Granted Patent
B2
US 12,201,725 · App. 18/360,514 · Granted Jan 21, 2025
Dry powder compositions of treprostinil prodrugs and methods of use thereof
Inventors:
Ju Du (Bridgewater, NJ); Adam Plaunt (Phillipsburg, NJ); Vladimir Malinin (Plainsboro, NJ)
Assignee:
Insmed Incorporated
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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 R 1 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, R 1 is hexadecyl, e.g., linear hexadecyl.
Claims (26)
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) DSPE-PEG2000 in a weight ratio of the DSPE-PEG2000 to the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof in a range of from about 0.1:1 DSPE-PEG2000: the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof to about 1:1 DSPE-PEG2000: the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, wherein the DSPE-PEG2000 is 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 (a) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
3. The dry powder composition of claim 2 , wherein (a) is a compound of Formula (I).
4. The dry powder composition of claim 1 , wherein R 1 is hexadecyl.
5. The dry powder composition of claim 4 , wherein R 1 is linear hexadecyl.
6. The dry powder composition of claim 1 , wherein the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is present at from about 0.5 wt % to about 2 wt % of the total weight of the dry powder composition.
7. The dry powder composition of claim 1 , wherein the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is present at from about 1 wt % to about 2 wt % of the total weight of the dry powder composition.
8. The dry powder composition of claim 1 , wherein the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is present at from about 1.2 wt % to about 1.8 wt % of the total weight of the dry powder composition.
9. The dry powder composition of claim 1 , wherein the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is present at from about 1.4 wt % to about 1.6 wt % of the total weight of the dry powder composition.
10. The dry powder composition of claim 1 , wherein the weight ratio of the DSPE-PEG2000 to the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is in a range of from about 0.3:1 DSPE-PEG2000: the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof to about 0.7:1 DSPE-PEG2000: the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.
11. The dry powder composition of claim 1 , wherein the weight ratio of the DSPE-PEG2000 to the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof is about 0.5:1 DSPE-PEG2000: the compound of Formula (I), or an enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof.
12. The dry powder composition of claim 1 , wherein the leucine is present at from about 15 wt % to about 40 wt % of the total weight of the dry powder composition.
13. The dry powder composition 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.
14. The dry powder composition of claim 13 , wherein the leucine is present at from about 20 wt % to about 30 wt % of the total weight of the dry powder composition.
15. The dry powder composition 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.
16. The dry powder composition of claim 1 , wherein the sugar is mannitol.
17. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is distearoylphosphatidylethanolamine-polyethylene glycol 2000.
18. The dry powder composition of claim 1 , wherein the DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000.
19. The dry powder composition of claim 3 , wherein R 1 is linear hexadecyl.
20. The dry powder composition of claim 19 , wherein the sugar is mannitol.
Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 22, 2024
From: DU, JU; PLAUNT, ADAM; MALININ, VLADIMIR
To: INSMED INCORPORATED
Reel/Frame 068373/0886 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jul 27, 2023
From: DU, JU; PLAUNT, ADAM; MALININ, VLADIMIR
To: INSMED INCORPORATED
Reel/Frame 064410/0482 →
Continuity (4)
Provisional Application
62840186
· Apr 29, 2019
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