Topiramate compositions and methods of enhancing its bioavailability

• US 9,744,137 B2
• Filed: 08/31/2007
• Issued: 08/29/2017
• Est. Priority Date: 08/31/2006
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Nangia, Avinash, Verma, Daya D., Jacob, Jules
• Primary Examiner(s): YOUNG, MICAH PAUL
• Application Number:
  US11/897,940
• Publication Number:
  US 20080085306A1
• Time in Patent Office: 3,651 Days
• Field of Search: 424465, 424489, 424464
• 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 pharmaceutical composition, comprising:

(a) only one active agent, the active agent being selected from the group consisting of topiramate and pharmaceutically acceptable salts thereof,

(b) particles having a core formulated as a matrix comprising the active agent coated with an enteric polymer coating

or particles having a core coated with a layer comprising the active agent, and further coated with an enteric polymer coating,

wherein the enteric polymer coating becomes soluble at a pH above 4.5 and delays the release of topiramate about 0.5 to about 4 hours.

2. The composition of claim 1, further comprising a release-controlling polymer selected from the group consisting of ammonio methacrylate copolymer, types A and B;

ethylcellulose aqueous dispersions, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and any combination thereof.

3. The composition of claim 1, wherein the composition comprises two or more cores.

4. The composition of claim 3, wherein at least one core is formulated for immediate release (IR).

5. The composition of claim 3, wherein at least one core comprises a release-controlling polymer.

6. The composition of claim 3, comprising a first immediate release core and a second core coated with a release-controlling polymer.

7. The composition of claim 6, wherein the release-controlling polymer is selected from ammonio methacrylate copolymer, types A and B;

ethylcellulose aqueous dispersions, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, or any combination thereof.

8. The composition of claim 1, wherein 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, ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins, carboxymethyl ethylcellulose, co-polymerized methacrylic acid/methacrylic acid methyl esters, or any combination thereof.

9. The composition of claim 1, wherein the composition comprises micronized topiramate having a median particle size in the range of 1-250 microns.

10. The composition of claim 1, further comprising at least one basifying agent.

11. The composition of claim 1, further comprising a least one surfactant or co-surfactant.

12. The composition of claim 1 for once-a-day administration.

13. The composition of claim 1, wherein the matrix further comprises at least one pharmaceutically acceptable excipient selected from a group consisting of binding agents, bulking agents, and disintegrants.

14. The composition of claim 1, wherein at least one core is coated with an IR layer.

15. The composition of claim 1, wherein at least one core is coated with an extended release (XR) layer.

16. The composition of claim 3, wherein a first core is an immediate release core and a second core is coated with a release-controlling polymer.

17. The composition of claim 15, wherein the XR layer comprises a release-controlling polymer selected from the group consisting of ammonio methacrylate copolymer, types A and B;

ethylcellulose aqueous dispersions, hydroxyethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, and any combination thereof.

18. The composition of claim 1, wherein the particles are encapsulated in a gelatin capsule.

19. The composition of claim 1, wherein the particles are multiparticulate beads or pellets.

20. The composition of claim 19, wherein the multiparticulate beads or pellets are encapsulated in a gelatin capsule.

21. The composition of claim 1, wherein the Cmax produced by dosing the composition in vivo is higher by about 20% to about 80% of the Cmax of the same amount of topiramate administered as an immediate release composition.

22. The composition of claim 1, wherein the AUC produced by dosing the composition in vivo is higher by about 70% to about 140% of the AUC of the same amount of topiramate administered as an immediate release composition.

23. The composition of claim 1, wherein the weight of the enteric polymer coating is about 7% to about 13% of the weight of the composition.

24. The composition of claim 1, wherein the topiramate or a pharmaceutically acceptable salt thereof is present in an amount of about 15 mg to about 400 mg.

25. The composition of claim 8, wherein the natural resin is zein, shellac, or copal collophorium.