VEGF antagonist formulations for intravitreal administration

• US 8,481,046 B2
• Filed: 12/19/2011
• Issued: 07/09/2013
• Est. Priority Date: 06/16/2006
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Furfine, Eric, Dix, Daniel, Frye, Kelly, Graham, Kenneth
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): LOCKARD, JON MCCLELLAND
• Application Number:
  US13/329,770
• Publication Number:
  US 20120087929A1
• Time in Patent Office: 568 Days
• Field of Search: None
• US Class Current: 424/192.1
• CPC Class Codes: A61K 38/179 for growth factors; for growth regulators
• CPC Class Codes: A61K 38/1793 for cytokines; for lymphokines; for interferons
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: 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
• CPC Class Codes: 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
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: 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
• CPC Class Codes: A61M 5/178 Syringes
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/4705 stimulating, promoting or activating activity
• CPC Class Codes: C07K 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

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 of residues 27-457 of SEQ ID NO:4.

Claims

1. A method of producing a lyophilized formulation of a VEGF antagonist, comprising the step of subjecting to lyophilization a prelyophilization formulation, which comprises

(a) 5-50 mg/ml of a vascular endothelial growth factor (VEGF) antagonist, comprising amino acids 27-457 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, to generate a lyophilized formulation.

2. The method of claim 1, wherein the prelyophilization formulation comprises 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, wherein the pH is about 6.2-6.3.

3. The method of claim 1, wherein the prelyophilization formulation comprises 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.

4. The method of claim 1, wherein the prelyophilization formulation comprises 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.

5. A method of producing a lyophilized formulation of a VEGF antagonist, comprising the step of subjecting to lyophilization a prelyophilization formulation, which comprises

(a) 5-50 mg/ml of a vascular endothelial growth factor (VEGF) antagonist, comprising amino acids 27-457 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, to generate a lyophilized formulation.

6. The method of claim 5, wherein the tonicity agent is sodium chloride at a concentration selected from the group consisting of 20 mM and 67.5 mM.

7. The method of claim 5, wherein the organic co-solvent is polysorbate at 0.015%.

8. The method of claim 5, 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.

9. The method of claim 5, wherein the sodium phosphate buffer is at 5 mM.