Topiramate compositions and methods of enhancing its bioavailability

• US 20080085306A1
• Filed: 08/31/2007
• Published: 04/10/2008
• Est. Priority Date: 08/31/2006
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Spherics, Inc.
• Inventors: Jacob, Jules, Nangia, Avinash, Verma, Daya
• Granted Patent: US 9,744,137 B2
• Time in Patent Office: Days
• US Class Current: 424/458
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28
• CPC Class Codes: A61K 9/2846 Poly(meth)acrylates
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/4891 Coated capsules; Multilayered drug free capsule shells with drug coating for immediate release A61K9/4808; osmotic devices A61K9/0004
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents

Abstract

The present invention is directed to pharmaceutical compositions that allow for once-daily or alternate day dosage forms of topiramate. The proposed delayed/extended release single dosage form is equivalent to the immediate-release multiple dose daily regimen, and upon administration, provides steady state blood levels of topiramate. Formulations with increased bioavailability and improved pharmacokinetics are disclosed. A once-a-day administration of topiramate is advantageous over the multiple dose regimen both in terms of patient compliance and reduced adverse events, thus providing better treatment of the conditions for which the topiramate is indicated.

Claims

1. A delayed-release oral topiramate pharmaceutical composition, comprising a core comprising topiramate or a pharmaceutically acceptable salt thereof and an enteric coating disposed around at least a portion of the core.

2. The topiramate pharmaceutical composition of claim 1, further characterized by one or more of:

said core is a monolithic core and said enteric coating completely or partially envelops the monolithic core and said core optionally further comprises a bioadhesive polymer coating disposed around at least a portion of the monolithic core, either interior or exterior to the enteric coating;

said composition comprises multiple layers and

said enteric coating optionally completely or partially envelops the multiple layers,

said composition optionally further comprises a bioadhesive coating disposed around at least a portion of the multiple layers, either interior or exterior to the enteric coating,

optionally at least one layer is formulated as an immediate release (IR) composition,

optionally at least one layer is formulated as a controlled or extended release (CR/XR) composition,

optionally at least one layer comprises a bioadhesive polymer,

optionally at least 50% of the topiramate or salt thereof in the composition is present in a central layer and about 50% of the topiramate or salt thereof is present in one or more peripheral layers, and/or

optionally about 70% of the topiramate or salt thereof in the composition is present in a central layer and about 30% of the topiramate or salt thereof is present in one or more peripheral layers wherein at least one of said peripheral layers comprises said bioadhesive polymer;

said composition comprises two or more cores comprising topiramate and

optionally at least one core is formulated for immediate release (IR),

optionally at least one core is formulated for controlled or extended release (CR/XR),

optionally at least one core comprises a release-controlling polymer,

optionally a first core is present as a plurality of particles and a second core is present as a coating disposed on the first core such as wherein the first core is formulated for controlled or extended release (CR/XR) and the second core is formulated for immediate release (IR),

optionally at least one core that comprises a release-controlling polymer further comprises an enteric coating, and/or

optionally at least one core that comprises a bioadhesive polymer is also coated with the enteric coating;

said core is disposed in a capsule optionally wherein the capsule is sealed with a sealing composition;

said core is disposed in a matrix;

said core is disposed in a gelatin capsule coated with said enteric coating and

optionally wherein the capsule is sealed with a sealing composition

optionally comprising a first immediate release core and a second core coated with a release rate-controlling polymer, and/or

optionally comprising a first immediate release core, a second core coated with an enteric coating polymer, and a third core coated with a release rate-controlling polymer;

the composition begins to release topiramate or the salt thereof in the intestine;

the enteric coating delays the release of topiramate by at least about 0.1-8 hours after administration based on the fasted state of the subject;

the enteric coating delays the release of topiramate by at least about 0.1-16 hours after administration based on the fed state of the subject;

the enteric coating is selected from cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins (such as zein, shellac and copal collophorium), carboxymethyl ethylcellulose, EUDRAGIT®

L12.5, EUDRAGIT®

L100, EUDRAGIT®

S12.5, EUDRAGIT®

S 100, EUDRAGIT®

L30D55, EUDRAGIT®

FS30D, EUDRAGIT®

L100-55, EUDRAGIT®

S100 (Rohm Pharma), KOLLICOAT®

MAE30D and 30DP (BASF), ESTACRYL®

30D (Eastman Chemical), AQUATERIC® and

AQUACOAT®

CPD30 (FMC)), Acryl-EZE™

, or any combination thereof;

the enteric coating becomes soluble at a pH above about pH 4.5;

the pharmaceutical composition comprises a salt of topiramate;

the release-controlling polymer, when present, is optionally selected from EUDRAGIT®

