Dry powder compositions of treprostinil prodrugs and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11759425-B2
Application number	US-202217893991-A
Country	US
Kind code	B2
Filing date	Aug 23, 2022
Priority date	Apr 29, 2019
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

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 method for treating pulmonary hypertension in a patient in need thereof, comprising administering an effective amount of a dry powder composition to the lungs of the patient by inhalation via a dry powder inhaler, wherein the dry powder composition consists of:
(a) from about 0.1 wt % to about 3 wt % of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R 1 is linear hexadecyl,
(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 method 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.

3. The method 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.

4. The method 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.

5. The method of claim 1 , wherein the DSPE-PEG2000 is distearoylphosphatidylethanolamine-polyethylene glycol 2000.

6. The method of claim 1 , wherein the DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000.

7. The method of claim 1 , wherein (a) is from about 0.1 wt % to about 3 wt % of treprostinil palmitil.

8. The method of claim 1 , wherein the sugar is mannitol.

9. The method of claim 8 , 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.

10. The method of claim 9 , 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.

11. The method of claim 10 , 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.

12. The method of claim 8 , 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.

13. The method of claim 12 , 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.

14. The method of claim 13 , 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.

15. The method of claim 9 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

16. The method of claim 10 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

17. The method of claim 11 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

18. The method of claim 12 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

19. The method of claim 13 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

20. The method of claim 14 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

21. The method of claim 9 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

22. The method of claim 10 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

23. The method of claim 11 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

24. The method of claim 12 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

25. The method of claim 13 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

26. The method of claim 14 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

27. The method of claim 1 , 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 Next Generation Impactor.

28. The method of claim 27 , wherein the aerosolized dry powder composition consists of particles with a fine particle fraction of from about 30% to about 60%, as measured by Next Generation Impactor.

29. The method of claim 1 , wherein the pulmonary hypertension is pulmonary arterial hypertension.

30. The method of claim 1 , wherein the pulmonary hypertension is idiopathic pulmonary arterial hypertension.

31. The method of claim 1 , wherein the pulmonary hypertension is associated with interstitial lung disease.

Assignees

• Insmed Inc

Inventors

• Du Ju
• Plaunt Adam
• Malinin Vladimir

Classifications

• A61K9/0075 Primary

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

• A61K9/1617 Primary

  Organic compounds, e.g. phospholipids, fats · 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

• A61P9/12

  Antihypertensives · CPC title