 April 2001 (30.04.2001)
`30 August 2001 (30.08.2001)
`
`US
`US
`
`(74) Agent‘ GROS’ F'°'°‘“9 N°V““‘iS AG’ C°’P°“"‘* I“‘e“e°'
`tual Property, Patent & Trademark Department, CH—4002
`Basel (CH).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`HRHUIDILINISJRKEKGKPKRKZLCLK
`7
`7
`7
`7
`7
`7
`I
`7
`7
`7
`7
`7
`7
`7
`LT, LU, LV, MA, MD, MK, MN, MX, NO, NZ, OM, PH,
`PL, PT, RO, RU, SE, SG, SI, SK, TJ, TM, TN, TR, TT, UA,
`US, UZ’ VN, YU, ZA‘ ZW‘
`
`(84) Designated States (regional): Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`
`CHs CYs DE DK ES: Ha FR~ GBs GR IE: ITs LUs Mca
`NL. PT. SE, TR).
`.
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`
`
`02/087558A1|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`(71) Applicant 0’or all designated States except A]? US): NO-
`VARTIS AG [CH/CH]; Lichtstasse 35, CH—4056 Basel
`(CH).
`
`(71) Applicant (for AT only): NOVARTIS-ERFINDUNGEN
`VERVVALTUNGSGESELLSCHAFT M.B.H. [AT/AT];
`Brunner Strasse 59, A—l230 Vienna (AT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): JOSHI, Yantindra
`[US/US]; 38 Walker Drive, Princeton, NJ 08540 (US).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: PHARMACEUTICAL COMPOSITION WIHCH REDUCES OR ELIMINATES DRUG ABUSE POTENTIAL
`
`(57) Abstract: A pharmaceutical composition which reduces or eliminates the drug abuse potential of central nervous system stim-
`ulant comprising: (a) a drug selected from the group consisting of methylphenidate, amphetamine, methamphetamine, and combi-
`nations thereof; and (b) a gel forming polymer wherein the gel forming polymer is a polymer that forms a gel when contacted with
`O moisture or placed in an aqueous solution. The present invention is based on the discovery that a central nervous system stimulant
`such as methylphenidate in combination with a gel forming polymer reduces or eliminates drug abuse potential by swelling in the
`B
`presence of moisture, and thus, preventing nasal absorption and injectability of the drug.
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`Pharmaceutical Composition which reduces or eliminates drug abuse potential
`
`The present invention relates to a pharmaceutical composition which reduces or eliminates
`
`drug abuse potential. More specifically, the composition comprises a central nervous
`
`system stimulant and a gel forming polymer.
`
`Background of the Invention
`
`Methylphenidate, which is commercially available under the trademark Flitalin ® from
`
`Novartis Pharmaceuticals Corporation, is a central nervous system stimulant. Other
`
`examples of central nervous stimulants are amphetamine and methamphetamine. Central
`
`nervous stimulants activate the brain stem arousal system to effect stimulation of the
`
`patient.
`
`Methylphenidate is the most commonly prescribed psychotropic medication for children in
`
`the United States, primarily for the treatment of children diagnosed with attention deficit
`
`disorder (ADD) and Attention Deficit Hyperactivity Disorder (ADHD), and thus, is widely
`
`available.
`
`in addition, methylphenidate has been found to be particularly useful for treating
`
`Acquired Immunodeficiency Syndrome (AIDS) patients who suffer from cognitive decline
`
`(See Navia et al., Annals of Neurology, 19:51?-524 (1986)).
`
`Methylphenidate is described in U.S. Patent Nos. 2,838,519 and 2,957,880. U.S. Patent
`
`Nos. 5,922,736; 5,908,850; 5,773,478; 6,113,879 describe administering d-threo
`
`methylphenidate to treat nervous system disorders. U.S. Patent Nos. 5,936,091 and
`
`5,965,734 describe processes and intermediates for preparing 2-substituted d-threo
`
`piperidines. U.S. Patent Nos. 6,100,401; 6,121,453; and 6,162,919 describe processes for
`
`preparing substantially the single enantiomer d-threo methylphenidate. U.S. Patent Nos.
