Sustained release composition of prostacyclin

Patent metadata

Field	Value
Publication number	US-9872864-B2
Application number	US-201214238147-A
Country	US
Kind code	B2
Filing date	Aug 10, 2012
Priority date	Aug 12, 2011
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The present invention relates to sustained release compositions of prostacyclin, as well as uses thereof, in particular for the prevention and/or treatment of pulmonary arterial hypertension.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising:
a treprostinil carrier-linked prodrug; and
optionally one or more pharmaceutically acceptable excipients;
wherein the concentration of the treprostinil carrier-linked prodrug is sufficient to maintain a therapeutically effective level of treprostinil in blood plasma for at least 12 hours after a single subcutaneous or intramuscular injection; and
wherein the treprostinil carrier-linked prodrug comprises:
a treprostinil drug; and
a promoiety, which promoiety comprises:
a carrier;
a reversible prodrug linker moiety; and
optionally one or more spacer moieties;

wherein one end of the reversible prodrug linker moiety is attached to the treprostinil through a reversible linkage;
wherein another end of the reversible prodrug linker moiety is attached through a permanent bond to either a spacer moiety permanently attached to the carrier moiety, or is directly attached through a permanent bond to the carrier moiety; and
wherein the prodrug linker moiety is non-enzymatically hydrolytically degradable.

2. The pharmaceutical composition of claim 1 ;
wherein the pharmaceutical composition comprises the treprostinil carrier-linked prodrug in a concentration of at least 0.05 mg/ml.

3. The pharmaceutical composition of claim 2 ;
wherein a single dose of the pharmaceutical composition comprises at least 0.05 mg of the treprostinil carrier-linked prodrug.

4. The pharmaceutical composition of claim 1 ;
wherein the time period between administration of a pharmaceutical composition is at least about 12 hours.

5. The pharmaceutical composition of claim 1 ;
wherein the pharmaceutical composition has a pharmacokinetic profile in vivo in a mammal with substantially no burst of the treprostinil carrier-linked prodrug.

6. The pharmaceutical composition of claim 1 ;
wherein the pharmaceutical composition is characterized by exhibiting a peak to trough ratio of the in a mammal of less than 5.

7. The pharmaceutical composition of claim 1 ;
wherein the treprostinil carrier-linked prodrug has an activity of <20% of the activity of free treprostinil.

8. The pharmaceutical composition of claim 1 ;
wherein, after subcutaneous or intramuscular administration of said treprostinil carrier-linked prodrug, more than 50% of the administered treprostinil dose is releasable within the blood compartment.

9. The pharmaceutical composition of claim 1 ;
wherein the promoiety of the prodrug comprises a linear or branched PEG moiety.

10. The pharmaceutical composition of claim 1 ;
wherein the treprostinil carrier-linked prodrug has an activity of <5% of the activity of free treprostinil.

11. A method for treating pulmonary hypertension, wherein the method comprises the step of:
subcutaneous or intramuscular administration, to a patient with pulmonary hypertension, of pharmaceutical composition of claim 1 ;
wherein the pharmaceutical composition releases therapeutically effective amounts of free treprostinil compound for a period of time of at least 12 hours.

12. The method of claim 11 ;
wherein the pharmaceutical composition of (b) comprises from about 0.05 to about 10 weight percent the treprostinil carrier-linked prodrug and from about 0.5 to about 20 weight percent total polymer content.

13. The pharmaceutical composition of claim 1 ;
wherein the pharmaceutical composition is characterized by exhibiting a peak to trough ratio of the treprostinil carrier-linked prodrug in a mammal of less than 2.

Assignees

• Sprogøe Kennett
• Rau Harald
• Hersel Ulrich
• Wegge Thomas
• Keil Oliver
• Zettler Joachim
• Ascendis Pharma As

Inventors

• Sprogøe Kennett
• Rau Harald
• Hersel Ulrich
• Wegge Thomas
• Keil Oliver
• Zettler Joachim

Classifications

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title