Claims for Patent: 8,431,155

Summary for Patent: 8,431,155

Title:	Bromocriptine formulations
Abstract:	The present application describes pharmaceutical formulations of bromocriptine mesylate and methods of manufacturing and using such formulations. The formulations are useful for improving glycemic control in the treatment of type 2 diabetes.
Inventor(s):	Cincotta; Anthony H. (Tiverton, RI), Bowe; Craig Michael (Encinitas, CA), Stearns; Paul Clark (San Diego, CA), Weston; Laura Jean (Escondido, CA)
Assignee:	VeroScience LLC (Tiverton, RI)
Application Number:	13/460,452
Patent Claims:	1. A tablet comprising micronized bromocriptine mesylate and one or more excipients; wherein the micronized bromocriptine mesylate is present in an amount that provides a dose of at least about 0.8 mg of bromocriptine per tablet; wherein the micronized bromocriptine mesylate has a Dv90 of less than about 10 .mu.m, and wherein not more than about 20% of the bromocriptine mesylate has a particle size of less than about 1 .mu.m; and wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein not more than about 50% of the bromocriptine mesylate has been released at about 7 minutes, not more than about 75% of the bromocriptine mesylate has been released at about 10 minutes, and at least about 90% of the bromocriptine mesylate has been released at about 30 minutes. 2. The tablet according to claim 1, wherein the bromocriptine mesylate is present in an amount that provides a dose of about 0.8 mg of bromocriptine per tablet. 3. The tablet according to claim 1, wherein the bromocriptine mesylate has a particle size distribution with a Dv90 of less than about 5 .mu.m. 4. The tablet according to claim 1, wherein the bromocriptine mesylate has a particle size distribution with a Dv99 of less than about 15 .mu.m. 5. The tablet according to claim 1, wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein at least about 90% of the bromocriptine mesylate has been released at about 20 minutes. 6. The tablet according to claim 1, wherein the tablet provides a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of the bromocriptine following administration of six of the tablets to adult subjects is between about 30 and 60 minutes when the tablets are administered under fasting conditions, or between about 90 and about 120 minutes, when the tablets are administered under high fat fed conditions. 7. A method for the manufacture of a bromocriptine mesylate tablet comprising: processing bromocriptine mesylate to reduce the average particle size of the bromocriptine mesylate to provide bromocriptine mesylate that has a Dv90 of less than about 10 .mu.m and wherein not more than about 20% of the bromocriptine mesylate has a particle size of less than about 1 .mu.m after the processing; blending the processed bromocriptine mesylate with excipients to form a mixture wherein the bromocriptine mesylate is substantially evenly distributed in the mixture, and compressing the mixture to form a tablet; wherein the tablet comprises bromocriptine mesylate in an amount that provides a dose of at least about 0.8 mg of bromocriptine; and wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein at least about 90% of the bromocriptine mesylate has been released at about 30 minutes. 8. The method according to claim 7, wherein the bromocriptine mesylate is present in an amount that provides a dose of about 0.8 mg of bromocriptine per tablet. 9. The method according to claim 7, wherein the processing comprises micronizing the bromocriptine mesylate. 10. The method according to claim 7, wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein at least about 90% of the bromocriptine mesylate has been released at about 20 minutes. 11. The method according to claim 7, wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein not more than about 50% of the bromocriptine mesylate has been released at about 7 minutes and not more than about 75% of the bromocriptine mesylate has been released at about 10 minutes. 12. The method according to claim 7, wherein the tablet provides a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of the bromocriptine following administration of six of the tablets to adult subjects is between about 30 and about 60 minutes when the tablets are administered under fasting conditions, or between about 90 and about 120 minutes when the tablets are administered under high fat fed conditions. 13. The method according to claim 7, wherein the mixture is transferred from a blending apparatus via a transfer unit to a tableting apparatus for compressing the mixture to form tablets that have a substantially uniform bromocriptine mesylate content. 14. A method for the manufacture of a bromocriptine mesylate tablet comprising: determining that bromocriptine mesylate has a particle size distribution equivalent to a volume-based particle size distribution with a Dv90 of less than about 10 .mu.m and wherein not more than about 20% of the bromocriptine mesylate has a particle size of less than about 1 .mu.m; blending the bromocriptine mesylate of determined particle size distribution with excipients to form a mixture wherein the bromocriptine mesylate is substantially evenly distributed in the mixture, and compressing the mixture to form a tablet; wherein the tablet comprises bromocriptine mesylate in an amount that provides a dose of at least about 0.8 mg of bromocriptine; and wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein at least about 90% of the bromocriptine mesylate has been released at about 30 minutes. 15. The method according to claim 14, wherein the bromocriptine mesylate is present in an amount that provides a dose of about 0.8 mg of bromocriptine per tablet. 16. The method according to claim 14, further comprising processing the bromocriptine mesylate prior to said determining to reduce the particle size of the bromocriptine mesylate to provide the bromocriptine mesylate that has a Dv90 of less than about 10 .mu.m. 17. The method according to claim 16, wherein the processing comprises micronizing the bromocriptine mesylate. 18. The method according to claim 14, wherein the mixture is transferred from a blending apparatus via a transfer unit to a tableting apparatus for compressing the mixture to form tablets that have a substantially uniform bromocriptine mesylate content. 19. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a bromocriptine mesylate tablet according to claim 1. 20. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising preparing at least one bromocriptine mesylate tablet by a method according to claim 7, and providing the bromocriptine mesylate tablet for oral administration to the patient. 21. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising preparing at least one bromocriptine mesylate tablet by a method according to claim 14, and providing the bromocriptine mesylate tablet for oral administration to the patient. 22. A tablet comprising micronized bromocriptine mesylate and one or more excipients; wherein the micronized bromocriptine mesylate is present in an amount that provides a dose of at least about 0.8 mg of bromocriptine per tablet; wherein the micronized bromocriptine mesylate has a Dv90 of less than about 10 .mu.m, and a volume-based particle size distribution with a span of about 2 or lower; and wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein at least about 90% of the bromocriptine mesylate has been released at about 30 minutes. 23. The tablet according to claim 22, wherein the bromocriptine mesylate has a particle size distribution with a Dv99 of less than about 15 .mu.m. 24. The tablet according to claim 22, wherein not more than about 20% of the bromocriptine mesylate has a particle size of less than about 1 .mu.m. 25. The tablet according to claim 22, wherein the tablet provides a dissolution profile, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37.degree. C., wherein not more than about 50% of the bromocriptine mesylate has been released at about 7 minutes, and not more than about 75% of the bromocriptine mesylate has been released at about 10 minutes. 26. The tablet according to claim 22, wherein the tablet provides a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of the bromocriptine following administration of six of the tablets to adult subjects is between about 30 and 60 minutes when the tablets are administered under fasting conditions, or between about 90 and about 120 minutes, when the tablets are administered under high fat fed conditions. 27. The tablet according to claim 26, wherein the tablet provides a pharmacokinetic profile wherein the C.sub.max of the bromocriptine is about 100 pg/mL. 28. The tablet according to claim 22, wherein the bromocriptine mesylate is present in an amount that provides a dose of about 0.8 mg of bromocriptine per tablet. 29. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a bromocriptine mesylate tablet according to claim 22.