Method of treating heart failure with preserved ejection fraction by administering milrinone

1. A method of treating a patient having heart failure with preserved ejection fraction (HFpEF) comprising administering to the patient milrinone, or a pharmaceutically acceptable salt thereof;

wherein the formulation permits delivery of milrinone in an amount to achieve steady state plasma levels effective to alleviate the symptoms of HFpEF; wherein delivery of milrinone is in the range of between 0.1 μg/kg body weight per minute to 20 μg/kg body weight per minute.

2. The method according to claim 1 wherein milrinone is administered intravenously.

3. The method according to claim 1 wherein milrinone is formulated as an oral controlled-release formulation.

4. The method according to claim 3 wherein the oral controlled-release formulation comprises:

a core comprising milrinone and one or more polymers and one or more excipients; and

a sustained-release coating.

5. The method according to claim 4 wherein the formulation further comprises:

hydroxypropylmethylcellulose or hydroxypropylcellulose 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;

wherein the hydroxypropylmethylcellulose or hydroxypropylcellulose (80,000 to 120,000) and the hydroxypropylmethylcellulose (about 50 cps) are in a weight ratio of 2:1 to 1:2, and the weight ratio of milrinone to total hydroxypropylmethylcellulose and hydroxypropylcellulose is 1:2 to 1:6.

6. The method according to claim 5 wherein the at least one pharmaceutically acceptable excipient is a binder or a lubricant or a mixture thereof.

7. The method according to claim 4 wherein the core further comprises:

a hydrophilic matrix comprising at least two natural gums, and at least one pharmaceutically acceptable excipient;

wherein the two natural gums are in a weight ratio of 2:1 to 1:2; and

the weight ratio of milrinone to the hydrophilic matrix is 1:1 to 1:2.5.

8. The method according to claim 7 wherein the hydrophilic matrix comprises xanthan gum, locust bean gum or a mixture thereof.

9. The method according to claim 4 wherein the core comprises:

a coating composition comprising milrinone,

one or more polymers, and one or more excipients, and

inert spherical particles;

wherein the coating composition is coated on the surface of the spherical particles;

wherein the weight ratio of milrinone to the spherical particles is about 1:5 to 1:25; and wherein the coated particles further comprise a sealing coating.

10. The method according to claim 9 wherein the inert spherical particles are sugar or starch spherical particles.

11. The method according to claim 9 wherein the coating composition further includes a plasticiser.

12. The method according to claim 9 wherein the weight ratio of milrinone to polymer and optionally plasticiser is 1.5:1 to 2:1.

13. The method according to claim 4 wherein the sustained-release coating comprises a microcrystalline cellulose, a cellulose ether, a hydroxypropylcellulose, or a copolymer of acrylic acid, methacrylic acid and/or their esters.

14. The method according to claim 4 further comprising one or more of a seal coating, a buffer coating and an enteric-release coating.

15. The method according to claim 1 wherein the administration achieves a plasma concentration of milrinone in the range of 100 to 400 ng/mL.

16. The method according to claim 1 wherein the formulation delivers milrinone 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 according to claim 1 further comprising the step of monitoring plasma concentrations of milrinone and if necessary, adjusting the dosage to achieve a plasma concentration in the range of 100 to 400 ng/mL.