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 method of treating heart failure, comprising administering to a human patient a nitroxyl donor composition, said composition comprising a compound of the formula (1):
and a cyclodextrin.
2. The method of claim 1 , 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.
3. The method of claim 1 , wherein the molar ratio between the compound of formula (1) and the cyclodextrin present in the composition is from about 0.02:1 to about 2:1.
4. The method of claim 1 , wherein the molar ratio between the compound of formula (1) and the cyclodextrin present in the composition is from about 0.05:1 to about 1.5:1.
5. The method of claim 1 , wherein the molar ratio between the compound of formula (1) and the cyclodextrin present in the composition is from about 0.5:1 to about 1:1.
6. The method of claim 1 , wherein the composition is suitable for parenteral administration.
7. The method of claim 6 , wherein the composition is suitable for intravenous administration.
8. The method of claim 6 , wherein the composition is formulated at a pH of from about 4 to about 6.
9. The method of claim 6 , wherein the composition is formulated at a pH of from about 5 to about 6.
10. The method of claim 6 , wherein the composition is formulated at a pH of from about 5.5 to about 6.
11. The method of claim 1 , wherein the heart failure is acute decompensated heart failure.
12. A method of treating heart failure, comprising administering to a human patient a nitroxyl donor composition comprising a compound of the formula (1):
wherein said composition is administered parenterally at a pH of from about 5 to about 6.5.
13. The method of claim 12 , wherein the composition is administered intravenously.
14. The method of claim 12 , wherein the composition is administered at a pH of from about 5.5 to about 6.
15. The method of claim 12 , wherein the composition is administered at a pH of about 6.
16. The method of claim 12 , wherein the composition further comprises a stabilizing agent.
17. The method of claim 16 , wherein the stabilizing agent is a cyclodextrin.
18. The method of claim 17 , wherein the cyclodextrin is a β-cyclodextrin.
19. The method of claim 1 , 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 + .