Pharmaceutical formulations of treprostinil prodrugs and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2024238309-A1
Application number	US-202117907179-A
Country	US
Kind code	A1
Filing date	Mar 25, 2021
Priority date	Mar 25, 2020
Publication date	Jul 18, 2024
Grant date	—

Abstract

The present disclosure provides pharmaceutical formulations of treprostinil prodrugs and methods for their preparation and use. In and use in treating pulmonary hypertension (e.g., pulmonary arterial hypertension), portopulmonary hypertension, and pulmonary fibrosis by inhalation via a metered dose inhaler. The formulations can include (a) a treprostinil prodrug, e.g., a treprostinil alkyl ester or amide, (b) polyoxyethylene (20) cetylether or at least one polyethylene glycol-lipid (PEGylated lipid), (c) at least one surfactant selected from the group consisting of polyethylene glycol (PEG) and propylene glycol, (d) at least one hydrofluoroalkane propellant, and (e) at least one alcohol cosolvent.

First claim

1 . A pharmaceutical formulation comprising:
(a) a compound of Formula (Ia):

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein R 1 is O; R 2 is dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl; and n is an integer from 0 to 5;
(b) polyoxyethylene (20) cetylether or at least one polyethylene glycol-lipid (PEGylated lipid);
(c) a surfactant selected from polyethylene glycol (PEG), propylene glycol, or a combination thereof,
(d) at least one hydrofluoroalkane propellant, and
(e) at least one alcohol cosolvent.

2 . The pharmaceutical formulation of claim 1 , wherein (a) is a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof.

3 . The pharmaceutical formulation of claim 1 or 2 , wherein n is 0 or 1.

4 . The pharmaceutical formulation of claim 1 or 2 , wherein n is 0.

5 . The pharmaceutical formulation of claim 1 or 2 , wherein n is 1.

6 . A pharmaceutical formulation comprising:
(a) a compound of Formula (Ib):

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, wherein n is O, R 1 is NH or O and R 2 is a linear C 5 -C 18 alkyl,
(b) polyoxyethylene (20) cetylether or at least one polyethylene glycol-lipid (PEGylated lipid),
(c) a surfactant selected from PEG, propylene glycol, or a combination thereof,
(d) at least one hydrofluoroalkane propellant, and
(e) at least one alcohol cosolvent.

7 . The pharmaceutical formulation of claim 6 , wherein (a) is a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof.

8 . The pharmaceutical formulation of claim 6 or 7 , wherein R 1 is NH.

9 . The pharmaceutical formulation of claim 6 or 7 , wherein R 1 is O.

10 . The pharmaceutical formulation of any one of claims 6-9 , wherein R 2 is linear heptyl, linear octyl, linear nonyl, linear decyl, linear undecyl, linear dodecyl, linear tridecyl, linear tetradecyl, linear pentadecyl, linear hexadecyl, linear heptadecyl or linear octadectyl.

11 . The pharmaceutical formulation of any one of claims 1-10 , wherein the compound of Formula (Ia) or (Ib), or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof, is present at a concentration of from about 0.5 to about 3 mg/mL.

12 . The pharmaceutical formulation of claim 11 , wherein the compound of Formula (Ia) or (Ib), or pharmaceutically acceptable salt thereof is present at a concentration of from about 0.5 to about 3 mg/mL.

13 . The pharmaceutical formulation of any one of claims 1-12 , wherein the polyoxyethylene (20) cetylether is present at a concentration of from about 0.25 to about 0.75 mg/mL.

14 . The pharmaceutical formulation of any one of claims 1-13 , wherein the polyoxyethylene (20) cetylether is present at a concentration of about 0.5 mg/mL.

15 . The pharmaceutical formulation of any one of claims 1-14 , wherein the at least one PEGylated lipid is one PEGylated lipid.

16 . The pharmaceutical formulation of claim 15 , wherein the at least one PEGylated lipid is one PEGylated lipid selected from the group consisting of DSPE (distearoylphosphatidylethanolamine)-PEG2000, DSG (disteraroylglycerol)-PEG2000, and DPG (diphosphatidylglycerol)-PEG2000.

