Bromocriptine formulations
The present disclosure describes pharmaceutical formulations of bromocriptine and method of manufacturing and using such formulations. The formulations are useful for treating physiological disorders including improving glycemic control in the treatment of type 2 diabetes. Also disclosed is synthesis of bromocriptine citrate, and compositions and dosage forms containing bromocriptine citrate.
1. A pharmaceutical formulation comprising bromocriptine citrate and an excipient, wherein the excipient comprises a fatty acid or a triglyceride, a non-lactose short chain saccharide, and citric acid and wherein the bromocriptine citrate is soluble in water to at least 200 mg/L at 20° C. and present in an amount that provides a dose of at least 0.1 mg of bromocriptine.
2. The pharmaceutical formulation of claim 1 , wherein at least about 80% of the acyl groups of the triglyceride are fatty acid acyl groups of C 6 -C 14 fatty acids.
3. The pharmaceutical formulation of claim 1 , wherein at least about 80% of the acyl groups of the triglyceride are fatty acid acyl groups of C 14 -C 26 fatty acids.
4. The pharmaceutical formulation of claim 1 , wherein at least about 80% of the acyl groups of the triglyceride are fatty acid acyl groups of C 16 -C 20 fatty acids.
5. The pharmaceutical formulation of claim 4 , wherein at least about 80% of the acyl groups of the triglyceride are fatty acid acyl groups of C 18 fatty acids.
6. The pharmaceutical formulation of claim 1 , wherein at least about 80% of the acyl groups of the triglyceride are stearoyl or 12-hydroxystearoyl groups.
7. The pharmaceutical formulation of claim 1 , wherein at least about 80% of the acyl groups of the triglyceride are saturated.
8. The pharmaceutical formulation of claim 1 , wherein the excipient comprises a hydrogenated vegetable oil.
9. The pharmaceutical formulation of claim 1 , wherein the excipient comprises at least one of hydrogenated castor oil, hydrogenated coconut oil, hydrogenated cottonseed oil, hydrogenated palm oil, hydrogenated palm kernel oil, hydrogenated soybean oil, or a combination thereof.
10. The pharmaceutical formulation of claim 1 , wherein the excipient comprises hydrogenated castor oil.
11. The pharmaceutical formulation of claim 1 , wherein the short chain saccharide is mannitol.
12. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation is free of magnesium and lactose.
13. The pharmaceutical formulation of claim 1 , wherein the formulation contains no more than 3% total related substances as determined by HPLC analysis using detection of UV absorption at 300 nm following storage of the formulation at a temperature of 40±2° C. at about 70±5% relative humidity for 6 weeks.
14. The pharmaceutical formulation of claim 1 , wherein the pharmaceutical formulation contains no more than 5% of bromocriptinine as determined by HPLC analysis using detection of UV absorption at 300 nm following storage of the pharmaceutical formulation at a temperature of 25±2° C. at about 60±5% relative humidity for 18 months.
15. The pharmaceutical formulation of claim 1 , wherein the formulation comprises a tablet or oral dosage form.
16. The pharmaceutical formulation of claim 1 , wherein the formulation comprises a parenteral dosage form.
17. The pharmaceutical formulation of claim 1 , wherein the bromocriptine is water soluble to at least 500 mg/L, and the formulation 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 37° C., wherein at least about 90% of the bromocriptine has been released at 20 minutes.
18. The pharmaceutical formulation of claim 1 , wherein the formulation contains no more than 5% of bromocriptinine as determined by HPLC analysis using detection of UV absorption at 300 nm following storage of the pharmaceutical formulation at a temperature of 25±2° C. at 60±5% relative humidity for 18 months.
19. The pharmaceutical formulation of claim 17 , wherein the formulation does not generate more than 8% bromocriptinine after 6 months under 40 C and 75% RH conditions, and is more stable in an aqueous environment than bromocriptine mesylate.
20. The pharmaceutical formulation of claim 1 , wherein the formulation 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 37° C., wherein at least about 80% of the bromocriptine has been released at about 30 minutes.
21. The pharmaceutical formulation of claim 17 , wherein the formulation contains no more than 5% of bromocriptinine as determined by HPLC analysis using detection of UV absorption at 300 nm following storage of the pharmaceutical formulation at a temperature of 25±2° C. at 60±5% relative humidity for 18 months.