`
`5,874,090 and 5,837,284 describe sustained release formulations of methylphenidate.
`
`In addition to their important medical uses, central nervous system stimulants are employed
`
`commonly, by such means as inhalation and intravenously, for illicit purposes, including
`
`emotional, psychological, euphoric, hallucinogenic, and psychedelic experiences. These
`
`purposes and the physical dependence accompanying the administration of these drugs
`
`has led to drug abuse. Drug abuse has become for many habituates a way of life. To a
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`rapidly growing segment of the world population, use of these drugs is often seen as
`
`fashionable.
`
`WO 97/33566 describes an opioid composition which has a low potential for abuse. This is
`
`achieved by incorporating an opioid antagonist in the composition in an amount to reduce
`
`the effect of the opioid. Examples of opioid antagonists disclosed in WO 97/33566 are
`
`naltrexone, naloxone, nalmefene, nalide, nalmexone, nalorphine, nalpuphine, nalorphine,
`
`and dinicotinate.
`
`While central nervous stimulants are a necessary part of modern medicine, it would be
`
`highly desirable to provide a pharmaceutical composition comprising a central nervous
`
`stimulant which reduces or eliminates drug abuse potential without decreasing the
`
`effectiveness of the drug.
`
`Summam of the Invention
`
`The present invention relates to a pharmaceutical composition which reduces or eliminates
`
`the drug abuse potential of central nervous system stimulant comprising: (a) a drug selected
`
`from the group consisting of methylphenidate, amphetamine, methamphetamine, and
`
`combinations thereof; and (b) a gel forming polymer wherein the gel forming polymer is a
`
`polymer that forms a gel when contacted with moisture or placed in an aqueous solution.
`
`The present invention is based on the discovery that a central nen/ous system stimulant
`
`such as methylphenidate in combination with gel forming polymer reduces or eliminates
`
`potential drug abuse by swelling in the presence of moisture which is, for example, present
`
`in the demiis layer of skin and mucous membrane, and thus, prevents nasal absorption and
`
`injectability of the drug.
`
`Description of the Invention
`
`The invention is directed to a pharmaceutical composition which reduces or eliminates the
`
`drug abuse potential of central nervous system stimulant. The composition comprises a
`
`central nervous system stimulant and a gel forming polymer. Component (a) of the
`
`composition of the invention is a central nervous system stimulant such as methylphenidate,
`
`amphetamine, and methamphetamine. Pharrnaceutically acceptable salt tonne of the
`
`central nervous system stimulant are included within the term “central nervous system
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`stimulant”. A combination of central nervous system stimulants may also be used.
`
`As used herein, “methylphenidate" includes the following four optical isomers: d-threo-
`
`methylphenidate, I-threo-methylphenidate, d-erythro-methylphenidate, and l-erythro-
`
`methylphenidate. A preferred isomer is d-threo-methylphenidate. A combination of isomers
`
`may also be used, for example, dl-threo-methylphenidate. Most preferably, the
`
`methylphenidate is methylphenidate hydrochloride.
`
`The effective dosage for the central nervous system stimulant may vary depending on the
`
`concentration of the drug, the mode of administration, the condition being treated, and the
`
`severity of the condition being treated. in addition, the effective dosage depends on a
`
`variety of factors which are specific to the patient being treated, such as species type, age,
`
`weight, and sex.
`
`In a preferred embodiment of the invention, the amount of central nervous system stimulant
`
`in the compositions of the invention is from about 0.1 to about 90 weight percent, more
`
`preferably from about 1 to about 50 weight percent, based on the total weight of the
`
`composition. Most preferably, the amount of central nervous system stimulant in the
`
`compositions is from about 2 to about 10 weight percent, based on the total weight of the
`
`composition.
