VEGF antagonist formulations for intravitreal administration

• US 8,092,803 B2
• Filed: 07/09/2010
• Issued: 01/10/2012
• Est. Priority Date: 06/16/2006
• Status: Active Grant

• Current Assignee: Regeneron Pharmaceuticals Incorporated
• Original Assignee: Regeneron Pharmaceuticals Incorporated
• Inventors: Furfine, Eric, Dix, Daniel, Graham, Kenneth S., Frye, Kelly
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): LOCKARD, JON MCCLELLAND
• Application Number:
  US12/833,417
• Publication Number:
  US 20110257601A1
• Time in Patent Office: 550 Days
• Field of Search: None
• US Class Current: 424/134.1
• 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 shown in SEQ ID NO:4.

Claims

1. A stable liquid ophthalmic formulation of a vascular endothelial growth factor (VEGF) antagonist, comprising:

(a) between 50 mg/ml to about 10 mg/ml of a VEGF antagonist comprising amino acids 27-475 of SEQ ID NO;

4;

(b) about 0.03% to about 0.1% polysorbate;

(c) about 5-40 mM of sodium phosphate buffer, pH of about 5.8 to about 7.0; and

(d) either;

(i) about 5% sucrose and about 40 to about 50 mM NaCl, or

(ii) about 135 mM NaCl,

wherein at least 99% of the VEGF antagonist is present in native conformation following storage at 5°

C. for 2 months as measured by size exclusion chromatography.

2. The formulation of claim 1, comprising between 50 mg/ml to about 10 mg/ml of the VEGF antagonist, about 10 mM sodium phosphate buffer, about 40 mM NaCl, about 0.03% polysorbate, and about 5% sucrose, pH about 6.2-6.3.

3. The formulation of claim 2, comprising about 10 to about 40 mg/ml of the VEGF antagonist.

4. The formulation of claim 3, comprising VEGF antagonist at a concentration of about 10 mg/ml.

5. The formulation of claim 3, comprising VEGF antagonist at a concentration of about 40 mg/ml.

6. The formulation of claim 1, comprising between 50 mg/ml to about 10 mg/ml of the VEGF antagonist, about 10 mM sodium phosphate buffer, about 135 mM NaCl and about 0.03% polysorbate, pH about 6.2-6.3.

7. The formulation of claim 6, comprising about 10 to about 40 mg/ml of the VEGF antagonist.

8. The formulation of claim 7, comprising VEGF antagonist at a concentration of about 10 mg/ml.

9. The formulation of claim 7, comprising VEGF antagonist at a concentration of about 40 mg/ml.

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

11. A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 4.

12. A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 5.

13. A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 6.

14. A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 8.

15. A pre-filled syringe suitable for intravitreal administration comprising the formulation of claim 9.

16. A non-liquid formulation of a vascular endothelial growth factor (VEGF) antagonist made according to the steps of:

(a) combining in a liquid solution the following excipients;

(i) about 5-50 mg/ml of the VEGF antagonist, comprising amino acids 27-475 of SEQ ID NO;

4;

(ii) about 5-25 mM of sodium phosphate buffer, pH about 5.8-7.0;

(iii) about 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

(iv) about 1-10% of a stabilizing agent selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol; and

(b) lyophilizing the combination of step (a),

wherein at least about 99% of the VEGF antagonist is present in native conformation as measured by size exclusion chromatography following storage at 5°

C. for 2 months.

17. The non-liquid formulation of claim 16, wherein about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, about 2.5% sucrose, and about 20 mM sodium chloride, pH about 6.2-6.3 are combined at step (a).

18. The non-liquid formulation of claim 16, wherein about 20 mg/ml of the VEGF antagonist, about 5 mM sodium phosphate buffer, about 0.015% polysorbate, and about 67.5 mM sodium chloride, pH about 6.2-6.3 are combined at step (a).

19. The non-liquid formulation of claim 16, wherein the formulation can be reconstituted in about 0.7 minutes or less.