VEGF antagonist formulations suitable for intravitreal administration

• US 10,400,025 B2
• Filed: 01/24/2018
• Issued: 09/03/2019
• 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, Frye, Kelly
• Primary Examiner(s): Saoud, Christine J
• Assistant Examiner(s): Lockard, Jon M
• Application Number:
  US15/879,294
• Publication Number:
  US 20180155408A1
• Time in Patent Office: 587 Days
• Field of Search: None
• 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 an amino acid sequence of SEQ ID NO:4.

Claims

1. A formulation suitable for intravitreal administration comprising:

(a) 1 mg/mL to 100 mg/mL of a vascular endothelial growth factor (VEGF) antagonist;

(b) an organic co-solvent;

(c) 5 mM to 40 mM of a phosphate buffer; and

(d) 1.0% to 10% of a stabilizing agent selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol;

wherein the VEGF antagonist is a fusion protein comprising an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component.

2. The formulation of claim 1, wherein the first VEGF receptor is human Flt1, and the second VEGF receptor is selected from the group consisting of human Flk1 and human Flt4.

3. The formulation of claim 2, wherein the fusion protein comprises amino acids 27-475 of SEQ ID NO:

4.

4. The formulation of claim 3, wherein the VEGF antagonist is a dimer of the fusion protein.

5. The formulation of claim 1, wherein the organic co-solvent is polysorbate 20.

6. The formulation of claim 1, wherein the phosphate buffer is sodium phosphate buffer.

7. The formulation of claim 1, wherein the stabilizing agent is sucrose.

8. A formulation suitable for intravitreal administration comprising:

(a) 40 mg/mL of a fusion protein comprising amino acids 27-475 of SEQ ID NO;

4;

(b) 0.03% polysorbate 20;

(c) 10 mM sodium phosphate buffer, pH 6.2; and

(d) 5% sucrose.

9. A method of maintaining stability of a formulation, comprising the steps of:

(a) adding a vascular endothelial growth factor (VEGF) antagonist to a solution at a concentration of from 1 mg/ml to 100 mg/ml, wherein the solution comprises;

(i) an organic co-solvent;

(ii) 5 mM to 40 mM of a phosphate buffer; and

(iii) 1.0% to 10% of a stabilizing agent selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol;

wherein the VEGF antagonist is a fusion protein comprising an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component; and

(b) maintaining the formulation over a period of time of from 1 month to 24 months whereby the formulation remain suitable for intravitreal administration.

10. The method of claim 9, wherein the first VEGF receptor is human Flt1, and the second VEGF receptor is selected from the group consisting of human Flk1 and human Flt4.

11. The method of claim 10, wherein the fusion protein comprises amino acids 27-475 of SEQ ID NO:

4.

12. The method of claim 11, wherein the VEGF antagonist is a dimer of the fusion protein.

13. The method of claim 9, wherein the organic co-solvent is polysorbate 20.

14. The method of claim 9, wherein the phosphate buffer is sodium phosphate buffer.

15. The method of claim 9, wherein the stabilizing agent is sucrose.