`
`Component (b) of the composition of the invention is a gel forming polymer. The gel forming
`
`polymer is any polymer that forms a gel when contacted with moisture or placed in an
`
`aqueous solution. The gel forming polymers may be used alone or in combination with other
`
`gel forming polymers. The gel forming polymers include natural and synthetic polymers,
`
`and may be crosslinked or not crosslinked. Examples of gel forming polymers include, but
`
`are not limited to, the following:
`
`(a) Polysaccharide such as agar, carrageenan, modified cellulose, and starch. Preferred
`
`carrageenans are GELCARIN GP911 and GELCARIN 379, which are available from FMC
`
`Corporation. Preferred modified celluloses are hydroxyethylcellulose,
`
`hydroxypropylmethylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl
`
`cellulose phthalate or acetate succinate, cellulose acetate phthalate, methyl cellulose
`
`phthalate, and microcrystalline cellulose. Preferred starches are cold water swelling
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`starches such as starches sold by National Starch under the trademarks NOVATION,
`
`ULTRA-SPERSE, and ULTRA-TEX, and sodium carboxymethyl starch, and starch acetate
`
`phthalate.
`
`(b) Gelatin. Preferred gelatins are GELATIN G 9382 and GELATIN G 2625, which are
`
`available from Sigma Chemicals.
`
`(c) Polygiucosamine or its various chemically modified variants. Preferred
`
`polyglucosamines are SEACURE 343 and SEACURE 443, which are available from
`
`Pronova Biopolymers. These materials form a gel at a pH of 5 to 7.
`
`(d) Hydrophilic colloid such as derivatives of alginic acid. Preferred derivatives of alginic
`
`acid are calcium alginate, sodium alginate, potassium alginate, and propylene glycol
`
`alginate.
`
`(e) Crosslinkable hydrophilic polymer. Preferred crosslinkable hydrophilic polymers are
`
`polyvinyl pyrrolidone, carboxymethylamide, potassium methacrylatedivinylbenzene
`
`copolymer, polyvinylalcohol, polyoxyethyleneglycol, polyethylene glycol,
`
`carboxypolymethylene, polymers and copolymers of acrylic acid and/or methacrylic acid
`
`and/or their esters (for example ACRYSOL and ACULYN, available from Rohm & Haas, and
`
`a homopolymer of acrylic acid crosslinked with allyl sucrose or allylpentaerythritol, and a
`
`copolymer of acrylic acid and an alkyl acrylate and crosslinked with allylpentaerythritol,
`
`wherein the alkyl group has from 10 to 30 carbon atoms, for example CARBOPOL,
`
`available from B. F. Goodrich), polyvinyl pyrrolidone/acrylic acid (for example ACRYLIDONE
`
`Anionic Copolymer 1033 or 1042, available from ISP), polymethyl vinyl ether/maleic
`
`anhydride (for example GANTREZ AN Copolymer S-97, available from GAF),
`
`polyethylene/maleic anhydride, polymethyl methacrylate, polyethyl methacrylate, polybutyl
`
`methacylate, polyisobutyl methacrylate, polyhexyl methacrylate, polyisodecyl methacrylate,
`
`polylauryl methacrylate, polyphenyl methacrylate, polymethyl acrylate, polyisopropyl
`
`acrylate, polyisobutyl acrylate, polyoctadecyl acrylate, copolymer of acrylic and methacrylic
`
`acid ester with a lower ammonium group content (for example EUDRAGIT RS, available
`
`'
`
`from Rohm & Haas), copolymer of acrylic and methacrylic acid ester and trimethyl
`
`ammonium methacrylate (for example EUDHAGIT FtL, available from Rohm & Haas),
`
`polyvinyl acetate; polyvinyl acetate phthalate, maleic acid anhydride-vinyl methyl ether,
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`styrene—maleic acid, 2-ethyl-hexyl-acrylate maleic acid anhydride, crotonic acid-vinyl
`
`acetate, glutaminic acid/glutamic acid ester, polyarginine, polyethylene, polypropylene,
`
`polyethylene oxide (for example POLYOX, available from Union Carbide), polyethylene
`
`terephthalate, polyvinyl isobutyl ether, polyvinyl chloride, polyurethane, and vinyl
`
`pyrrolidone/dimethylamino ethyl methacrylate, (for example GAFQUAT 755, available from
`
`GAF).
