# US 7,608,261 B2 · VEGF antagonist formulations suitable for intravitreal administration

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- Number: US 7,608,261 B2
- Document ID: US7608261B2
- Status: Granted
- Kind: B2
- Application number: 11/818,463
- Filed: 2007-06-14
- Published: 2007-12-20
- Granted: 2009-10-27
- Earliest claimed: 2006-06-16
- Assignees: Regeneron Pharmacuticals, Inc.
- Inventors: Eric Furfine; Daniel Dix; Kenneth S. Graham; Kelly Frye
- Web page: https://patentgrep.com/patent/US7608261B2

## CPC

- C07K 14/71: for growth factors; for growth regulators
- 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 9/0048: {Eye, e.g. artificial tears}
- 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 38/179: {for growth factors; for growth regulators}
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 47/02: Inorganic compounds
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/26: 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
- A61M 5/178: Syringes
- A61P 27/02: Ophthalmic agents
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/47: from mammals
- C07K 14/4705: {stimulating, promoting or activating activity}
- C07K 2319/00: Fusion polypeptide
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)}
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Ophthalmic formulations of a vascular endothelial growth factor (VEGF)-specific fusion protein antagonist are provided suitable for intravitreal administration to the eye. The ophthalmic formulations include a stable liquid formulation and a lyophilizable formulation. Preferably, the protein antagonist has the amino acid sequence shown in SEQ ID NO:4.

## Claims

### Claim 1

An ophthalmic formulation of a vascular endothelial growth factor (VEGF) antagonist, comprising
a) 1-100 mg/ml of a VEGF antagonist comprising the amino acid sequence of SEQ ID NO:4;
b) 0.01-5% of one or more organic co-solvent(s) which is one or more of polysorbate, polyethylene glycol (PEG), and propylene glycol;
c) 30-150 mM of a tonicity agent selected from sodium chloride or potassium chloride; and,
d) 5-40 mM of sodium phosphate buffer.

### Claim 2 (depends on 1)

The ophthalmic formulation of claim 1, further comprising 1-7.5% of a stabilizing agent is selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, or mannitol, pH between about 5.8-7.0.

### Claim 3 (depends on 2)

The ophthalmic formulation of claim 2, comprising about 1-100 mg/ml of the VEGF antagonist, 10 mM sodium phosphate buffer, 40 mM NaCl, 0.03% polysorbate, and 5% sucrose, pH about 6.2-6.3.

### Claim 4 (depends on 3)

The ophthalmic formulation of claim 3, comprising about 10-80 mg/ml of the VEGF antagonist.

### Claim 5 (depends on 4)

The ophthalmic formulation of claim 4, comprising VEGF antagonist at a concentration selected from the group consisting of 10 mg/ml, 20 mg/ml, 40 mg/ml, and 80 mg/ml.

### Claim 6 (depends on 1)

The ophthalmic formulation of claim 1, comprising 10-80 mg/ml VEGF antagonist, 10 mM sodium phosphate, 0.03% polysorbate, and 135 mM sodium chloride, pH about 6.2-6.3.

### Claim 7 (depends on 6)

The ophthalmic formulation of claim 6, comprising VEGF antagonist at a concentration selected from the group consisting of 10 mg/ml, 20 mg/ml, 40 mg/ml, and 80 mg/ml.

### Claim 8

A lyophilizable formulation of a vascular endothelial growth factor (VEGF) antagonist, comprising
a) 5-50 mg/ml of the VEGF antagonist, comprising the amino acid sequence of SEQ ID NO:4;
b) 5-25 mM of sodium phosphate buffer, pH about 5.8-7.0;
c) 0.01-0.15% of an organic co-solvent, selected from the group consisting of polysorbate, polyethylene glycol (PEG), propylene glycol, and a combination thereof; and,
d) 1-10% of a stabilizing agent selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol.

### Claim 9 (depends on 8)

The lyophilizable formulation of claim 8, comprising about 20 mg/ml of the VEGF antagonist, about 10 mM sodium phosphate buffer, about 0.03% polysorbate, about 0.1% PEG and about 2.5% sucrose, pH about 6.2-6.3.

### Claim 10 (depends on 8)

The lyophilizable formulation of claim 8, comprising about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, about 2.5% sucrose, and further comprising sodium chloride at about 20 mM, pH about 6.2-6.3.

### Claim 11 (depends on 8)

The lyophilizable formulation of claim 8, comprising about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, and further comprising sodium chloride at about 67.5 mM, pH about 6.2-6.3.

### Claim 12

A lyophilizable formulation of a vascular endothelial growth factor (VEGF) antagonist, comprising
a) 5-50 mg/ml of the VEGF antagonist, comprising the amino acid sequence of SEQ ID NO:4;
b) 5-25 mM of a phosphate buffer, pH about 5.8-7.0;
c) 0.01-0.15% of an organic co-solvent, selected from the group consisting of polysorbate, polyethylene glycol (PEG), propylene glycol, and a combination thereof; and
d) 20-150 mM of a tonicity agent.

### Claim 13 (depends on 12)

The lyophilizable formulation of claim 12, wherein the tonicity agent is sodium chloride at a concentration selected from the group consisting of 20 mM and 67.5 mM.

### Claim 14 (depends on 12)

The lyophilizable formulation of claim 12, wherein the organic co-solvent is polysorbate at 0.015%.

### Claim 15 (depends on 12)

The lyophilizable formulation of claim 12, wherein the VEGF antagonist is at a concentration selected from the group consisting of 5 mg/ml, 10 mg/ml, 20 mg/ml, and 40 mg/ml.

### Claim 16 (depends on 12)

The lyophilizable formulation of claim 12, wherein the sodium phosphate buffer is at 5 mM.

### Claim 17 (depends on 1)

A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 1.