# US 2010/0166730 A1 · Liquid, Aqueous Pharmaceutical Composition of Factor VII Polypeptides

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- Number: US 2010/0166730 A1
- Document ID: US20100166730A1
- Status: Published application
- Kind: A1
- Application number: 12/536,872
- Filed: 2009-08-06
- Published: 2010-07-01
- Earliest claimed: 2003-07-01
- Assignees: Novo Nordisk Health Care A/G
- Inventors: Michael Bech Jensen; Birthe Lykkegaard Hansen; Troels Kornfelt; Kristen Kramer Jacobsen
- Web page: https://patentgrep.com/patent/US20100166730A1

## CPC

- A61K 33/24: Heavy metals; Compounds thereof
- 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 33/26: Iron; Compounds thereof
- A61K 33/32: Manganese; Compounds thereof
- A61K 33/34: Copper; Compounds thereof
- A61K 38/4846: {Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- A61K 47/20: containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- 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 is directed to liquid, aqueous pharmaceutical compositions containing Factor VII polypeptides, and methods for preparing and using such compositions, as well as vials containing such compositions, and the use of such compositions in the treatment of a Factor VII-responsive syndrome, e.g., bleeding disorders, including those caused by clotting Factor deficiencies (e.g. haemophilia A, haemophilia B, coagulation Factor VII deficiency); by thrombocytopenia or von Willebrand's disease, or by clotting Factor inhibitors, and intra cerebral haemorrhage, or excessive bleeding from any cause. The preparations may also be administered to patients in association with surgery or other trauma or to patients receiving anticoagulant therapy. More particularly, the invention relates to liquid compositions stabilised against chemical and/or physical degradation. The main embodiment is represented by a liquid, aqueous pharmaceutical composition comprising a Factor VII polypeptide (i); a buffering agent (ii) suitable for keeping pH in the range of from about 4.0 to about 9.0; at least one metal-containing agent (iii), wherein said metal is selected from the group consisting of first transition series metals of oxidation state +II, except zinc, such as chromium, manganese, iron, cobalt, nickel, and copper; and a non-ionic surfactant (iv).

## Claims

### Claim 1

A liquid, aqueous pharmaceutical composition comprising
(i) a Factor VII polypeptide;
(ii) a buffering agent suitable for keeping pH in the range of from about 4.0 to about 9.0;
(iii) at least one metal-containing agent, wherein said metal is a first transition series metal of oxidation state +II other than zinc; and
(iv) a non-ionic surfactant.

### Claim 2 (depends on 1)

The composition according to claim 1, wherein the metal of the metal-containing agent is selected from the group consisting of chromium, manganese, iron, cobalt, nickel, and copper.

### Claim 3 (depends on 1)

The composition according to claim 1, wherein the metal-containing agent (iii) is at least one selected from the group consisting of chromium(II) chloride, manganese(II) chloride, iron(II) chloride, cobalt(II) chloride, nickel(II) chloride, and copper(II) chloride.

### Claim 4 (depends on 1)

The composition according to claim 1, wherein the concentration of the metal-containing agent (iii) is at least 1 μM.

### Claim 5 (depends on 1)

The composition according to claim 1, wherein the metal of the metal-containing agent (iii) is copper and the concentration of said agent is at least 5 μM.

### Claim 6 (depends on 1)

The composition according to claim 1, wherein the metal of the metal-containing agent (iii) is manganese and the concentration of said agent is at least 100 μM.

### Claim 7 (depends on 1)

The composition according to claim 1, wherein the Factor VII polypeptide is human Factor VIIa.

### Claim 8 (depends on 1)

The composition according to claim 1, wherein the Factor VII polypeptide is a Factor VII sequence variant.

### Claim 9 (depends on 1)

The composition according to claim 1, wherein the Factor VII polypeptide is present in a concentration of 0.1-15 mg/mL.

### Claim 10 (depends on 1)

The composition according to claim 1, which has a pH in the range of from about 4.0 to about 8.0.

### Claim 11 (depends on 1)

The composition according to claim 1, wherein the buffering agent (ii) comprises at least one component selected from the group consisting of acids and salts of MES, PIPES, ACES, BES, TES, HEPES, TRIS, glycinamide, phosphoric acid, acetic acid, lactic acid, and succinic acid.

