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Claims for Patent: 8,298,580

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Claims for Patent: 8,298,580

Title:Sustained-release formulations of topiramate
Abstract: Pharmaceutical compositions of topiramate for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined release profile. Method of treating or preventing pathological disorders in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided.
Inventor(s): Liang; Likan (Boyds, MD), Wang; Hua (Clarksville, MD), Bhatt; Padmanabh P. (Rockville, MD), Vieira; Michael L. (Gaithersburg, MD)
Assignee: Supernus Pharmaceuticals, Inc. (Rockville, MD)
Application Number:12/926,931
Patent Claims: 1. A sustained release formulation of topiramate comprising topiramate as an active ingredient, which is released from the formulation along a pre-determined release profile, the formulation comprising: (a) at least two different extended release topiramate-containing components, wherein each component comprises a release controlling coating specific for its component and comprising a coating material selected from the group consisting of cellulosic polymers and acrylic polymers, and, optionally, (b) an immediate release (IR) topiramate-containing component comprising: (i) a complexing agent selected from the group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, cyclodextrin, and cyclodextrin derivative, and/or (ii) an enhancing agent selected from the group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene glycol-3350, polyvinylpyrrolidone-K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, and combinations thereof; wherein all of the components release topiramate in a continuous manner and at least one of the two XR components releases the topiramate contained therein such that greater than or equal to about 80% of the topiramate is released in vitro in less than or equal to about 4 hours.

2. The formulation of claim 1, wherein the IR component exhibits a release profile such that 80% of the active ingredient is dissolved in not more than 1 hour.

3. The formulation according to claim 1, wherein at least one of the two XR components further comprises a binder selected from the group consisting of starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone.

4. The formulation according to claim 1, wherein at least one of the two XR components further comprises a pore former selected from the group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(.alpha.-.omega.)alkylenediols; alkali metal salts and alkaline earth metal salts, and combinations thereof.

5. The formulation of claim 1, wherein at least a part of the active ingredient is in a form of micronized particles.

6. The formulation of claim 1, wherein the formulation is in a dosage form of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles.

7. The formulation of claim 1, wherein the total amount of topiramate in the formulation is from 0.5 to 3000 mg.

8. The formulation of claim 1, wherein at least one of the two XR components comprises an inert carrier selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.

9. The formulation of claim 1, wherein the release controlling coating comprises ethylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol, polyacrylates, polymethacrylates or copolymers thereof.

10. The formulation of claim 1, wherein the formulation provides for a maximum steady state plasma concentration (Cmax) of topiramate which is in the range from 50% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an immediate release formulation BID.

11. The formulation of claim 1, wherein the formulation provides for a relative steady state AUC in the range of 80% to 125% of the AUC of the same amount of topiramate administered as an immediate release formulation BID.

12. The formulation of claim 1, further comprising an additional pharmaceutically active ingredient in combination with topiramate.

13. A method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a sustained release formulation of topiramate according to claim 1.

14. The method of claim 13, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder (ADHD), impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, amyotropic lateral sclerosis (ALS).

15. The method of claim 14, wherein the condition is epilepsy.

16. The method of claim 14, wherein the condition is migraine.

17. A sustained release formulation of topiramate comprising topiramate as an active ingredient, which is released from the formulation along a pre-determined release profile, the formulation comprising: (a) at least two different extended release topiramate-containing components, wherein each component comprises a release controlling coating specific for its component and comprising a coating material selected from the group consisting of cellulosic polymers and acrylic polymers, and, optionally, (b) an immediate release (IR) topiramate-containing component comprising: (i) a complexing agent selected from the group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, alpha-cyclodextrin, cyclodextrin, and cyclodextrin derivative, and/or (ii) an enhancing agent selected from the group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, polyethylene glycol-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, polyethylene-polypropylene glycol, polyethylene glycol-3350, polyvinylpyrrolidone-K25, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, hydroxypropylmethylcellulose (HPMC), substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, menthol, and combinations thereof; wherein all of the components release topiramate in a continuous manner and at least one of the two XR components releases the topiramate contained therein such that greater than or equal to about 80% of the topiramate is released in vitro in less than or equal to about 4 hours, and wherein the components in the formulation are present according to the following proportions: TABLE-US-00007 F. No. 1 2 3 4 5 % XR1 20 50 10 10 15 % XR2 80 0 84 80 70 % XR3 0 50 0 0 15 % IR 0 0 6 10 0

wherein XR1, XR2, XR3, and IR release topirmate in a continuous manner such that: 1. for in-vitro dissolution, for XR1, 1.5 h<=T.sub.80%<=4 h; for XR2, 5 h<=T.sub.80%<=8 h; for XR3, 8 h<T.sub.80%<=10 h; for IR, T.sub.80%<=1 h; and/or 2. for a single initial dose in vivo, for XR1, 4 h<=T.sub.max<=8.5 h; for XR2, T.sub.max>=16 h; for XR3, T.sub.max>=16 h.

18. The formulation of claim 17, wherein the IR component exhibits: a. for in-vitro dissolution, T.sub.80%<=30 min; and/or b. for a single initial dose in vivo, T.sub.max<=2 h.

19. The formulation according to claim 17, wherein at least one of the two XR components further comprises an binder selected from the group consisting of starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone.

20. The formulation according to claim 17, wherein at least one of the two XR components further comprises a pore former selected from the group consisting of glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, hydroxyalkylcelluloses, carboxyalkylcelluloses, hydroxypropylmethylcellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, carbomer, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or block polymers thereof, polyglycols, poly(.alpha.-.beta.)alkylenediols; alkali metal salts and alkaline earth metal salts, and combinations thereof.

21. The formulation of claim 17, wherein at least a part of the active ingredient is in a form of micronized particles.

22. The formulation of claim 17, wherein the formulation is in a dosage form of a tablet, a pill, a capsule, a caplet, a troche, a pouch, or sprinkles.

23. The formulation of claim 17, wherein the total amount of topiramate in the formulation is from 0.5 to 3000 mg.

24. The formulation of claim 17, wherein at least one of the two XR components comprises an inert carrier selected from the group consisting of cellulose spheres, silicon dioxide, starch and sugar spheres.

25. The formulation of claim 17, wherein the formulation provides for a maximum steady state plasma concentration (Cmax) of topiramate which is in the range from 50% to 125% of the maximum plasma concentration produced by the same amount of topiramate administered as an immediate release formulation BID.

26. The formulation of claim 17, wherein the formulation provides for a relative steady state AUC in the range of 80% to 125% of the AUC of the same amount of topiramate administered as an immediate release formulation BID.

27. The formulation of claim 17, further comprising an additional pharmaceutically active ingredient in combination with topiramate.

28. A method of treatment of a neurological and/or psychiatric condition in a mammalian subject, comprising orally administering to the subject a therapeutically effective amount of a sustained release formulation of topiramate according to claim 17.

29. The method of claim 28, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette's syndrome, infantile spasms, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, border line personality disorder, addiction, autism, chronic neurodegenerative disorders, acute neurodegeneration, ALS.

30. The method of claim 29, wherein the condition is epilepsy.

31. The method of claim 29, wherein the condition is migraine.
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