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 composition comprising 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,
wherein the composition is in the form of a dry powder.
2. The composition of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.
3. The composition of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
4. The composition of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
5. The composition of claim 1 , wherein R 2 is tetradecyl.
6. The composition of claim 1 , wherein R 2 is pentadecyl.
7. The composition of claim 1 , wherein R 2 is hexadecyl.
8. The composition of claim 7 , wherein R 2 is linear hexadecyl.
9. The composition of claim 4 , wherein R 2 is hexadecyl.
10. The composition of claim 9 , further comprising DSPE-PEG2000.
11. The composition of claim 9 , wherein R 2 is linear hexadecyl.
12. The composition of claim 1 , wherein R 2 is heptadecyl.
13. The composition of claim 1 , wherein R 2 is octadecyl.
14. The composition of claim 1 , further comprising a PEGylated lipid.
15. The composition of claim 14 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.
16. The composition of claim 14 , wherein the PEGylated lipid comprises PEG2000.
17. The composition of claim 14 , wherein the PEGylated lipid comprises PEG1000.
18. The composition of claim 14 , wherein the PEGylated lipid comprises cholesterol.
19. The composition of claim 14 , wherein the PEGylated lipid comprises a phospholipid.
20. The composition of claim 14 , wherein the PEGylated lipid comprises distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).
21. The composition of claim 14 , wherein the PEGylated lipid comprises distearoylphosphatidylethanolamine (DSPE).
22. The composition of claim 14 , wherein the PEGylated lipid is DSPE-PEG2000.
23. A method for treating pulmonary hypertension (PH) in a patient in need thereof, comprising, administering to the patient via pulmonary administration, a therapeutically effective amount of a composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof:
wherein R 1 is O; R 2 is linear tetradecyl, linear pentadecyl, linear hexadecyl, linear heptadecyl or linear octadecyl; and n is an integer from 0 to 5,
wherein the composition is in the form of a dry powder, and
wherein the pulmonary administration is carried out via a dry powder inhaler.
24. The method of claim 23 , wherein R 2 is linear hexadecyl, and n is 1.
25. The method of claim 23 , wherein the PH is pulmonary arterial hypertension (PAH).
26. The method of claim 24 , wherein the PH is pulmonary arterial hypertension (PAH).
27. The composition of claim 14 , wherein R 2 is linear hexadecyl and n is 1.
28. The composition of claim 16 , wherein R 2 is linear hexadecyl and n is 1.
29. The composition of claim 21 , wherein R 2 is linear hexadecyl and n is 1.
30. The composition of claim 22 , wherein R 2 is linear hexadecyl and n is 1.
31. The method of claim 26 , wherein the composition further comprises a PEGylated lipid.
32. The method of claim 31 , wherein the PEGylated lipid is DSPE-PEG2000.
33. The method of claim 31 , wherein the PEGylated lipid comprises a phospholipid.
34. The method of claim 33 , wherein the phospholipid is distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphoethanolamine (DMPE) or distearoyl glycerol (DSG).
35. The method of claim 33 , wherein the phospholipid is distearoylphosphatidylethanolamine (DSPE).
36. The method of claim 34 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.
37. The method of claim 35 , wherein the PEGylated lipid comprises PEG400, PEG500, PEG1000, PEG2000, PEG3000, PEG4000 or PEG5000.
38. The method of claim 34 , wherein the PEGylated lipid comprises PEG2000.
39. The method of claim 35 , wherein the PEGylated lipid comprises PEG2000.