Bromocriptine formulations
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.
1. A method for the manufacture of a dosage form, comprising:
processing bromocriptine to reduce its average particle size;
blending the processed bromocriptine with one or more excipients to form a mixture; and
compressing the mixture to form a solid dosage form, wherein the solid 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° C., wherein at least about 80% of the bromocriptine has been released at about 30 minutes.
2. The method of claim 1 , wherein the bromocriptine has a Dv90 of about 10 μm or lower.
3. The method of claim 1 , wherein the bromocriptine has volume-based particle size distribution with a span of about 2 or lower.
4. The method 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° C., wherein at least about 90% of the bromocriptine has been released at about 30 minutes.
5. The method 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° 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.
6. The method of claim 1 , wherein the wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T max ) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to a subject under fasting conditions or the T 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.
7. A method for the manufacture of a dosage form, comprising:
processing bromocriptine to reduce its average particle size and provide bromocriptine in micronized form;
blending the bromocriptine with one or more excipients to form a mixture; and
compressing the mixture to form a solid dosage form, 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° C., wherein at least about 80% of the bromocriptine has been released at about 30 minutes.
8. The method of claim 7 , wherein the bromocriptine has a Dv90 of about 20 μm or lower.
9. The method of claim 7 , wherein the bromocriptine has volume-based particle size distribution with a span of about 2 or lower.
10. The method of claim 7 , 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° C., wherein at least about 90% of the bromocriptine has been released at about 30 minutes.
11. The method of claim 7 , 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° 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.
12. The method of claim 7 , wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T 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 max of bromocriptine is between about 90 and about 120 minutes following oral administration of the dosage form to a subject under high fat fed conditions.
13. The method of claim 7 ,
wherein the bromocriptine has a Dv90 of about 15 μm or lower; and
wherein the bromocriptine has a particle size distribution with a span of about 2 or lower.
14. The method of claim 13 , 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° C., wherein at least about 90% of the bromocriptine has been released at about 30 minutes.
15. The method of claim 13 , 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° 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.
16. The method of claim 13 , wherein the wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T max ) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to a subject under fasting conditions or the T 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.
17. The method of claim 1
wherein the bromocriptine has a Dv99 of less than about 15 μm; and
wherein the dosage form has a dissolution profile wherein at least about 80% of the bromocriptine has been released at about 30 minutes, when tested in USP Apparatus Type 2 Paddle Method at 50 rpm in 500 mL of 0.1 N hydrochloric acid at about 37° C.
18. The method of claim 17 , comprising determining that the bromocriptine has a Dv99 of about 15 μm or lower.
19. The method of claim 17 , 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° C., wherein at least about 90% of the bromocriptine has been released at about 30 minutes.
20. The method of claim 17 , 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° 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.
21. The method of claim 17 , wherein the wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T max ) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to a subject under fasting conditions or the T 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 method of claim 1
wherein the bromocriptine has a Dv50 of 5 μm 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° C., wherein at least about 80% of the bromocriptine has been released at about 30 minutes.
23. The method of claim 22 , 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° C., wherein at least about 90% of the bromocriptine has been released at about 30 minutes.
24. The method of claim 22 , 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° 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.
25. The method of claim 22 , wherein the wherein the dosage form exhibits a pharmacokinetic profile wherein the time to maximum plasma concentration (T max ) of bromocriptine is between about 30 and about 60 minutes following oral administration of the dosage form to a subject under fasting conditions or the T 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.