17 . The pharmaceutical formulation of any one of claims 1-14 , wherein the at least one PEGylated lipid consists of a double or triple combination of DSPE-PEG2000, DSG-PEG2000, and DPG-PEG2000.

18 . The pharmaceutical formulation of any one of claims 1-17 , wherein the at least one PEGylated lipid is present at a concentration of from about 0.2 to about 3 mg/mL.

19 . The pharmaceutical formulation of any one of claims 1-18 , wherein the surfactant is one surfactant selected from the group consisting of PEG400, PEG1000, and propylene glycol.

20 . The pharmaceutical formulation of any one of claims 1-18 , wherein the surfactant consists of a double or triple combination of PEG400, PEG1000, and propylene glycol.

21 . The pharmaceutical formulation of any one of claims 1-20 , wherein the surfactant is present at a concentration of from about 0.75 to about 6 mg/mL.

22 . The pharmaceutical formulation of any one of claims 1-21 , wherein the at least one hydrofluoroalkane propellant is one hydrofluoroalkane propellant.

23 . The pharmaceutical formulation of claim 22 , wherein the at least one hydrofluoroalkane propellant is one hydrofluoroalkane propellant selected from the group consisting of 1,1,1,2-tetrafluoroethane (HFA134a), 1,1,1,2,3,3,3-heptafluoro-n-propane (HFA227ea), and 1,1-difluoroethane (FA152a).

24 . The pharmaceutical formulation of any one of claims 1-21 , wherein the at least one hydrofluoroalkane propellant consists of a double or triple combination of HFA134a, HFA227ea, and HFA152a.

25 . The pharmaceutical formulation of any one of claims 1-24 , wherein the at least one alcohol cosolvent is one alcohol cosolvent.

26 . The pharmaceutical formulation of claim 25 , wherein the at least one alcohol cosolvent is one alcohol cosolvent selected from the group consisting of ethanol and isopropyl alcohol.

27 . The pharmaceutical formulation of any one of claims 1-24 , wherein the at least one alcohol cosolvent is a combination of ethanol and isopropyl alcohol.

28 . The pharmaceutical formulation of any one of claims 1-27 , wherein the at least one alcohol cosolvent is present at a concentration of from about 3% to about 10% (w/w) based on the total weight of the pharmaceutical formulation.

29 . A pharmaceutical formulation comprising:
(a) a compound of Formula (II):

or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof at a concentration of from about 0.5 to about 3 mg/mL, wherein R 2 is dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, or octadecyl,
(b) polyoxyethylene (20) cetylether at a concentration of from about 0.25 to about 0.75 mg/mL, or at least one PEGylated lipid selected from the group consisting of DSPE-PEG2000, DSG-PEG2000, and DPG-PEG2000 at a concentration of from about 0.2 to about 3 mg/mL,
(c) a surfactant selected from PEG400, PEG1000, propylene glycol, or a combination thereof at a concentration of from about 0.75 to about 6 mg/mL,
(d) at least one hydrofluoroalkane propellant selected from the group consisting of HFA134a, HFA227ea, and HFA152a, and
(e) at least one alcohol cosolvent selected from the group consisting of ethanol and isopropyl alcohol at a concentration of from about 3% to about 10% (w/w) based on the total weight of the pharmaceutical formulation.

30 . The pharmaceutical formulation of claim 29 , wherein (a) is a compound of Formula (II) or a pharmaceutically acceptable salt thereof.

31 . The pharmaceutical formulation of claim 29 or 30 , wherein the polyoxyethylene (20) cetylether is present at a concentration of about 0.5 mg/mL.

32 . A pharmaceutical formulation consisting of
(a) a comp

Assignees

• Insmed Inc

Inventors

• Malinin Vladimir
• Plaunt Adam

Classifications

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K9/008

  comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI] · CPC title

• A61K9/0078

  for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions · CPC title

• A61K31/5575 Primary

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

• A61K31/23 Primary

  of acids having a carboxyl group bound to a chain of seven or more carbon atoms · CPC title