Heterocyclic compounds and their uses

Patent metadata

Field	Value
Publication number	US-9951015-B2
Application number	US-201414210713-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 14, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

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

First claim

What is claimed:

1. An oral pharmaceutical formulation comprising:
omecamtiv mecarbil dihydrochloride hydrate;
a control release agent;
a pH modifying agent comprising maleic acid, fumaric acid, tartaric acid, glutamic acid, or a combination thereof;
a filler; and
a lubricant.

2. A pharmaceutical formulation according to claim 1 , wherein the pH modifying agent is fumaric acid.

3. A pharmaceutical formulation according to claim 1 , wherein the filler is selected from starches, lactose, mannitol, cellulose derivatives, calcium phosphate, a sugar, and any combination thereof.

4. A pharmaceutical formulation according to claim 1 , wherein the control release agent comprises hypromellose having a viscosity of 100,000 mPa·s at 2% concentration in water at 20° C.

5. A pharmaceutical formulation according to claim 1 , wherein the control release agent comprises hypromellose having a viscosity of 100 mPa·s at 2% concentration in water at 20° C.

6. A pharmaceutical formulation according to claim 1 , wherein the control release agent is a mixture of hypromellose having a viscosity of 100,000 mPa·s at 2% concentration in water at 20° C. and hypromellose having a viscosity of 100 mPa·s at 2% concentration in water at 20° C.

7. A pharmaceutical formulation according to claim 1 , wherein the filler is a combination of microcrystalline cellulose and lactose monohydrate.

8. A pharmaceutical formulation according to claim 1 , wherein the lubricant is magnesium stearate.

9. The pharmaceutical formulation according to claim 1 , in the form of a tablet.

10. The pharmaceutical formulation according to claim 1 comprising:
3-30% w/w omecamtiv mercarbil dihydrochloride hydrate;
15-35% w/w control release agent;
20-45% w/w pH modifying agent;
25-65% w/w filler; and
0.1-1.0% w/w lubricant.

11. 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 hydrate, of less than 2:1 to 1:1.

12. The pharmaceutical formulation according to claim 11 , having a weight ratio of the pH-modifying agent to the omecamtiv mecarbil dihydrochloride hydrate, of 1:1.

13. The pharmaceutical formulation according to claim 1 , comprising:
5-7% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

14. The pharmaceutical formulation according to claim 13 , wherein the control release agent comprises hypromellose having a viscosity of 100,000 mPa·s at 2% concentration in water at 20° C.

15. The pharmaceutical formulation according to claim 13 , wherein the control release agent comprises hypromellose having a viscosity of 100 mPa·s at 2% concentration in water at 20° C.

16. The pharmaceutical formulation according to claim 13 , wherein the filler comprises microcrystalline cellulose.

17. The pharmaceutical formulation according to claim 13 , wherein the filler comprises lactose monohydrate.

18. The pharmaceutical formulation according to claim 1 , comprising:
17-20% w/w omecamtiv mecarbil dihydrochloride hydrate;
21-29% w/w control release agent;
34-41% w/w filler;
17-20% w/w fumaric acid; and
0.2-2% w/w lubricant.

19. The pharmaceutical formulation according to claim 18 , wherein the control release agent comprises hypromellose having a viscosity of 100,000 mPa·s at 2% concentration in water at 20° C.

20. The pharmaceutical formulation according to claim 18 , wherein the control release agent comprises hypromellose having a viscosity of 100 mPa·s at 2% concentration in water at 20° C.

21. The pharmaceutical formulation according to claim 18 , wherein the filler comprises microcrystalline cellulose.

22. The pharmaceutical formulation according to claim 18 , wherein the filler comprises lactose monohydrate.

23. The pharmaceutical formulation according to claim 1 , comprising:
12-25% w/w omecamtiv mecarbil dihydrochloride hydrate;
25-35% w/w control release agent;
25-40% w/w filler;
12-25% w/w fumaric acid; and
0.2-4% w/w lubricant.

24. The pharmaceutical formulation according to claim 1 , comprising:
3-10% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

25. The pharmaceutical formulation according to claim 1 , comprising:
12-25% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

26. An oral pharmaceutical formulation comprising:
omecamtiv mecarbil dihydrochloride hydrate;
a control release agent;
a pH modifying agent comprising maleic acid, fumaric acid, tartaric acid, glutamic acid, or a combination thereof;
a filler; and
a lubricant, wherein
the control release agent comprises (a) hypromellose having a viscosity of 100,000 mPa.s at 2% concentration in water at 20° C., (b) hypromellose having a viscosity of 100 mPa.s at 2 % concentration in water at 20° C., or (c) a mixture of (a) and (b); and
the filler comprises (a) microcrystalline cellulose, (b) lactose monohydrate, or (c) a mixture of (a) and (b).

27. The pharmaceutical formulation according to claim 26 , comprising:
3-30% w/w omecamtiv mercarbil dihydrochloride hydrate;
15-35% w/w control release agent;
20-45% w/w pH modifying agent;
25-65% w/w filler; and
0.1-1.0% w/w lubricant.

28. The pharmaceutical formulation according to claim 26 , comprising:
5-7% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

29. The pharmaceutical formulation according to claim 26 , comprising:
17-20% w/w omecamtiv mecarbil dihydrochloride hydrate;
21-29% w/w control release agent;
34-41% w/w filler;
17-20% w/w fumaric acid; and
0.2-2% w/w lubricant.

30. The pharmaceutical formulation according to claim 26 , comprising:
12-25% w/w omecamtiv mecarbil dihydrochloride hydrate;
25-35% w/w control release agent;
25-40% w/w filler;
12-25% w/w fumaric acid; and
0.2-4% w/w lubricant.

31. The pharmaceutical formulation according to claim 26 , comprising:
3-10% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

32. The pharmaceutical formulation according to claim 26 , comprising:
12-25% w/w omecamtiv mecarbil dihydrochloride hydrate;
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.

33. The pharmaceutical formulation according to claim 1 , in the form of a tablet, and wherein the pH modifying agent is fumaric acid, the control release agent is a mixture of hypromellose having a viscosity of 100,000 mPa.s at 2% concentration in water at 20° C. and hypromellose having a viscosity of 100 mPa.s at 2% concentration in water at 20° C.; the filler is a combination of microcrystalline cellulose and lactose monohydrate; and the lubricant is magnesium stearate.

Assignees

• Amgen Inc
• Cytokinetics Inc

Inventors

• Bi Mingda
• Kuehl Robert

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61K9/2054

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

• A61K9/2013

  Organic compounds, e.g. phospholipids, fats · CPC title

• A61K9/2018

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