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