Heterocyclic compounds and their uses

Patent metadata

Field	Value
Publication number	US-11384053-B2
Application number	US-201916579360-A
Country	US
Kind code	B2
Filing date	Sep 23, 2019
Priority date	Mar 14, 2013
Publication date	Jul 12, 2022
Grant date	Jul 12, 2022

Abstract

Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.

First claim

What is claimed:

1. An oral solid pharmaceutical formulation comprising:
omecamtiv mecarbil dihydrochloride monohydrate;
a control release agent comprising hydroxypropylmethylcellulose;
a pH modifying agent comprising maleic acid, fumaric acid, tartaric acid, glutamic acid, or a combination thereof;
a filler comprising microcrystalline cellulose, lactose monohydrate, or a mixture thereof; and
a lubricant.

2. A process for making a pharmaceutical formulation according to claim 1 , comprising:
blending a mixture comprising omecamtiv mecarbil dihydrochloride monohydrate, the control release agent, the pH modifying agent, and the filler;
lubricating the blended mixture using the lubricant;
granulating the lubricated blend;
lubricating the resultant granulation using the lubricant; and
compressing the lubricated granulation into desired form.

3. A method of treating a disease selected from acute heart failure and chronic heart failure, comprising administering a pharmaceutical formulation according to claim 1 to a patient in need thereof.

4. The pharmaceutical formulation according to claim 1 , having a weight ratio (w/w
%:w/w %) of the pH-modifying agent to the omecamtiv mecarbil dihydrochloride monohydrate, of less than 2:1 to 1:1.

5. The pharmaceutical formulation according to claim 1 , comprising:
5-7% w/w omecamtiv mecarbil dihydrochloride monohydrate;
27-33% w/w control release agent;
52-58% w/w filler;
6-9% w/w fumaric acid; and
0.2-2% w/w lubricant.

6. A method of treating a disease selected from acute heart failure and chronic heart failure, comprising administering a pharmaceutical formulation according to claim 5 to a patient in need thereof.

7. The pharmaceutical formulation according to claim 1 , comprising:
3-10% w/w omecamtiv mecarbil dihydrochloride monohydrate;
20-40% w/w control release agent;
42-67% w/w filler;
4-11% w/w fumaric acid; and
0.2-4% w/w lubricant.

8. A method of treating a disease selected from acute heart failure and chronic heart failure, comprising administering a pharmaceutical formulation according to claim 7 to a patient in need thereof.

9. The pharmaceutical formulation according to claim 1 , comprising:
12-25% w/w omecamtiv mecarbil dihydrochloride monohydrate;
13-37% w/w control release agent;
24-50% w/w filler;
12-25% w/w fumaric acid; and
0.2-4% w/w lubricant.

10. A method of treating a disease selected from acute heart failure and chronic heart failure, comprising administering a pharmaceutical formulation according to claim 9 to a patient in need thereof.

11. The pharmaceutical formulation of claim 1 , comprising omecamtiv mecarbil dihydrochloride monohydrate Form A.

12. The pharmaceutical formulation of claim 11 , wherein the omecamtiv mecarbil dihydrochloride monohydrate Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 14.9, 20.1, 21.4, and 26.8±2θ using Cu Kα radiation.

13. The pharmaceutical formulation of claim 12 , wherein the X-ray powder diffraction pattern further comprises peaks at 8.4, 24.2, 26.0, and 33.3±2θ using Cu Kα radiation.

14. The pharmaceutical formulation of claim 12 , wherein the X-ray powder diffraction pattern further comprises peaks at 6.2, 9.7, 13.2, 14.3, 15.4, 16.3, 16.9, 18.9, 19.5, 20.7, 21.8, 22.8, 23.6, 25.1, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7±2θ using Cu Kα radiation.

15. The pharmaceutical formulation of claim 11 , wherein the omecamtiv mecarbil dihydrochloride monohydrate Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 6.2, 6.6, 8.4, 9.7, 13.2, 14.3, 14.9, 15.4, 16.3, 16.9, 18.9, 19.5, 20.1, 20.7, 21.4, 21.8, 22.8, 23.6, 24.3, 25.1, 26.0, 26.8, 27.3, 27.7, 28.4, 29.4, 30.2, 31.2, 31.5, 31.9, 33.3, 33.9, 34.5, 34.9, 36.1, 36.8, 37.7, 38.5, and 39.7±2θ using Cu Kα radiation.

16. The pharmaceutical formulation according to claim 11 , wherein the oral formulation is in the form of a tablet.

17. The pharmaceutical formulation of claim 11 , wherein the omecamtiv mecarbil dihydrochloride monohydrate Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 8.4, 14.9, 15.4, and 26.8±0.2° 2θ using Cu Kα radiation.

18. The pharmaceutical formulation of claim 17 , wherein the X-ray powder diffraction pattern further comprises peaks at 16.3, 19.5, 21.8, 22.8, 27.7, and 28.4±0.2° 2θ using Cu Kα radiation.

19. The pharmaceutical formulation of claim 17 , wherein the X-ray powder diffraction pattern further comprises peaks at 9.7, 25.1, 27.3, 29.4, 30.2, 31.2, 34.5, and 34.9±0.2° 2θ using Cu Kα radiation.

20. The pharmaceutical formulation of claim 11 , wherein the omecamtiv mecarbil dihydrochloride monohydrate Form A is characterized by an X-ray powder diffraction pattern comprising peaks at 6.6, 14.9, 16.3, 19.5, and 26.8±0.2° 2θ using Cu Kα radiation.

21. The pharmaceutical formulation of claim 20 , wherein the X-ray powder diffraction pattern further comprises peaks at 21.8, 22.8, 27.7, and 28.4±0.2° 2θ using Cu Kα radiation.

Assignees

• Cytokinetics Inc

Inventors

• Bi Mingda
• Kuehl Robert

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K47/38

  Cellulose; Derivatives thereof · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title