Prostacyclin compounds, compositions and methods of use thereof
Prostacyclin compounds and compositions comprising the same are provided herein. Specifically, prostacyclin compounds comprising treprostinil covalently linked to a linear C 5 -C 18 alkyl, branched C 5 -C 18 alkyl, linear C 2 -C 18 alkenyl, branched C 3 -C 18 alkenyl, aryl, aryl-C 1 -C 18 alkyl or an amino acid or a peptide (e.g., dipeptide, tripeptide, tetrapeptide) are described. The linkage, in one embodiment, is via a carbamate, amide or ester bond. Prostacyclin compounds provided herein can also include at least one hydrogen atom substituted with at least one deuterium atom. Methods for treating pulmonary hypertension (e.g., pulmonary arterial hypertension) and portopulmonary hypertension are also provided.
1. A method of treating pulmonary fibrosis in a patient in need thereof comprising administering to the patient via pulmonary administration, a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof,
wherein R 1 is 0;
R 2 is tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl and
n is an integer from 0 to 5.
2. The method of claim 1 , wherein pulmonary administration comprises administration via a metered dose inhaler, a dry powder inhaler or a nebulizer.
3. The method of claim 1 , wherein the effective amount of the compound of Formula (II), or the pharmaceutically acceptable salt thereof, is administered once daily.
4. The method of claim 1 , wherein the effective amount of the compound of Formula (II), or the pharmaceutically acceptable salt thereof, is administered two or more times daily.
5. The method of claim 1 , wherein n is 1.
6. The method of claim 1 , wherein R 2 is hexadecyl.
7. The method of claim 6 , wherein n is 1.
8. The method of claim 1 , wherein n is 1, R 2 is hexadecyl and pulmonary administration comprises administration via a nebulizer.
9. The method of claim 8 , wherein the nebulizer is a vibrating mesh nebulizer.
10. The method of claim 1 , wherein n is 1, R 2 is hexadecyl and pulmonary administration comprises administration via a dry powder inhaler.
11. The method of claim 1 , wherein the composition comprises a lipid-polyethylene glycol (PEG) conjugate.
12. The method of claim 11 , wherein the PEG is PEG-400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG5000.
13. The method of claim 11 , wherein the PEG is PEG2000.
14. The method of claim 11 , wherein the lipid is cholesterol.
15. The method of claim 11 , wherein the lipid is a phospholipid.
16. The method of claim 11 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanol amine (DMPE) or distearoyl glycerol (DSG).
17. The method of claim 11 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG1000, DSPE-PEG2000 or DSG-PEG2000.
18. The method of claim 11 , wherein the lipid-PEG conjugate is DSPE-PEG2000.
19. The method of claim 10 , wherein the composition comprises a lipid-polyethylene glycol (PEG) conjugate.
20. The method of claim 19 , wherein the PEG is PEG-400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG5000.
21. The method of claim 19 , wherein the PEG is PEG2000.
22. The method of claim 19 , wherein the lipid is cholesterol.
23. The method of claim 19 , wherein the lipid is a phospholipid.
24. The method of claim 23 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanol amine (DMPE) or distearoyl glycerol (DSG).
25. The method of claim 19 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG1000, DSPE-PEG2000 or DSG-PEG2000.
26. The method of claim 19 , wherein the lipid-PEG conjugate is DSPE-PEG2000.
27. The method of claim 1 , wherein the composition comprises a hydrophobic additive.
28. The method of claim 27 , wherein the hydrophobic additive is a hydrocarbon, a terpene or a hydrophobic lipid, alkyl ester, cholesteryl ester or an alkyl-glyceride.
29. The method of claim 27 , wherein the hydrophobic additive is a terpene.
30. The method of claim 29 , wherein the terpene is squalane.
31. The method of claim 27 , wherein the composition comprises a lipid-polyethylene glycol (PEG) conjugate.
32. The method of claim 31 , wherein the PEG is PEG400, PEG500, PEG 1000, PEG2000, PEG3000, PEG4000 or PEG-5000.
33. The method of claim 32 , wherein the PEG is PEG-2000.
34. The method of claim 31 , wherein the lipid is cholesterol.
35. The method of claim 31 , wherein the lipid is a phospholipid.
36. The method of claim 35 , wherein the lipid is distearoyl phosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).
37. The method of claim 31 , wherein the lipid-PEG conjugate is cholesterol-PEG2000, DSPE-PEG 1000, DSPE-PEG2000 or DSG-PEG2000.
38. The method of claim 31 , wherein the lipid-PEG conjugate is DSPE-PEG2000.
39. The method of claim 31 , wherein the hydrophobic additive is a terpene.
40. The method of claim 39 , wherein the terpene is squalane.
41. The method of claim 40 , wherein the lipid-PEG conjugate is DSPE-PEG2000.