Heterocyclic compounds and their uses
Provided are certain pharmaceutical formulations of omecamtiv mecarbil and methods for their preparation and use.
1. A method of treating a disease selected from acute heart failure and chronic heart failure, comprising administering an oral pharmaceutical formulation to a patient in need thereof, the oral pharmaceutical formulation comprising:
a pharmaceutically acceptable salt of omecamtiv mecarbil, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt of omecamtiv mecarbil;
a control release agent;
a pH modifying agent selected from maleic acid, fumaric acid, tartaric acid, glutamic acid, and any combination thereof;
a filler; and
a lubricant.
2. The method of claim 1 , wherein the pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt of omecamtiv mecarbil is omecamtiv mecarbil dihydrochloride hydrate.
3. The method according to claim 1 , wherein the pH modifying agent is fumaric acid.
4. The method according to claim 1 , wherein the filler is selected from starches, lactose, mannitol, cellulose derivatives, calcium phosphate, a sugar, and any combination thereof.
5. The method 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.
6. The method 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.
7. The method 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.
8. The method according to claim 1 , wherein the filler is a combination of microcrystalline cellulose and lactose monohydrate.
9. The method according to claim 1 , wherein the lubricant is magnesium stearate.
10. The method according to claim 1 , wherein the formulation is in the form of a tablet.
11. The method according to claim 1 , wherein the formulation comprises:
3-30% w/w of a pharmaceutically acceptable salt of omecamtiv mecarbil, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt of omecamtiv mecarbil;
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.
12. The method of claim 1 , wherein the disease is acute heart failure.
13. The method of claim 1 , wherein the disease is chronic heart failure.
14. The method according to claim 1 , wherein the formulation comprises:
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.
15. The method according to claim 1 , wherein the formulation comprises:
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.
16. The method according to claim 1 , wherein the formulation comprises:
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.
17. The method according to claim 1 , wherein the formulation comprises:
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.
18. The method according to claim 1 , wherein the formulation comprises:
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.
19. A process for making an oral pharmaceutical formulation, comprising:
blending a mixture comprising a pharmaceutically acceptable salt of omecamtiv mecarbil, or a pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt of omecamtiv mecarbil, a control release agent, a pH modifying agent, and a filler;
lubricating the blended mixture using a lubricant;
granulating the lubricated blend;
lubricating the resultant granulation using the lubricant; and
compressing the lubricated granulation into desired form to provide the oral pharmaceutical formulation.
20. The process of claim 19 , wherein the pharmaceutically acceptable hydrate of a pharmaceutically acceptable salt of omecamtiv mecarbil is as omecamtiv mecarbil dihydrochloride hydrate.