`
`(f) An acrylate ester polymerized with a monomer selected from a vinyl-substituted
`
`heterocyclic compound containing at least one of a nitrogen or a sulfur atom,
`
`(meth)acryIamide, a mono- or di-C1-C4 alkylamino C1-C4 alkyl (meth)acrylate, or a mono or
`
`di-C1-C4 alkylamino C1-C4 alkyl acrylamide. Specific examples of such monomers are N,N-
`
`dimethylamino ethyl methacrylate, N,N-diethylamino ethyl acrylate, N,N-diethylamino ethyl
`
`methacrylate, N-t-butylamino ethyl acrylate, N-t-butylamino ethyl methacrylate, N,N-
`
`dimethylamino propyl acrylamide, N,N-dimethylamino propyl methacrylamide, N,N-
`
`diethylamino propyl acrylamide, and N,N-diethylamino propyl methacrylamide,
`
`In a preferred embodiment the gel forming polymer is selected from polyethylene oxide,
`
`sodium alginate, a homopolymer of acrylic acid crosslinked with allyl sucrose or
`
`allylpentaerythritol, and a copolymer of acrylic acid and an alkyl acrylate and crosslinked
`
`with allylpentaerythritol, wherein the alkyl group has from 10 to 30 carbon atoms.
`
`The gel forming polymer preferably has a molecular weight of from about 70,000 to about
`
`2,000,000. More preferably, the molecular weight of the gel forming polymer is from about
`
`100,000 to about 1,000,000.
`
`The amount of gel forming polymer in the compositions of the invention is preferably from
`
`about 2 to 40 weight percent, based on the total weight of the composition. More
`
`preferably, the amount of gel forming polymer is from about 5 to about 30 weight percent,
`
`more preferably from about 10 to about 20 weight percent.
`
`The pH range of the gel forming polymers is preferably between about 5.5 and 8.5. A base
`
`such as sodium or calcium hydroxide can be added to increase the pH to the desired range.
`
`Similarly, buffers such as calcium carbonate, diethyl carbonate, diphenyl carbonate, and
`
`sodium citrate, may be added to control the pH.
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`Conventional methods of preparing the gel forming polymers in the various forms are known
`
`by those skilled in the art. Such methods include solution polymerization, precipitation
`
`polymerization and emulsion polymerization.
`
`Additional ingredients which may be used in the compositions of the invention include
`
`natural and/or artificial ingredients which are commonly used to prepare oral pharmaceutical
`
`dosage forms. Examples of additional ingredients include enteric coating agents, diluents,
`
`binders, humectants, disintegrants, anti caking agents, amino acids, fibers, solubilizers,
`
`emulsifiers, flavorants, sweeteners, enzymes, tillers, buffers, stabilizers, colorants, dyes,
`
`plasticlzing agents, antioxidants, anti-adherents, preservatives, electrolytes, glidants,
`
`lubricants, and carrier materials. A combination of additional ingredients may also be used.
`
`Such ingredients are known to those skilled in the art, and thus, only a limited number will
`
`be specifically referenced. Preferably the additional ingredients are used in the
`
`compositions of the invention in an amount that corresponds to an amount generally
`
`recognized as safe (GRAS) and effective by the United States Food and Drug
`
`Administration, the Environmental Protection Agency, the United States Department of
`
`Agriculture, or other comparable regulatory agency. For those additional ingredients for
`
`which no regulatory approval has been obtained, then an amount generally accepted in the
`
`art as both safe and efficacious is preferred.
`
`Examples of humectants that can be used in the compositions of the invention include but
`
`are not limited to: sucrose, sorbitol, glycerol, propylene glycol, poly-(ethylene glycol), N-
`
`methyl pyrrolidone, N-ethyl pyrrolidone, diacetone alcohol, .gamma.-butyryl lactone, ethyl
`
`lactate, low molecular weight polyethylene glycol, or combinations thereof.
`
`Examples of glidants that can be used in the compositions of the invention include but are
`
`not limited to: silica, magnesium trisilicate, powdered cellulose, starch, and talc. Colloidal
`
`silica and colloidal silicone dioxide are particularly preferred.
`
`Examples of fillers that can be used in the compositions of the invention include but are not
`
`limited to: confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose,
`
`sucrose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, and tribasic
`
`calcium phosphate.
