Dry powder compositions of treprostinil prodrugs and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2025177306-A1
Application number	US-202418974779-A
Country	US
Kind code	A1
Filing date	Dec 9, 2024
Priority date	Apr 29, 2019
Publication date	Jun 5, 2025
Grant date	—

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.

First claim

1 - 131 . (canceled)

132 . 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 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 %.

133 . The method of claim 132 , wherein (a) is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

134 . The method of claim 133 , wherein (a) is a compound of Formula (I).

135 . The method of claim 132 , wherein R 1 is hexadecyl.

136 . The method of claim 135 , wherein R 1 is linear hexadecyl.

137 . The method of claim 132 , 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.

138 . The method of claim 132 , 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.

139 . The method of claim 132 , 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.

140 . The method of claim 132 , 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.

141 . The method of claim 132 , wherein the leucine is present at from about 18 wt % to about 33 wt % of the total weight of the dry powder composition.

142 . The method of claim 132 , wherein the leucine is present at from about 25 wt % to about 30 wt % of the total weight of the dry powder composition.

143 . The method of claim 132 , wherein the sugar is mannitol.

144 . The method of claim 132 , wherein the DSPE-PEG2000 is distearoylphosphatidylethanolamine-polyethylene glycol 2000.

145 . The method of claim 132 , wherein the DSPE-PEG2000 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000.

146 . The method of claim 134 , wherein R 1 is linear hexadecyl.

147 . The method of claim 146 , wherein the sugar is mannitol.

148 . The method of claim 132 , wherein the pulmonary hypertension is pulmonary arterial hypertension.

149 . The method of claim 147 , wherein the pulmonary hypertension is pulmonary arterial hypertension.

150 . The method of claim 132 , wherein the pulmonary hypertension is associated with interstitial lung disease.

151 . The method of claim 147 , wherein the pulmonary hypertension is associated with interstitial lung disease.

Assignees

• Insmed Inc

Inventors

• Du Ju
• Plaunt Adam
• Malinin Vladimir

Classifications

• A61K31/216

  of acids having aromatic rings, e.g. benactizyne, clofibrate · CPC title

• A61K31/198

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• A61K9/145

  with organic compounds · CPC title

• A61P9/12

  Antihypertensives · 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