Extended-release topiramate capsules

• US 8,652,527 B1
• Filed: 03/19/2013
• Issued: 02/18/2014
• Est. Priority Date: 03/13/2013
• Status: Active Grant

• Current Assignee: Upsher-Smith Laboratories, LLC (SAWAI GROUP HOLDINGS Co., Ltd.)
• Original Assignee: Upsher-Smith Laboratories Incorporated (SAWAI GROUP HOLDINGS Co., Ltd.)
• Inventors: Betterman, Sarah Michelle, Tantry, Jaidev Srinvas, Patrick, Laura Marie
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Shomer, Isaac
• Application Number:
  US13/847,042
• Time in Patent Office: 336 Days
• Field of Search: None
• US Class Current: 424/489
• 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 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 9/16 Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• 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 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: C07D 311/02 ortho- or peri-condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 493/12 in which the condensed system contains three hetero rings
• CPC Class Codes: C07D 493/14 Ortho-condensed systems

Abstract

An extended-release topiramate capsule that includes a capsule shell containing a single population of coated particles; wherein each coated particle includes a core and a coating thereon; wherein each particle core includes a homogeneous mixture comprising topiramate throughout its core; and wherein the coating includes one or more release controlling agent(s).

Claims

1. An extended-release topiramate capsule comprising:

a capsule shell comprising a single population of coated particles;

wherein each coated particle comprises a core and a coating thereon;

wherein each particle core comprises a homogeneous mixture throughout its core,

the mixture comprising;

40 wt-% to 50 wt-% of topiramate, based on the total weight of an uncoated particle core;

45 wt-% to 55 wt-% of one or more filler(s), based on the total weight of an uncoated particle core; and

3 wt-% to 7 wt-% of one or more binder(s), based on the total weight of an uncoated particle core;

wherein the coating comprises;

55 wt-% to 65 wt-% of one or more release control agent(s), based on the total weight of the coating;

20 wt-% to 25 wt-% of one or more pore former(s), based on the total weight of the coating; and

10 wt-% to 20 wt-% of one or more plasticizer(s), based on the total weight of the coating;

wherein the particles are coated in an amount sufficient to provide a weight gain of 8% to 14%.

2. The extended-release topiramate capsule of claim 1 which, when dosed to a healthy human subject once daily, achieves at steady-state, an AUC_0-24h, C_max, and C_min in the subject'"'"'s plasma that are within the 80% to 125% bioequivalence criteria compared to immediate-release topiramate dosed twice per day.

3. The extended-release topiramate capsule of claim 1 which, when dosed to a healthy human subject once daily in the morning, achieves at steady-state, a reduction of fluctuation index of at least 15% compared to immediate-release topiramate dosed twice per day.

4. The extended-release topiramate capsule of claim 1 which, when dosed to a healthy human subject once daily in the morning, achieves at steady-state, a C_min in the subject'"'"'s plasma that is higher than the C_min compared to immediate-release topiramate dosed twice per day.

5. The extended-release topiramate capsule of claim 1 which, when a single-dose is given to a healthy human subject, achieves an AUC_0-inf of 170 to 210 h·

μ

g/mL within a 95% confidence interval, and a C_max of 2 to 4 μ

g/mL within a 95% confidence interval.

6. The extended-release topiramate capsule of claim 1 which, when dosed once daily to a population of human patients suffering from epilepsy, achieves a reduction in incidence of at least one side effect compared to immediate-release topiramate dosed at the same total daily dose divided twice per day.

7. The extended-release topiramate capsule of claim 1 wherein the particles are coated in an amount sufficient to provide a weight gain of 10% to 12%.

8. The extended-release topiramate capsule of claim 1 which is chemically stable for at least 12 months.

9. The extended-release topiramate capsule of claim 8 which is chemically stable for at least 24 months when stored in a sealed container with desiccant.

10. The extended-release topiramate capsule of claim 1 wherein the capsule shell is a hydroxypropyl methylcellulose capsule.

11. The extended-release topiramate capsule of claim 1 which is free of an immediate-release component.

12. The extended-release topiramate capsule of claim 1 wherein the one or more filler(s) is selected from the group of microcrystalline cellulose, dibasic calcium phosphate, lactose, tribasic calcium phosphate, mannitol, and combinations thereof.

13. The extended-release topiramate capsule of claim 12 wherein the filler is microcrystalline cellulose.

14. The extended-release topiramate capsule of claim 1 wherein the one or more binder(s) is selected from the group of hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinyl pyrrolidine, starch, natural gum, and combinations thereof.

15. The extended-release topiramate capsule of claim 14 wherein the binder is hydroxypropyl methylcellulose.

16. The extended-release topiramate capsule of claim 1 wherein the one or more release controlling agent(s) is selected from the group of ethylcellulose, polyvinyl acetate, polyacrylate and polymethacrylate, copolymers thereof, and combinations thereof.

17. The extended-release topiramate capsule of claim 16 wherein the release controlling agent is ethylcellulose.

18. The extended-release topiramate capsule of claim 1 wherein the one or more pore former(s) is selected from the group of hypromellose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum, sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starch glycolate, croscarmellose sodium, starch, mannitol, glucose, sucrose, fructose, mannose, galactose, sorbitol, dextran, sodium chloride, potassium chloride, calcium chloride, and combinations thereof.

19. The extended-release topiramate capsule of claim 18 wherein the pore former is hydroxypropyl methylcellulose.

20. The extended-release topiramate capsule of claim 1 wherein the one or more plasticizer(s) is selected from the group of diethyl phthalate, triethyl citrate, dibutyl sebacate, polyethylene glycol, triacetin, tributyl citrate, glycerol, propylene glycol, and combinations thereof.