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`Examples of lubricants that can be used in the compositions of the invention include but are
`
`not limited to: stearic acids and its salts such as Mg, Al or Ca stearate, polyethylene glycol
`
`4000 - 8000, talc, sodium benzoate, sodium acetate, leucine, sodium oleate, sodium lauryl
`
`sulfate, and magnesium lauryl sulfate.
`
`Examples of solubilizers and/or emulsifiers that can be used in the compositions of the
`
`invention include but are not limited to: sorbitan fatty acid esters such as sorbitan trioleate,
`
`phosphatides such as lecithin, acacia, tragacanth, polyoxyethylated sorbitan monooleate
`
`and other ethoxylated fatty acid esters of sorbitan, polyoxyethylated fats, polyoxyethylated
`
`oleotriglycerides, linolizated oleotriglycerides, polyethylene oxide condensation products of
`
`fatty alcohols, alkylphenols or fatty acids or also 1-methyl-3-(2-hydroxyethy|)imidazolidone-
`
`(2). In this context, polyoxyethylated means that the substances in question contain
`
`polyoxyethylene chains, the degree of polymerization of which generally lies between 2 and
`
`40 and in particular between 10 and 20.
`
`Examples of antioxidants that can be used in the compositions of the invention include but
`
`are not limited to: sodium sulphite, sodium hydrogen sulphite, sodium metabisulphite,
`
`ascorbic acid, ascorbylpalmitate, -myristate, -stearate, gallic acid, gallic acid alkyl ester,
`
`butylhydroxyamisol, nordihydroguaiaretic acid, tocopherols as well as synergists
`
`(substances which bind heavy metals through complex formation, for example lecithin,
`
`ascorbic acid, phosphoric acid ethylene diamine tetracetic acid, citrates, tartrates). Addition
`
`of synergists substantially increases the antioxygenic effect of the antioxidants.
`
`Examples of preservatives that can be used in the compositions of the invention include but
`
`are not limited to: sorbic acid. p-hydroxybenzoic acid esters, benzoic acid, sodium
`
`benzoate, trichloroisobutyl alcohol, phenol, cresol, benzethonium chloride, chlorhexidine
`
`and formalin derivatives.
`
`The total amount of additional ingredients in the compositions of the invention are
`
`preferably from about 30 to about 75 weight percent, based on the total weight of the
`
`composition. More preferably, the total amount of additional ingredients is from about 50 to
`
`about 70 weight percent, most preferably from about 53 to about 67 weight percent, based
`
`on the total weight of the composition.
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`The following examples further describe the materials and methods used in carrying out the
`
`invention. The examples are not intended to limit the invention in any manner.
`
`EXAMPLE 1
`
`Preparation of Chewable Tablets Containing 2.5% dl-Methylphenidate and 10% Gel
`
`Forming Polymer.
`
`Composition
`
`dl-methylphenidate
`POLYOX®
`lactose
`talc
`mannitol
`stearic acid
`5% gelatin solution in demineralized water
`saccharin
`
`5.0 gm
`20.0 gm
`75.0 gm
`3.0 gm
`90.0 gm
`2.0 gm
`4.0 gm
`1.0 gm
`
`All the solid ingredients are first forced through a sieve of 0.25 mm mesh width. The
`
`mannitol, dl-methylphenidate, and lactose are mixed, granulated with the addition of gelatin
`
`solution, forced through a sieve of 2 mm mesh width, dried at 50° C and again forced
`
`through a sieve of 1.7 mm mesh width. POLYOX®, talc and saccharin are added to the
`
`dried mixture of drug substance. The stearic acid is added and the final blend is made.
`
`The resulting blend is compr essed to form 7 mm round standard concave tablets.
`
`EXAMPLE 2
`
`Preparation of Tablets Containing 4% d—Methylphenidate and 1.2% Gel Forming Polymer.
