Claims for Patent: 9,993,474

Summary for Patent: 9,993,474

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:	15/618,055
Patent Claims:	1. A dosage form comprising: bromocriptine in micronized form and one or more excipients; wherein the dosage form provides for absorption of a substantial amount of bromocriptine through the gastric and/or intestinal mucosa when administered to a subject; and wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to the subject under fasting conditions or the T.sub.max of bromocriptine is between about 90 and about 120 minutes following oral administration of the dosage form to the subject under high fat fed conditions. 2. The dosage form of claim 1, wherein the bromocriptine is in the form of a salt of bromocriptine. 3. The dosage form of claim 1, wherein the bromocriptine is in the form of bromocriptine mesylate. 4. The dosage form of claim 1, wherein the dosage form is in the form of a tablet. 5. The dosage form of claim 1, wherein not more than about 20% of the bromocriptine has a particle size of less than about 1 .mu.m. 6. The dosage form of claim 1, wherein the bromocriptine has volume-based particle size distribution with a span of about 2.5 or lower. 7. The dosage form of claim 1, wherein the bromocriptine has volume-based particle size distribution with a span of about 2 or lower. 8. The dosage form of claim 1, wherein the dosage form 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 has been released at about 7 minutes, and not more than about 75% of the bromocriptine has been released at about 10 minutes and at least about 80% of the bromocriptine has been released at about 30 minutes. 9. The dosage form of claim 1, wherein the dosage form 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 has been released at about 30 minutes. 10. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a dosage form according to claim 1. 11. The method of claim 10, wherein the dosage form is administered in the morning within about two hours after waking. 12. A dosage form comprising: bromocriptine and one or more excipients; wherein the dosage form provides for absorption of a substantial amount of bromocriptine through the gastric and/or intestinal mucosa when administered to a subject; wherein the bromocriptine has a volume based particle size distribution with a Dv90 of less than 15 .mu.m and a span of less than 2 and wherein the dosage form 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 80% of the bromocriptine has been released at about 30 minutes. 13. The dosage form of claim 12, wherein the bromocriptine is in the form of a salt of bromocriptine. 14. The dosage form of claim 12, wherein the bromocriptine is in the form of bromocriptine mesylate. 15. The dosage form of claim 12, wherein the dosage form is in the form of a tablet. 16. The dosage form of claim 12, wherein not more than about 20% of the bromocriptine has a particle size of less than about 1 .mu.m. 17. The dosage form of claim 12, wherein the dosage form 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 has been released at about 7 minutes, and not more than about 75% of the bromocriptine has been released at about 10 minutes and at least about 80% of the bromocriptine has been released at about 30 minutes. 18. The dosage form of claim 12, wherein the dosage form 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 has been released at about 30 minutes. 19. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a dosage form according to claim 12. 20. The method of claim 19, wherein the dosage form is administered in the morning within about two hours after waking. 21. A dosage form comprising: bromocriptine and one or more excipients; wherein the dosage form provides for absorption of a substantial amount of bromocriptine through the gastric and/or intestinal mucosa when administered to a subject; wherein the bromocriptine has a volume based particle size distribution with a Dv90 of less than 15 .mu.m and a span of less than 2 and wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to the subject under fasting conditions or the T.sub.max of bromocriptine is between about 90 and about 120 minutes following oral administration of the dosage form to the subject under high fat fed conditions. 22. The dosage form of claim 21, wherein the bromocriptine is in the form of a salt of bromocriptine. 23. The dosage form of claim 21, wherein the bromocriptine is in the form of bromocriptine mesylate. 24. The dosage form of claim 21, wherein the dosage form is in the form of a tablet. 25. The dosage form of claim 21, wherein not more than about 20% of the bromocriptine has a particle size of less than about 1 .mu.m. 26. The dosage form of claim 21, wherein the dosage form 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 has been released at about 7 minutes, and not more than about 75% of the bromocriptine has been released at about 10 minutes and at least about 80% of the bromocriptine has been released at about 30 minutes. 27. The dosage form of claim 21, wherein the dosage form 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 has been released at about 30 minutes. 28. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a dosage form according to claim 21. 29. The method of claim 28, wherein the dosage form is administered in the morning within about two hours after waking. 30. A dosage form comprising: bromocriptine and one or more excipients; wherein the dosage form provides for absorption of a substantial amount of bromocriptine through the gastric and/or intestinal mucosa when administered to a subject; wherein the bromocriptine has a Dv50 of 5 .mu.m or lower and a span of 2 or lower; and wherein the dosage form 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 80% of the bromocriptine has been released at about 30 minutes. 31. The dosage form of claim 30, wherein the bromocriptine is in the form of a salt of bromocriptine. 32. The dosage form of claim 30, wherein the bromocriptine is in the form of bromocriptine mesylate. 33. The dosage form of claim 30, wherein the dosage form is in the form of a tablet. 34. The dosage form of claim 30, wherein the bromocriptine is in micronized form. 35. The dosage form of claim 30, wherein not more than about 20% of the bromocriptine has a particle size of less than about 1 .mu.m. 36. The dosage form of claim 30, wherein the bromocriptine has volume-based particle size distribution with a span of about 2.5 or lower. 37. The dosage form of claim 30, wherein the bromocriptine has volume-based particle size distribution with a span of about 2 or lower. 38. The dosage form of claim 30, wherein the dosage form 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 has been released at about 7 minutes, and not more than about 75% of the bromocriptine has been released at about 10 minutes. 39. The dosage form of claim 30, wherein the dosage form 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 has been released at about 30 minutes. 40. The dosage form of claim 30, wherein the wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to the subject under fasting conditions or the T.sub.max of bromocriptine is between about 90 and about 120 minutes following oral administration of the dosage form to the subject under high fat fed conditions. 41. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a dosage form according to claim 30. 42. The method of claim 41, wherein the dosage form is administered in the morning within about two hours after waking. 43. A dosage form comprising: bromocriptine and one or more excipients; wherein the dosage form provides for absorption of a substantial amount of bromocriptine through the gastric and/or intestinal mucosa when administered to a subject; wherein the bromocriptine has a volume based particle size distribution with a Dv50 of less than 5 .mu.m and a span of less than 2; and wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T.sub.max) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to the subject under fasting conditions or the T.sub.max of bromocriptine is between about 90 and about 120 minutes following oral administration of the dosage form to the subject under high fat fed conditions. 44. The dosage form of claim 43, wherein the bromocriptine is in the form of a salt of bromocriptine. 45. The dosage form of claim 43, wherein the bromocriptine is in the form of bromocriptine mesylate. 46. The dosage form of claim 43, wherein the dosage form is in the form of a tablet. 47. The dosage form of claim 43, wherein not more than about 20% of the bromocriptine has a particle size of less than about 1 .mu.m. 48. The dosage form of claim 43, wherein the dosage form 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 has been released at about 7 minutes, and not more than about 75% of the bromocriptine has been released at about 10 minutes and at least about 80% of the bromocriptine has been released at about 30 minutes. 49. The dosage form of claim 43, wherein the dosage form 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 has been released at about 30 minutes. 50. A method of treatment for improving glycemic control in a type 2 diabetes patient comprising orally administering to the patient a dosage form according to claim 43. 51. The method of claim 50, wherein the dosage form is administered in the morning within about two hours after waking.