# US 9,872,864 B2 · Sustained release composition of prostacyclin

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- Number: US 9,872,864 B2
- Document ID: US9872864B2
- Status: Granted
- Kind: B2
- Application number: 14/238,147
- Filed: 2012-08-10
- Published: 2014-10-09
- Granted: 2018-01-23
- Earliest claimed: 2011-08-12
- Assignees: Ascendis Pharma A/S
- Applicants: Kennett Sprogøe; Harald Rau; Ulrich Hersel; Thomas Wegge; Oliver Keil; Joachim Zettler
- Inventors: Kennett Sprogøe; Harald Rau; Ulrich Hersel; Thomas Wegge; Oliver Keil; Joachim Zettler
- Web page: https://patentgrep.com/patent/US9872864B2

## CPC

- A61K 31/5585: having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
- A61K 31/557: Eicosanoids, e.g. leukotrienes {or prostaglandins}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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.

### Claim 6 (depends on 1)

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.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 1)

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

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 1)

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.