### Claim 12 (depends on 1)

The composition according to claim 1, wherein the concentration of the buffering agent (ii) is 1-100 mM.

### Claim 13 (depends on 1)

The composition according to claim 1, wherein the non-ionic surfactant (iv) is at least one selected from the group consisting of polysorbates, poloxamers, polyoxyethylene alkyl ethers, ethylene/polypropylene block co-polymers, polyethyleneglycol (PEG), polyxyethylene stearates, and polyoxyethylene castor oils.

### Claim 14 (depends on 1)

The composition according to claim 1, further comprising a tonicity modifying agent (v).

### Claim 15 (depends on 14)

The composition according to claim 14, wherein the tonicity modifying agent (v) is at least one selected from the group consisting of neutral salts, amino acids, peptides of 2-5 amino acid residues, monosaccharides, disaccharides, polysaccharides, and sugar alcohols.

### Claim 16 (depends on 15)

The composition according to claim 15, wherein at least one tonicity modifying agent (v) is a neutral salt selected from the group consisting of sodium salts, potassium salts, calcium salts, and magnesium salts.

### Claim 17 (depends on 14)

The composition according to claim 14, wherein the tonicity modifying agent (v) is sodium chloride in combination with at least one selected from the group consisting of calcium chloride, calcium acetate, magnesium chloride and magnesium acetate.

### Claim 18 (depends on 14)

The composition according to claim 14, wherein the tonicity modifying agent (v) is present in a concentration of at least 1 mM.

### Claim 19 (depends on 14)

The composition according claim 14, wherein at least one tonicity modifying agent (v) is an ionic strength modifying agent (v/a).

### Claim 20 (depends on 14)

The composition according to claim 14, which has an ionic strength of at least 50 mM.

### Claim 21 (depends on 14)

The composition according to claim 14, which has an osmolality of 300±50 milliosmol/kg.

### Claim 22 (depends on 1)

The composition according to claim 1, further comprising an antioxidant (vi).

### Claim 23 (depends on 22)

The composition according to claim 22, wherein the antioxidant (vi) is selected from L-methionine, D-methionine, methionine analogues, methionine-containing peptides, methionine-homologues, ascorbic acid, cysteine, homocysteine, gluthatione, cystine, and cysstathionine.

### Claim 24 (depends on 1)

The composition according to claim 1, further comprising a preservative (vii).

### Claim 25 (depends on 24)

The composition according to claim 24, wherein the preservative (vii) is selected from the group consisting of phenol, benzyl alcohol, orto-cresol, meta-cresol, para-cresol, methyl paraben, propyl paraben, benzalkonium chloride, and benzaethonium chloride.

### Claim 26 (depends on 1)

The liquid, aqueous pharmaceutical composition according to claim 1, which comprises:
(i) 0.1-15 mg/mL of a Factor VII polypeptide;
(ii) a buffering agent suitable for keeping pH in the range of from about 4.0 to about 9.0;
(iii) a copper-containing agent in concentration of at least 5 μM;
(iv) a non-ionic surfactant; and
(v) a tonicity modifying agent in a concentration of at least 5 mM.

### Claim 27 (depends on 1)

The liquid, aqueous pharmaceutical composition according to claim 1, which comprises:
(i) 0.1-15 mg/mL of a Factor VII polypeptide;
(ii) a buffering agent suitable for keeping pH in the range of from about 4.0 to about 9.0;
(iii) a manganese-containing agent in concentration of at least 100 μM;
(iv) a non-ionic surfactant; and
(v) at least one tonicity modifying agent in a concentration of at least 5 mM.

### Claim 28

A method for preparing a liquid, aqueous pharmaceutical composition of a Factor VII polypeptide, comprising the step of providing the Factor VII polypeptide (i) in a solution comprising
a buffering agent (ii) suitable for keeping pH in the range of from about 4.0 to about 9.0;
at least one metal-containing agent (iii), wherein said metal is selected from the group consisting of first transition series metals of oxidation state +II, except zinc; and
a non-ionic surfactant (iv).

### Claim 29 (depends on 1)

A method for treating a Factor VII-responsive syndrome, the method comprising administering to a subject in need thereof an effective amount of a liquid, aqueous pharmaceutical composition as defined in claim 1.

### Claim 30 (depends on 1)

An air-tight container containing a liquid, aqueous pharmaceutical composition as defined in claim 1, and optionally an inert gas.