Pharmaceutical compositions comprising nitroxyl donors
The present disclosure provides nitroxyl donating pharmaceutical compositions comprising N-substituted hydroxylamine derivatives. The compositions are highly efficacious in treating cardiovascular diseases (e.g., heart failure), have a suitable toxicological profile, and are sufficiently stable for intravenous or oral administration.
1. A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and an aqueous buffer, wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1)
and
wherein the composition has a pH of from about 5 to about 6.5.
2. The pharmaceutical composition of claim 1 , wherein the aqueous buffer provides a pH to the composition of from about 5.5 to about 6.2.
3. The pharmaceutical composition of claim 1 , wherein the aqueous buffer provides a pH to the composition of about 6.
4. The pharmaceutical composition of claim 1 , wherein the buffer is a phosphate or acetate buffer.
5. The pharmaceutical composition of claim 1 , further comprising a stabilizing agent.
6. The pharmaceutical composition of claim 5 , wherein the stabilizing agent is a cyclodextrin.
7. The pharmaceutical composition of claim 6 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
8. The pharmaceutical composition of claim 4 , wherein the aqueous buffer is a potassium phosphate buffer.
9. The pharmaceutical composition of claim 4 , wherein the aqueous buffer is a potassium acetate buffer.
10. The pharmaceutical composition of claim 6 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with (CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
11. The pharmaceutical composition of claim 6 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1.
12. The pharmaceutical composition of claim 6 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1.
13. The pharmaceutical composition of claim 6 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1.
14. A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1):
15. The pharmaceutical composition of claim 14 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
16. The pharmaceutical composition of claim 14 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with (CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
17. The pharmaceutical composition of claim 14 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1.
18. The pharmaceutical composition of claim 14 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1.
19. The pharmaceutical composition of claim 14 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.1:1 to about 1:1.
20. The pharmaceutical composition of claim 14 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1.
21. The pharmaceutical composition of claim 17 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
22. The pharmaceutical composition of claim 17 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
23. The pharmaceutical composition of claim 18 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
24. The pharmaceutical composition of claim 18 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
25. The pharmaceutical composition of claim 19 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
26. The pharmaceutical composition of claim 19 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a 3-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
27. The pharmaceutical composition of claim 20 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
28. The pharmaceutical composition of claim 20 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
29. An admixture comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1; and wherein the N-hydroxysulfonamide type nitroxyl donor is a compound of the formula (1):
30. The admixture of claim 29 , which is formed by lyophilization.
31. The admixture of claim 29 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1.
32. The admixture of claim 29 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1.
33. The admixture of claim 29 , wherein the molar ratio between the N-hydroxysulfonamide type nitroxyl donor and the cyclodextrin present in the composition is from about 0.1:1 to about 1:1.
34. The admixture of claim 29 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
35. The admixture of claim 29 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
36. The admixture of claim 29 , further comprising a buffering agent.
37. The admixture of claim 36 , wherein the buffering agent is potassium acetate.
38. The admixture of claim 37 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin having six or seven sulfo-n-butyl ether groups per cyclodextrin molecule.
39. The admixture of claim 37 , wherein the cyclodextrin is a sulfo-n-butyl ether derivative of β-cyclodextrin, which is a β-cyclodextrin having at least one —OH group that is derivatized by replacing the hydrogen atom thereof with —(CH 2 ) 4 —S(O) 2 —O − Z + , wherein each Z is a Na + .
40. The pharmaceutical composition of claim 1 for use in the treatment of heart failure.
41. The pharmaceutical composition of claim 1 for use in the treatment of acute decompensated heart failure.
42. The pharmaceutical composition of claim 14 for use in the treatment of heart failure.
43. The pharmaceutical composition of claim 14 for use in the treatment of acute decompensated heart failure.
44. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for parenteral administration.
45. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is suitable for intravenous administration.
46. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is suitable for parenteral administration.
47. The pharmaceutical composition of claim 14 , wherein the pharmaceutical composition is suitable for intravenous administration.
48. A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and an aqueous buffer, wherein the N-hydroxysulfonamide type nitroxyl donor is a pharmaceutically acceptable salt of a compound of the formula (1)
and
wherein the composition has a pH of from about 5 to about 6.
49. A pharmaceutical composition comprising a N-hydroxysulfonamide type nitroxyl donor and a cyclodextrin, wherein the N-hydroxysulfonamide type nitroxyl donor is a pharmaceutically acceptable salt of a compound of the formula (1):