RL100, EUDRAGIT®

RS 100, ethylcellulose aqueous dispersions (AQUACOAT®

, SURELEASE®

), hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, KOLLICOAT®

SR30D, or any combination thereof, such as wherein the release-controlling polymer comprises ethylcellulose, EUDRAGIT®

RL100, EUDRAGIT®

RS100, or a combination thereof;

said composition is formulated to provide an effective dose over at least about 48, about 36, about 30, about 24, about 18, or about 12 hours after administration to the patient;

the effective plasma levels are between 1-10 μ

g/mL for epilepsy treatment;

the effective plasma levels are between 2-8 μ

g/mL for migraine prophylaxis;

said composition is formulated as a once-a-day composition and optionally contains about mg 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, or 400 mg of topiramate;

said composition is formulated as an alternate day composition;

said composition comprises topiramate having a median particle size in the range of 1-250 microns and/or micronized topiramate;

said composition comprises micronized topiramate having a median particle size range of 2-microns;

said composition comprises topiramate pellets with a diameter ranging from 0.1 to 2 mm;

said composition comprises topiramate pellets with a diameter ranging from 0.3 to 1.5 mm;

said composition further comprises at least one basifying agent;

said composition further comprises a least one surfactant or co-surfactant;

the topiramate is crystalline;

the topiramate is amorphous;

the topiramate is a mixture of a crystalline form and an amorphous form, optionally

wherein the ratio between said crystalline form and said amorphous form is from 1;

20 to 1;

0.5 or 20;

1 to 0.5;

1, or

wherein the ratio between said crystalline form and an said amorphous form is from 1;

5 to 1;

1 or 5;

1 to 1;

1;

the Cmax of said composition in the plasma of a fed beagle dog is less than the Cmax of an immediate-release formulation of the same dosage of topiramate when measured for 36 hours after administration of a single dose of said composition to the fed beagle;

the Cmax of said composition in the plasma of a human occurs 1-30 hours after administration;

the Tmax of said composition in the plasma of a fed beagle dog is later than the Tmax of an immediate-release formulation of an identical dosage of topiramate when measured for 36 hours after administration of a single dose of said composition to the fed beagle;

the Tmax of said composition in the plasma of a fed human is later than the Tmax of an immediate-release formulation of an identical dosage of topiramate when measured for 5 days after administration of a single dose of said composition to the fed human;

the AUC of said composition in the plasma of a fed beagle dog is at least about 5, about 10, about 20, or about 25% greater than the AUC of an immediate-release formulation of an identical dosage of topiramate when measured for 36 hours after administration of a single dose of said composition to the fed beagle;

the Tmax of said composition in the plasma of a fed human is at least 1 hour after administration;

the Tmax of said composition in the plasma of a human is timed to occur when said human is sleeping,

the concentration of said composition in the plasma of a human is timed to decrease for at least 2, 4, 6, or 8 hours while said human is sleeping;

the Tmax of said composition in the plasma of a fed human is 20-25 hours after administration;

the concentration of said composition in the plasma of a human is timed to decrease by at least 10, 25, 50, or 75 while said human is sleeping;

said composition is formulated to provide an effective dose over at least 4-48 hours after administration to the patient;

the AUC of said composition in the plasma of a fed beagle dog is at least 25% greater than the AUC of an immediate-release formulation of an identical dosage of topiramate when measured for 36 hours after administration of a single dose of said composition to the fed beagle; and

/or

said composition further comprises a pharmaceutically active agent, optionally wherein

the active agent is selected from anti-epileptic drug, calcium channel blocker, beta-blocker, anti-depressant, and anti-inflammatory,

the active agent is selected from budipine, diazepam, lamotrigine, phenytoin, phenobarbital, carbamazepine, oxcarbazepine, valproate, ethosuximide, clonazepam, lamotrigine, vigabatrin, tiagabine, gabapentin, beta-blockers, almotriptan malate, declorazepam, metformin, leptin, ephedrine, fluoextine, bupropion, zonisamide, phentermine, amphetamines, amfepramone, phenylpropanolamine, mazindol, fenfluramines, sibutramine, orlistat, paroxetine, clozapine, risperidone, lithium, and bupropion,

the active agent is selected from phenyloin, phenobarbital, carbamazepine, oxcarbazepine, valproate, ethosuximide, clonazepam, diazepam, lamotrigine, vigabatrin, tiagabine, gabapentin, and felbamate, or

the active agent is selected from phenyloin, phenobarbital, and carbamazepine.

