# US 10,441,639 B2 · Pharmaceutical composition comprising plasminogen and uses thereof

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- Number: US 10,441,639 B2
- Document ID: US10441639B2
- Status: Granted
- Kind: B2
- Application number: 15/536,877
- Filed: 2015-12-18
- Published: 2017-12-21
- Granted: 2019-10-15
- Earliest claimed: 2014-12-19
- Assignees: Prometic Biotherapeutics, Inc.
- Applicants: Prometic Biotherapeutics, Inc.
- Inventors: Davida Blackman; Stacy Plum; William Garzon-Rodriguez; Martin Robitaille; Betty Yu
- Web page: https://patentgrep.com/patent/US10441639B2

## CPC

- A61K 38/484: {Plasmin (3.4.21.7)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- C12N 9/6435: {Plasmin (3.4.21.7), i.e. fibrinolysin}
- C12Y 304/21007: Plasmin (3.4.21.7), i.e. fibrinolysin
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Pharmaceutical compositions comprising plasminogen or a biologically active variant thereof are disclosed. In an embodiment, the composition comprises a tonicity modifier, a bulking agent, and a stabilizing agent and has a pH of about 3.0 to about 10.0. In another embodiment, the composition contains an amount of particles in suspension equal to or greater than 10 μm which is lower than 6000 particles per 100 ml, and preferably lower than 2000 particles per 100 ml. Uses of these compositions as a medicament is contemplated. Various therapeutic uses of these pharmaceutical compositions is also contemplated.

## Claims

### Claim 1

A pharmaceutical composition comprising:
plasminogen, in a concentration from 0.01 mg/ml to 80 mg/ml;
a tonicity modifier, which contains sodium, wherein the tonicity modifier is in a concentration adjusted to reach an osmolality of the composition between 180 mOsm and 350 mOsm; and
a stabilizing agent, which is arginine or glycine, in a concentration from 20 mM to 200 mM;
wherein the composition has a pH of 3.0 to 10.0, and
wherein (a) the plasminogen represents at least 80% of the total protein content of the composition;
(b) the composition further comprises a non-reducing sugar, which is sucrose;
(c) the plasminogen is constituted of more than 80% of Glu-plasminogen; or
(d) the composition contains an amount of particles equal to or greater than 10 μm that is lower than 6000 particles per container, when the container has a nominal content of less than or equal to 100 ml.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pH is from 5.0 to 8.0.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the concentration of plasminogen is from 5 mg/ml to 60 mg/ml.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein plasminogen represents at least 80% of the total protein content of the composition.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the stabilising agent is arginine.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the stabilising agent is glycine.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, wherein the stabilising agent is in a concentration of 25 mM to 75 mM.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tonicity modifier is sodium chloride.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tonicity modifier is present in a concentration of 30 mM to 250 mM.

### Claim 10 (depends on 1)

The pharmaceutical composition of claim 1, wherein the tonicity modifier is present in a concentration of from 30 mM to 100 mM.

### Claim 11 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a non-reducing sugar, which is sucrose.

### Claim 12 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition is substantially free of aprotinin.

### Claim 13 (depends on 1)

The pharmaceutical composition of claim 1, wherein said plasminogen is constituted of more than 80% of Glu-plasminogen.

### Claim 14 (depends on 1)

The pharmaceutical composition of claim 1, wherein said plasminogen is Glu-plasminogen.

### Claim 15 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition contains an amount of particles equal to or greater than 10 μm that is lower than 6000 particles per container, when the container has a nominal content of less than or equal to 100 ml.

### Claim 16 (depends on 1)

The pharmaceutical composition of claim 1, which is suitable for intravenous, subcutaneous, topical, intradermal, ophthalmic and/or intramuscular administration.

### Claim 17 (depends on 1)

The pharmaceutical composition of claim 1, which is a liquid composition, a liquid composition suitable for lyophilisation, a liquid composition suitable for freezing, a lyophilised composition, a frozen composition or a reconstituted composition.

### Claim 18

A pharmaceutical composition comprising plasminogen, which contains an amount of particles equal to or greater than 10 μm that is lower than 6000 particles per container, when the container has a nominal content of less than or equal to 100 ml, which comprises a stabilising agent that is arginine or glycine.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, wherein the stabilising agent is arginine.

### Claim 20 (depends on 18)

The pharmaceutical composition of claim 18, wherein the stabilising agent is glycine.

### Claim 21 (depends on 18)

The pharmaceutical composition of claim 18, wherein the stabilising agent is in a concentration from 20 mM to 200 mM.

### Claim 22 (depends on 18)

The pharmaceutical composition of claim 18, further comprising a non-reducing sugar, which is sucrose.

### Claim 23 (depends on 18)

The pharmaceutical composition of claim 18, wherein the concentration of plasminogen is from 0.01 mg/ml to 80 mg/ml.

### Claim 24 (depends on 18)

The pharmaceutical composition of claim 18, wherein plasminogen represents more than 95% of the total protein content of the composition.

### Claim 25 (depends on 18)

The pharmaceutical composition of claim 18, which further comprises a tonicity modifier, which contains sodium.

### Claim 26 (depends on 25)

The pharmaceutical composition of claim 25, wherein the tonicity modifier is sodium chloride.

### Claim 27 (depends on 25)

The pharmaceutical composition of claim 25, wherein the tonicity modifier is in a concentration adjusted to reach an osmolality of the pharmaceutical composition between 180 mOsm and 350 mOsm.

### Claim 28 (depends on 25)

The pharmaceutical composition of claim 25, wherein the tonicity modifier is present in a concentration of 30 mM to 250 mM.

### Claim 29 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition has an osmolality between 180 mOsm and 350 mOsm.

### Claim 30 (depends on 18)

The pharmaceutical composition of claim 18, wherein the pharmaceutical composition has a pH of 5.0 to 8.0.

### Claim 31 (depends on 18)

The pharmaceutical composition of claim 18, wherein the composition is substantially free of aprotinin.

### Claim 32 (depends on 18)

The pharmaceutical composition of claim 18, wherein said plasminogen consists of more than 80% of Glu-plasminogen.

### Claim 33 (depends on 18)

The pharmaceutical composition of claim 18, wherein said plasminogen is Glu-plasminogen.

### Claim 34 (depends on 18)

The pharmaceutical composition of claim 18, which is suitable for intravenous, subcutaneous, topical, intradermal, ophthalmic and/or intramuscular administration.

### Claim 35 (depends on 18)

The pharmaceutical composition of claim 18, which is a liquid composition, a liquid composition suitable for lyophilisation, a liquid composition suitable for freezing, a lyophilised composition, a frozen composition or a reconstituted composition.

### Claim 36

A pharmaceutical composition having a pH of 6.0 to 8.0 comprising:
i) from 2 mg/ml to 20 mg/ml of Glu-plasminogen;
ii) from 30 mM to 100 mM of sodium chloride;
iii) from 10 mM to 100 mM of glycine;
iv) from 50 mM to 150 mM of sucrose; and
v) from 2 mM to 30 mM of a citrate buffer.

### Claim 37 (depends on 36)

The pharmaceutical composition of claim 36, wherein said composition has a pH of 6.0 to 7.0 and comprises:
i) from 5 mg/ml to 20 mg/ml of Glu-plasminogen;
ii) from 35 mM to 75 mM of sodium chloride;
iii) from 25 mM to 75 mM of glycine;
iv) from 54 mM to 108 mM of sucrose; and
v) 10 mM of sodium citrate buffer.

### Claim 38 (depends on 1)

The pharmaceutical composition of claim 1, wherein the composition comprises any combination of at least two of (a)-(d).