Dry powder compositions of treprostinil prodrugs and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11458098-B2
Application number	US-202016860428-A
Country	US
Kind code	B2
Filing date	Apr 28, 2020
Priority date	Apr 29, 2019
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

Abstract

The present disclosure provides a dry powder composition of treprostinil prodrugs and a method of treating pulmonary hypertension (e.g., pulmonary arterial hypertension), portopulmonary hypertension, or pulmonary fibrosis in a patient in need thereof. The dry powder composition includes (a) from about 0.1 wt % to about 3 wt % of a compound of Formula (I):or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, (b) from about 0.01 wt % to about 3 wt % of DSPE-PEG2000, (c) from about 10 wt % to about 50 wt % of leucine, and the balance being (d) a sugar selected from the group consisting of trehalose and mannitol. The entirety of (a), (b), (c), and (d) is 100 wt %, and R1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl. The method includes administering an effective amount of the dry powder composition to the lungs of the patient by inhalation via a dry powder inhaler. In certain compositions and methods provided herein, R1 is hexadecyl, e.g., linear hexadecyl.

First claim

The invention claimed is:

1. A dry powder composition consisting of:
(a) from about 0.1 wt % to about 3 wt % of a compound of Formula (I):

or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl,
(b) from about 0.01 wt % to about 3 wt % of DSPE-PEG2000 selected from the group consisting of distearoylphosphatidylethanolamine-polyethylene glycol 2000 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000,
(c) from about 10 wt % to about 50 wt % of leucine, and
the balance being (d) a sugar selected from the group consisting of trehalose and mannitol,
wherein the entirety of (a), (b), (c), and (d) is 100 wt %.

2. The dry powder composition of claim 1 , wherein R 1 is hexadecyl.

3. The dry powder composition of claim 2 , wherein R 1 is linear hexadecyl.

4. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is present at from about 0.03 wt % to about 2.1 wt % of the total weight of the dry powder composition.

5. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is present at from about 0.05 wt % to about 1.5 wt % of the total weight of the dry powder composition.

6. The dry powder composition of claim 1 , consisting of (a) about 1.5 wt % of the compound of Formula (I), (b) about 0.75 wt % of the DSPE-PEG2000, (c) about 29.30 wt % of the leucine, and (d) about 68.45 wt % of the mannitol, wherein R 1 is linear hexadecyl.

7. A method for treating pulmonary hypertension in a patient in need thereof, comprising administering an effective amount of the dry powder composition of claim 1 to the lungs of the patient by inhalation via a dry powder inhaler.

8. The method of claim 7 , wherein the pulmonary hypertension is pulmonary arterial hypertension.

9. The method of claim 8 , wherein the pulmonary arterial hypertension is class I pulmonary arterial hypertension, as characterized by the New York Heart Association (NYHA).

10. The method of claim 8 , wherein the pulmonary arterial hypertension is class II pulmonary arterial hypertension, as characterized by the NYHA.

11. The method of claim 8 , wherein the pulmonary arterial hypertension is class III pulmonary arterial hypertension, as characterized by the NYHA.

12. The method of claim 8 , wherein the pulmonary arterial hypertension is class IV pulmonary arterial hypertension, as characterized by the NYHA.

13. The method of claim 7 , wherein the pulmonary hypertension is group 1 pulmonary hypertension, as characterized by the World Health Organization (WHO).

14. The method of claim 7 , wherein the pulmonary hypertension is group 2 pulmonary hypertension, as characterized by the WHO.

15. The method of claim 7 , wherein the pulmonary hypertension is group 3 pulmonary hypertension, as characterized by the WHO.

16. The method of claim 7 , wherein the pulmonary hypertension is group 4 pulmonary hypertension, as characterized by the WHO.

17. The method of claim 7 , wherein the pulmonary hypertension is group 5 pulmonary hypertension, as characterized by the WHO.

18. The method of claim 7 , wherein the administering comprises aerosolizing the dry powder composition and administering an aerosolized dry powder composition to the lungs of the patient via inhalation, wherein the aerosolized dry powder composition consists of particles with an MMAD of from about 1 μm to about 3 μm, as measured by NGI.

19. The method of claim 18 , wherein the aerosolized dry powder composition consists of particles with a fine particle fraction of from about 30% to about 60%, as measured by NGI.

20. A system for treating pulmonary hypertension, portopulmonary hypertension, or pulmonary fibrosis, consisting of:
the dry powder composition of claim 1 , and
a dry powder inhaler (DPI).

21. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is distearoylphosphatidylethanolamine-polyethylene glycol 2000.

22. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000.

23. The dry powder composition of claim 1 , wherein (a) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

24. The dry powder composition of claim 1 , wherein (a) is a compound of Formula (I).

25. The dry powder composition of claim 24 , wherein R 1 is linear hexadecyl.

26. The dry powder composition of claim 25 , wherein the sugar is mannitol.

27. The dry powder composition of claim 26 , wherein the compound of Formula (I) is present at from about 1 wt % to about 2 wt % of the total weight of the dry powder composition, and the DSPE-PEG2000 is present at from about 0.1 wt % to about 2 wt % of the total weight of the dry powder composition.

28. The dry powder composition of claim 27 , wherein the DSPE-PEG2000 is present at from about 0.3 wt % to about 1.4 wt % of the total weight of the dry powder composition.

29. The dry powder composition of claim 28 , wherein the DSPE-PEG2000 is present at from about 0.5 wt % to about 1 wt % of the total weight of the dry powder composition.

30. The dry powder composition of claim 26 , wherein the compound of Formula (I) is present at from about 1.4 wt % to about 1.6 wt % of the total weight of the dry powder composition, and the DSPE-PEG2000 is present at from about 0.14 wt % to about 1.6 wt % of the total weight of the dry powder composition.

31. The dry powder composition of claim 30 , wherein the DSPE-PEG2000 is present at from about 0.42 wt % to about 1.12 wt % of the total weight of the dry powder composition.

32. The dry powder composition of claim 31 , the DSPE-PEG2000 is present at from about 0.7 wt % to about 0.8 wt % of the total weight of the dry powder composition.

33. The dry powder composition of claim 27 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

34. The dry powder composition of claim 28 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

35. The dry powder composition of claim 29 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

36. The dry powder composition of claim 30 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

37. The dry powder composition of claim 31 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

38. The dry powder composition of claim 32 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

39. The dry powder composition of claim 27 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

40. The dry powder composition of claim 28 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the

Assignees

• Insmed Inc

Inventors

• Du Ju
• Plaunt Adam
• Malinin Vladimir

Classifications

• A61K31/5575

  having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha · CPC title

• A61K9/0075 Primary

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61K9/146 Primary

  with organic macromolecular compounds · CPC title

• A61K9/1623

  Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules · CPC title