`
`Composition
`
`d-methylphenidate
`PEG 8000
`sucrose
`starch
`lactose
`
`10.0 gm
`3.0 gm
`3.0 gm
`20.0 gm
`170 gm
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`talc
`magnesium stearate
`sodium alginate
`demineralized water
`
`. 9 -
`
`2.0 gm
`2.0 gm
`40.0 grn
`
`All the solid ingredients are first forced through a sieve of 0.6 mm mesh width. The dl-
`
`methylphenidate, a ponion of the lactose, starch, and sucrose are mixed then granulated
`
`with the PEG 8000 solution. The granulation is dried overnight at 50°C, and then forced
`
`through a sieve of 1.2 mm mesh width. The remaining lactose, talc, magnesium stearate
`
`and sodium alginate are blended with the dried material. The resulting blend is compressed
`
`to form 8 mm round standard concave tablets.
`
`EXAMPLE 3
`
`Preparation of Capsules Containing 8% dl-Methylphenidate and 20% Gel Fonning Polymer.
`
`Composition (for 1000 tablets)
`
`dl-methylphenidate
`microcrystalline cellulose
`modified starch
`magnesium stearate
`CARBOPOL®
`
`20.0 gm
`88.0 gm
`88.0 gm
`4.0 gm
`50.0 gm
`
`The microcrystalline cellulose, modified starch, and dl-methylphenidate are granulated with
`
`water and then passed through a 0.9 mm mesh screen and dried at 50° C. The dried
`
`material is passed through a 0.9 mm mesh screen and blended with the magnesium
`
`stearate and CARBOPOL®. The resulting blend is encapsulated using size #1 hard shell
`
`gelatin capsule.
`
`EXAMPLE 4
`
`Study of Swelling Activity
`
`A tablet prepared in Example 1 is placed on a glass plate and crushed to form a powder.
`
`The powder is added to 1 ml of water and stirred for one minute. Gel formation occurs.
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`EXAMPLE 5
`
`Study of Swelling Activity
`
`A tablet prepared in Example 2 is placed on a glass plate and crushed to form a powder.
`
`The powder is added to 1 ml of water and stirred for one minute. Gel formation occurs.
`
`EXAMPLE 6
`
`Study of Swelling Activity
`
`A capsule prepared in Example 3 is placed on a glass plate and crushed. The material is
`
`combined with 1 ml of water. Gel formation occurs.
`
`The present invention is based on the discovery that a central nervous system stimulant
`
`such as methylphenidate in combination with a gel forming polymer reduces or eliminates
`
`potential drug abuse by swelling in the presence of moisture which is, for example, present
`
`in the dermis layer of skin and mucous membrane, and thus, preventing nasal absorption
`
`and injectability of the drug.
`
`'
`
`While the invention has been described with particular reference to certain embodiments
`
`thereof, it will be understood that changes and modifications may be made by those of
`
`ordinary skill within the scope and spirit of the following claims:
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`Purdue 2023
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`Amneal v. Purdue, IPR2016-01027
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`Purdue 2023
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`W0 02/087558
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`PCT/EP02/04722
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`-11-
`
`Claims:
`
`1.
`
`A pharmaceutical composition which reduces or eliminates the drug abuse potential of
`
`central nervous system stimulant comprising
`
`(a) a drug selected from the group consisting of methylphenidate, amphetamine,
`
`methamphetamine, and combinations thereof; and
`
`(b) a gel forming polymer wherein the gel forming polymer is a polymer that forms a gel
`when contacted with moisture or placed in an aqueous solution.
`
`2.
`
`The composition according to claim 1 wherein the gel forming polymer is selected
`
`from the group consisting of a polysaccharide, gelatin, polyglucosamine, hydrophilic colloid,
`
`crosslinkable hydrophilic polymer, an acrylate ester polymerized with a monomer selected
`
`from the group consisting of a vinyl-substituted heterocyclic compound containing at least
`
`one of a nitrogen or a sulfur atom, (meth)acry|amide, a mono- or di-C1-C4 alkylamino C1-C4
`
`alkyl (meth)acrylate, and a mono or di-C1-C4 alkylamino C1-C4 alkyl acrylamide, and
`
`combinations thereof.
`
`3.
`
`The composition according to claim 2 wherein the polysaccharide is selected from the
`
`group consisting of an agar, carrageenan, modified cellulose, and starch.
