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 hypertension (PH) associated with interstitial lung disease 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 O;
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 the patient is a WHO Group III PH patient.
3. The method of claim 1 , wherein R 2 is linear tetradecyl, linear pentadecyl, linear hexadecyl, linear heptadecyl or linear octadecyl.
4. The method of claim 1 , wherein n is 0 or 1.
5. The method of claim 1 , wherein n is O.
6. The method of claim 1 , wherein n is 1.
7. The method of claim 1 , wherein R 2 is hexadecyl, and n is 1.
8. The method of claim 2 , wherein R 2 is linear hexadecyl, and n is 1.
9. The method of claim 3 , wherein R 2 is linear hexadecyl, and n is 1.
10. The method of claim 1 , wherein the composition further comprises a PEGylated lipid.
11. The method of claim 8 , wherein the composition further comprises a PEGylated lipid.
12. The method of claim 9 , wherein the composition further comprises a PEGylated lipid.
13. The method of claim 10 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.
14. The method of claim 10 , wherein the PEGylated lipid comprises PEG2000.
15. The method of claim 10 , wherein the PEGylated lipid comprises cholesterol.
16. The method of claim 10 , wherein the PEGylated lipid comprises a phospholipid.
17. The method of claim 10 , wherein the PEGylated lipid comprises distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).
18. The method of claim 10 , wherein the PEGylated lipid comprises distearoylphosphatidylethanolamine (DSPE).
19. The method of claim 10 , wherein the PEGylated lipid is cholesterol-PEG2000, DSPE-PEG1000, DSPE-PEG2000, or DSG-PEG2000.
20. The method of claim 10 , wherein the PEGylated lipid is DSPE-PEG2000.
21. The method of claim 11 , wherein the PEGylated lipid is DSPE-PEG2000.
22. The method of claim 12 , wherein the PEGylated lipid is DSPE-PEG2000.
23. The method of claim 1 , wherein the pulmonary administration comprises administration via a metered dose inhaler, a dry powder inhaler, or a nebulizer.
24. The method of claim 1 , wherein the composition is administered once daily.
25. The method of claim 1 , wherein the composition is administered two or more times daily.
26. The method of claim 1 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.
27. The method of claim 7 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.
28. The method of claim 8 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.
29. The method of claim 9 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.
30. The method of claim 24 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.
31. The method of claim 25 , wherein the composition is in the form of a dry powder, and the pulmonary administration comprises administration via a dry powder inhaler.