21. The extended-release topiramate capsule of claim 20 wherein the plasticizer is diethyl phthalate.

22. The extended-release topiramate capsule of claim 1 wherein each particle core further comprises one or more stabilizer(s) selected from the group of calcium hydroxide, calcium carbonate, sodium bicarbonate, magnesium carbonate, and combinations thereof.

23. An extended-release topiramate capsule comprising:

a capsule shell comprising a single population of coated particles;

wherein each coated particle comprises a core and a coating thereon;

wherein each particle core comprises a homogeneous mixture throughout its core,

the mixture comprising;

40 wt-% to 50 wt-% of topiramate, based on the total weight of an uncoated particle core;

45 wt-% to 55 wt-% of one or more filler(s), based on the total weight of an uncoated particle core;

wherein the one or more filler(s) is selected from the group of microcrystalline cellulose, dibasic calcium phosphate, lactose, tribasic calcium phosphate, mannitol, and combinations thereof; and

3 wt-% to 7 wt-% of one or more binder(s), based on the total weight of an uncoated particle core;

wherein the one or more binder(s) is selected from the group of hydroxypropyl methylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, polyvinyl pyrrolidine, starch, natural gum, and combinations thereof;

wherein the coating comprises;

55 wt-% to 65 wt-% of one or more release control agent(s), based on the total weight of the coating;

wherein the one or more release controlling agent(s) is selected from the group of ethylcellulose, polyvinyl acetate, polyacrylate and polymethacrylate, copolymers thereof, and combinations thereof;

20 wt-% to 25 wt-% of one or more pore former(s), based on the total weight of the coating;

wherein the one or more pore former(s) is selected from the group of hypromellose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyethylene glycol, guar gum, xanthan gum, sodium alginate, polyvinylpyrrolidone, crospovidone, sodium starch glycolate, croscarmellose sodium, starch, mannitol, glucose, sucrose, fructose, mannose, galactose, sorbitol, dextran, sodium chloride, potassium chloride, calcium chloride, and combinations thereof; and

10 wt-% to 20 wt-% of one or more plasticizer(s), based on the total weight of the coating;

wherein the one or more plasticizer(s) is selected from the group of diethyl phthalate, triethyl citrate, dibutyl sebacate, polyethylene glycol, triacetin, tributyl citrate, glycerol, propylene glycol, and combinations thereof;

wherein the particles are coated in an amount sufficient to provide a weight gain of 8% to 14%.

24. The extended-release topiramate capsule of claim 23 which, when dosed to a healthy human subject once daily, achieves at steady-state, an AUC_0-24h, C_max, and C_min in the subject'"'"'s plasma that are within the 80% to 125% bioequivalence criteria compared to immediate-release topiramate dosed twice per day.

25. The extended-release topiramate capsule of claim 23 which, when dosed to a healthy human subject once daily in the morning, achieves at steady-state a reduction of fluctuation index of at least 15% compared to immediate-release topiramate dosed twice per day.

26. The extended-release topiramate capsule of claim 23 which, when dosed to a healthy human subject once daily in the morning, achieves at steady-state a C_min in the subject'"'"'s plasma that is higher than the C_min compared to immediate-release topiramate dosed twice per day.

27. The extended-release topiramate capsule of claim 23 which, when given as a single-dose to a healthy human subject, achieves an AUC_0-inf of 170 to 210 h·

μ

g/mL within a 95% confidence interval, and a C_max of 2 to 4 μ

g/mL within a 95% confidence interval.

28. The extended-release topiramate capsule of claim 23 which, when dosed once daily to a population of human patients suffering from epilepsy, achieves a reduction in incidence of at least one side effect compared to immediate-release topiramate dosed at the same total daily dose divided twice per day.

29. An extended-release topiramate capsule comprising:

a capsule shell comprising a single population of coated particles;

wherein each coated particle comprises a core and a coating thereon;

wherein each particle core comprises a homogeneous mixture throughout its core,

the mixture comprising;

40-50 wt-% of topiramate, based on the total weight of an uncoated particle core;

45-55 wt-% of microcrystalline cellulose, based on the total weight of an uncoated particle core; and

3-7 wt-% of hydroxypropyl methylcellulose, based on the total weight of an uncoated particle core;

wherein the coating comprises;

55-65 wt-% of ethylcellulose, based on the total weight of the coating;

20-25 wt-% of hydroxypropyl methylcellulose, based on the total weight of the coating; and

10-20 wt-% of diethyl phthalate, based on the total weight of the coating;

wherein the particles are coated in an amount sufficient to provide a weight gain of 8% to 14%.

30. An extended-release topiramate capsule comprising:

a capsule shell comprising a single population of coated particles;

wherein each coated particle comprises a core and a coating thereon;

wherein each particle core comprises a homogeneous mixture throughout its core,

the mixture comprising;

44-46 wt-% of topiramate, based on the total weight of an uncoated particle core;

48-52 wt-% of microcrystalline cellulose, based on the total weight of an uncoated particle core; and

4-6 wt-% of hydroxypropyl methylcellulose, based on the total weight of an uncoated particle core;

wherein the coating comprises;

60-62 wt-% of ethylcellulose, based on the total weight of the coating;

22-24 wt-% of hydroxypropyl methylcellulose, based on the total weight of the coating; and

15-18 wt-% of diethyl phthalate, based on the total weight of the coating;

wherein the particles are coated in an amount sufficient to provide a weight gain of 10-12%.