Uses of milrinone controlled-release formulation
The present invention relates to oral controlled-release formulations of 5-(pyridinyl)-2(1H)-pyridinone compounds and their use in the treatment of a subject with heart failure, a stage, class or manifestation of heart failure, or at risk of developing or exhibiting symptoms of heart failure. The formulations of the invention release the compounds in the range of between 0.1 μg/kg body weight/minute and 20 μg/kg body weight/minute.
1. A method of treating a subject with heart failure, said method comprising administering to the subject 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;
(ii) a sustained release coating; and
(iii) an enteric coating;
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. The method of claim 1 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.375 μg/kg body weight/minute to about 0.75 μg/kg body weight/minute.
3. The method of claim 1 , wherein the subject is a human.
4. The method of claim 1 , further comprising the step of monitoring plasma concentrations of milrinone, or a pharmaceutically acceptable salt thereof, and if necessary, adjusting the dosage to achieve a plasma concentration in the range of 100 to 400 ng/mL.
5. The method of claim 1 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.1 μg/kg body weight/minute to about 1.0 μg/kg body weight/minute.
6. The method of claim 1 , wherein the ratio of hydroxypropylmethylcellulose (80,000 to 120,000 cps) to hydroxypropylmethylcellulose (50 cps) is about 1:1.
7. The method of claim 1 , wherein the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3.
8. A method of treating a subject with a stage, class or manifestation of heart failure, said method comprising administering to the subject 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;
(ii) a sustained release coating; and
(iii) an enteric coating;
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.
9. The method of claim 8 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.375 μg/kg body weight/minute to about 0.75 μg/kg body weight/minute.
10. The method of claim 8 , wherein the subject is a human.
11. The method of claim 8 , further comprising the step of monitoring plasma concentrations of milrinone, or a pharmaceutically acceptable salt thereof, and if necessary, adjusting the dosage to achieve a plasma concentration in the range of 100 to 400 ng/mL.
12. The method of claim 8 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.1 μg/kg body weight/minute to about 1.0 μg/kg body weight/minute.
13. The method of claim 8 , wherein the ratio of hydroxypropylmethylcellulose (80,000 to 120,000 cps) to hydroxypropylmethylcellulose (50 cps) is about 1:1.
14. The method of claim 8 , wherein the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3.
15. A method of treatment that permits the release of milrinone, or a pharmaceutically acceptable salt thereof, effective to ameliorate symptoms of heart failure in a subject for a period of at least 6 hours, said method comprising administering to the subject 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;
(ii) a sustained release coating; and
(iii) an enteric coating;
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.
16. The method of claim 15 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.375 μg/kg body weight/minute to about 0.75 μg/kg body weight/minute.
17. The method of claim 15 , wherein the subject is a human.
18. The method of claim 15 , further comprising the step of monitoring plasma concentrations of milrinone, or a pharmaceutically acceptable salt thereof, and if necessary, adjusting the dosage to achieve a plasma concentration in the range of 100 to 400 ng/mL.
19. The method of claim 15 , wherein the formulation delivers milrinone, or a pharmaceutically acceptable salt thereof, to the blood stream at a rate of from about 0.1 μg/kg body weight/minute to about 1.0 μg/kg body weight/minute.
20. The method of claim 15 , wherein the ratio of hydroxypropylmethylcellulose (80,000 to 120,000 cps) to hydroxypropylmethylcellulose (50 cps) is about 1:1.
21. The method of claim 15 , wherein the ratio of milrinone, or a pharmaceutically acceptable salt thereof, to total hydroxypropylmethylcellulose is about 1:3.