`
`4.
`
`The composition according to claim 3 wherein the polysaccharide is selected from the
`
`group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium
`
`carboxymethyl cellulose, hydroxypropyl methyl cellulose phthalate or acetate succinate,
`
`cellulose acetate phthalate, methyl cellulose phthalate, microcrystalline cellulose, a cold
`
`water swelling starch, sodium carboxymethyl starch, and starch acetate phthalate.
`
`5.
`
`The composition according to claim 2 wherein the hydrophilic colloid is a derivative of
`
`alginic acid.
`
`6.
`
`The composition according to claim 5 wherein the derivative of alginic acid is selected
`
`from the group consisting of calcium alginate, sodium alginate, potassium alginate, and
`
`propylene glycol alginate.
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`Purdue 2023
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`Amneal v. Purdue, IPR2016-01027
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`Purdue 2023
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`W0 02/087558
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`PCT/EP02/04722
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`-12-
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`7.
`
`The composition according to claim 2 wherein the crosslinkable hydrophilic polymer is
`
`selected from the group consisting of polyvinyl pyrrolidone, carboxymethylamide, potassium
`
`methacrylatedivinylbenzene, polyvinylalcohol, polyoxyethyleneglycol, polyethylene glycol,
`
`carboxypolymethylene, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone/acrylic
`
`acid, polymethyl vinyl ether/maleic anhydride, polyethylene/maleic anhydride, polymethyl
`
`methacrylate, polyethyl methacrylate, polybutyl methacylate, polyisobutyl methacrylate,
`
`polyhexyl methacrylate, polyisodecyl methacrylate, polylauryl methacrylate, polyphenyl
`
`methacrylate, polymethyl acrylate, polyisopropyl acrylate, polyisobutyl acrylate,
`
`polyoctadecyl acrylate, copolymer of acrylic and methacrylic acid ester with a lower
`
`ammonium group content, copolymer of acrylic and methacrylic acid ester and trimethyl
`
`ammonium methacrylate, polyvinyl acetate, polyvinyl acetate phthalate, maleic acid
`
`anhydride-vinyl methyl ether, styrene-maleic acid, 2-ethyl-hexyl-acrylate maleic acid
`
`anhydride, crotonic acid-vinyl acetate, glutaminic acid/glutamic acid ester, polyarginine,
`
`polyethylene, polypropylene, polyethylene oxide, polyethylene terephthalate, polyvinyl
`
`isobutyl ether, polyvinyl chloride, polyurethane, and vinyl pyrrolidone/dimethylamino ethyl
`
`methacrylate.
`
`8.
`
`The composition according to claim 2 wherein the acrylate ester is polymerized with a
`
`monomer selected from the group consisting of N,N-dimethylamino ethyl methacrylate, N,N-
`diethylamino ethyl acrylate, N,N-diethylamino ethyl methacrylate, N-t-butylamino ethyl
`
`acrylate, N-t-butylamino ethyl methacrylate, N,N-dimethylamino propyl acrylamide, N,N-
`
`dimethylamino propyl methacrylamlde. N.N- diethylamino propyl acrylamide, and N,N-
`
`diethylamino propyl methacrylamlde.
`
`9.
`
`The composition according to claim 2 wherein the gel forming polymer is selected
`
`from the group consisting of polyethylene oxide, sodium alginate, a homopolymer of acrylic
`
`acid crosslinked with allyl sucrose or allylpentaerythritol, and a copolymer of acrylic acid and
`
`an alkyl acrylate and crosslinked with allylpentaerythritol, wherein the alkyl group has from
`
`10 to 30 carbon atoms.
`
`10. The composition according to claim 1 wherein the gel fonning polymer has a
`
`molecular weight of from about 70,000 to about 2,000,000.
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`Purdue 2023
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`Amneal v. Purdue, IPR2016-01027
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`Purdue 2023
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`W0 02/087558
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`-13-
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`11. The composition according to claim 10 wherein the gel forming polymer has a
`
`molecular weight of from about 100,000 to about 1,000,000.
`
`12. The composition according to claim 1 wherein the gel forming polymer is not
`
`crosslinked.
