Milrinone controlled-release formulation

1. An oral controlled-release formulation comprising:

(i) a core comprising:

(a) milrinone, or a pharmaceutically acceptable salt thereof;

(b) hydroxypropylmethylcellulose having a viscosity of 80,000 to 120,000 cps:

hydroxypropylmethylcellulose having a viscosity of about 50 cps;

and at least one pharmaceutically acceptable excipient;

and

(ii) a sustained release coating; and

(iii) an enteric coating; wherein the formulation permits the release of milrinone, or a pharmaceutically acceptable salt thereof, into the bloodstream in an amount that is effective to ameliorate symptoms of heart failure for a period of at least 6 hours,

wherein the hydroxypropylmethylcellulose (80,000 to 120,000 cps) and the hydroxypropylmethylcellulose (about 50 cps) are in a ratio of about 1.5:1 to 1:1.5, and the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3 to 1:5, and

wherein the formulation exhibits zero order release of about 100% of milrinone, or a pharmaceutically acceptable salt thereof, over about 12 hours at pH 6.8.

2. An oral controlled-release formulation comprising:

(i) a core comprising:

(a) milrinone, or a pharmaceutically acceptable salt thereof;

(b) hydroxypropylmethylcellulose having a viscosity of 80,000 to 120,000 cps;

hydroxypropylmethylcellulose having a viscosity of about 50 cps;

and one or more pharmaceutically acceptable excipients;

and

(ii) a sustained release coating; and

(iii) an enteric coating; wherein the formulation permits the release of milrinone, or a pharmaceutically acceptable salt thereof, into the bloodstream at a rate that maintains the plasma level of milrinone, or a pharmaceutically acceptable salt thereof, in the range of 100 to 400 ng/ml for a period of at least 6 hours,

wherein the hydroxypropylmethylcellulose (80,000 to 120,000 cps) and the hydroxypropylmethylcellulose (about 50 cps) are in a ratio of about 1.5:1 to 1:1.5, and the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3 to 1:5, and

wherein the formulation exhibits zero order release of about 100% of milrinone, or a pharmaceutically acceptable salt thereof, over about 12 hours at pH 6.8.

3. An oral controlled-release formulation comprising:

(i) a core comprising:

(a) milrinone, or a pharmaceutically acceptable salt thereof;

(b) hydroxypropylmethylcellulose having a viscosity of 80,000 to 120,000 cps;

hydroxypropylmethylcellulose having a viscosity of about 50 cps;

and one or more pharmaceutically acceptable excipients;

and

(ii) a sustained release coating; and

(iii) an enteric coating; wherein the formulation permits the release of milrinone, or a pharmaceutically acceptable salt thereof, into the bloodstream at a rate of from about 0.1 to 1 pg/kg body weight/minute for a period of at least 6 hours,

wherein the hydroxypropylmethylcellulose (80,000 to 120,000 cps) and the hydroxypropylmethylcellulose (about 50 cps) are in a ratio of about 1.5:1 to 1:1.5, and the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3 to 1:5, and

wherein the formulation exhibits zero order release of about 100% of milrinone, or a pharmaceutically acceptable salt thereof, over about 12 hours at pH 6.8.

4. The oral controlled-release formulation of claim 1 , wherein the ratio of hydroxypropylmethylcellulose (80,000 to 120,000 cps) to hydroxypropylmethylcellulose (50 cps) is about 1:1.

5. The oral controlled-release formulation of claim 1 , wherein the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3.

6. The oral controlled-release formulation of claim 1 , wherein the at least one pharmaceutically acceptable excipient is a binder, a lubricant, or a mixture thereof.

7. The oral controlled-release formulation of claim 6 , wherein the binder is microcrystalline cellulose.

8. The oral controlled-release formulation of claim 1 , wherein milrinone, or a pharmaceutically acceptable salt thereof, is present in an amount of 10-30% w/w of the core.

9. The oral controlled-release formulation of claim 1 , wherein the hydroxypropylmethylcellulose (80,000 to 120,000 cps) is present in an amount of 20-40% w/w of the core.

10. The oral controlled-release formulation of claim 1 , wherein the hydroxypropylmethylcellulose (about 50 cps) is present in an amount of 20-40% w/w of the core.

11. The oral controlled-release formulation of claim 6 , wherein the binder is present in an amount of 16-30% w/w of the core.

12. The oral controlled-release formulation of claim 1 , wherein the sustained-release coating comprises a cellulose derivative or a copolymer of acrylic acid, methacrylic acid and/or their esters.

13. The oral controlled-release formulation of claim 12 , wherein the cellulose derivative is ethylcellulose.

14. The oral controlled-release formulation of claim 12 , wherein the sustained-release coating further comprises a low viscosity hydroxypropylmethylcellulose.

15. The oral controlled-release formulation of claim 1 , wherein the sustained-release coating comprises a copolymer of acrylic acid, acrylic ester, methacrylic acid, methacrylic ester or mixtures thereof, optionally with a methacrylic ester with quaternary ammonium groups.

16. The oral controlled-release formulation of claim 1 , wherein the formulation comprises more than one sustained-release coating.

17. The oral controlled-release formulation of claim 1 , further comprising one or more of a seal coating, a buffer coating and an enteric release coating.

18. The oral controlled-release formulation of claim 1 , wherein the enteric coating comprises Eudragit.

19. The oral controlled-release formulation of claim 18 , wherein the enteric coating comprises 25% Eudragit.

20. The oral controlled-release formulation of claim 18 , wherein the enteric coating comprises 30% Eudragit.