92. A method of treating epilepsy in an individual, comprising administering to the individual the topiramate pharmaceutical composition of claim 1, optionally further comprising conjointly administering a pharmaceutically active agent.

95. A method of migraine prophylaxis, comprising administering to an individual the topiramate pharmaceutical composition of claim 1, optionally further comprising conjointly administering a pharmaceutically active agent.

98. A method of treating obesity, obsessive compulsive disorder, addiction, or bipolar disorder in an individual, comprising administering to the individual the topiramate pharmaceutical composition of claim 1, optionally further comprising conjointly administering a pharmaceutically active agent.

101. A method of reducing topiramate-induced cognitive impairment in an individual receiving topiramate therapy, comprising administering to the individual the topiramate pharmaceutical composition of claim 1.

3-62. -62. (canceled)

63. A method of preparing a topiramate pharmaceutical composition, comprising coating a composition comprising topiramate with an enteric coating, or a method of preparing a topiramate capsule dosage form comprising loading a capsule body with a topiramate core, joining the capsule body with a cap to form a capsule, sealing the capsule body and the cap with a sufficient amount of sealing composition.

65. The method of claim 63, further characterized by one or more of:

further comprising coating the capsule dosage form with an enteric coating; and

/or

the enteric coating substantially inhibits the release of topiramate from the composition in the upper gastrointestinal (GI) tract, optionally

wherein the release is delayed from 1-10 hrs,

wherein the release is delayed from 2-8 hrs, or

wherein the release is delayed from 4-6 hrs.

64. (canceled)

66-69. -69. (canceled)

70. An oral topiramate pharmaceutical composition, comprising cores comprising at least two layers.

71. The topiramate pharmaceutical composition of claim 70, further characterized by one or more of:

one layer comprises a release-controlling polymer;

one layer comprises an immediate release composition;

one layer comprises a enteric polymer;

an immediate release layer is disposed about a controlled or extended release composition;

said composition comprises at least three layers;

the cores are disposed in a capsule;

the capsule is not banded; and

said capsule is coated with an enteric coating.

72-80. -80. (canceled)

81. A topiramate pharmaceutical composition, wherein the topiramate is micronized to have a median particle size range of 0.5-50 microns or

a topiramate pharmaceutical composition, comprising three regions:

a) first and second regions, each comprising a controlled or extended release (CR/XR) topiramate component and an immediate release (IR) topiramate component; and

b) a third region substantially free of topiramate and comprising a pharmaceutical excipient;

wherein the third region separates the first region from the second region.

82-87. -87. (canceled)

88. A method of administering topiramate, comprising administering a pharmaceutical composition comprising topiramate to a human such that the Cmax of topiramate occurs while the human is sleeping or a method of administering topiramate, comprising administering a pharmaceutical composition comprising topiramate to a human such that the plasma concentration of topiramate decreases while the patient is sleeping.

89. (canceled)

90. The method of claim 89, further characterized by one or more of:

the plasma concentration of topiramate decreases for at least 1, 2, 4, 6, or 8 hours while the patient is sleeping;

or

the plasma concentration of topiramate decreases by at least 10, 25, 50, or 75 percent while the patient is sleeping.

91. (canceled)

93-94. -94. (canceled)

96-97. -97. (canceled)

99-100. -100. (canceled)

102. A once-daily delayed release topiramate formulation.

103. The formulation of claim 102, further characterized by one or more of:

said formulation comprises topiramate, a surfactant, a basifying agent, and an enteric polymer, and optionally

further comprises at least one release-rate controlling polymer, optionally at least two release-rate controlling polymers,

further comprises a glidant,

comprises topiramate pellets encapsulated in a gelatin capsule,

administration of the topiramate pharmaceutical composition produces less cognitive impairment than administration of an IR topiramate composition,

administration of the topiramate pharmaceutical composition produces less cognitive impairment as measured by the Computerized Neurophysicological Test Battery (CNTB) than administration of an IR topiramate composition,

administration of the topiramate pharmaceutical composition produces less cognitive impairment as measured by a Controlled Oral Word Association Test (COWAT) than administration of an IR topiramate composition,

administration of the topiramate pharmaceutical composition produces less cognitive impairment as measured by a Symbol Digital Modalities Test (SDMT) than administration of an IR topiramate composition.

104-111. -111. (canceled)