`
`13. The composition according to claim 1 wherein the gel forming polymer is crosslinked.
`
`14. The composition according to claim 1 which additionally comprises a pH modifier.
`
`15. The composition according to claim 14 wherein the pH modifier is selected from the
`
`group consisting of sodium hydroxide, calcium hydroxide, calcium carbonate, diethyl
`
`carbonate, diphenyl carbonate, and combinations thereof.
`
`16. The composition according to claim 1 wherein the gel forming polymer is present in an
`
`amount of from about 2 to about 40 weight percent, based on the total weight of the
`
`composition.
`
`17.
`
`The composition according to claim 16 wherein the gel forming polymer is present in
`
`an amount of from about 10 to about 20 weight percent, based on the total weight of the
`
`composition.
`
`18. The composition according to claim 1 wherein the central nervous system stimulant is
`
`present in an amount of from about 0.1 to about 90 weight percent, based on the total
`
`weight of the composition.
`
`19. The composition according to claim 18 wherein the central nervous system stimulant
`
`is present in an amount of from about 1 to about 50 weight percent, based on the total
`
`weight of the composition.
`
`20. The composition according to claim 19 wherein the central nervous system stimulant
`
`is present in an amount of from about 2 to about 10 weight percent, based on the total
`
`weight of the composition.
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`Purdue 2023
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`Amneal v. Purdue, IPR2016-01027
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`Purdue 2023
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`W0 02/087558
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`-14-
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`21.
`
`The composition according to claim 1 which is in a form selected from the group
`
`consisting of powder, granules, solution, suspension, emulsion, and combinations thereof.
`
`22.
`
`23.
`
`24.
`
`25.
`
`26.
`
`The composition according to claim 1 which is in a form of a solid.
`
`The composition according to claim 22 wherein the composition is administered in a
`
`form selected from the group consisting of a capsule, cachet, and tablet.
`
`A method for the reduction or elimination of the drug abuse potential of central
`
`nervous system stimulants, which method comprises administering to a subject in
`
`need thereof a composition as claimed in any of the prevous claims.
`
`The use of a composition according to any 01 claims 1
`
`to 23 in the reduction or
`
`elimination of the drug abuse potential of central nervous system stimulants.
`
`The use of a composition according to any of claims 1 to 23 claims in the manufacture
`
`of a medicament for the reduction or elimination of the drug abuse potential of central
`
`nervous system stimulants.
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`Purdue 2023
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`Amneal v. Purdue, IPR2016-01027
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`Purdue 2023
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`

`
`INTERNAHONALSEARCHREPORT
`
`CLASSIFICATION OF S BJECT MATTEFI
`IPC 7
`A61K31 135
`A61K31/445
`
`A61P25/30
`
`mmgwwmmnm
`
`PCT/EP 02/04722
`
`According to international Patent Classification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 7
`A61K
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practical. search terms used)
`
`EPO-Internal, WPI Data, PAJ, BIOSIS, MEDLINE, CHEM ABS Data
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document, with indication, where appropriate. oi the relevant passages
`
`Relevant to claim No.
`
`NO 00 35450 A (KRISHNAMURTHY THINNAYAN N
`;DARKE ANDREN (CA); EURO CELTIQUE SA (LU)
`22 June 2000 (2000-06-22)
`page 16, last paragraph —page 19,
`paragraph 1; claim 1;
`tables 32,34,36,38
`
`N0 00 23055 A (SHIRE LAB INC ;BURNSIDE
`BETH A (US); CHANG RONG KUN (US); COUCH
`R1) 27 April 2000 (2000-04-27)
`page 11, paragraphs 3,4; claim 1
`
`N0 99 62496 A (ALZA CORP)
`9 December 1999 (1999-12-09)
`claim 1; example 1
`
`NO 01 05407 A (SHIRE LAB INC)
`25 January 2001 (2001-01-25)
`claim 1; examples
`
`El Further documents are listed in the continuation of box C.
`° Special categories of cited documents :
`
`'A' document defining the general state of the art which is not
`considered to be of particular relevance
`‘E’ earlier document but published on or afterthe inter