VEGF antagonist formulations suitable for intravitreal administration

• US 10,464,992 B2
• Filed: 10/12/2018
• Issued: 11/05/2019
• 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:
  US16/159,269
• Publication Number:
  US 20190031735A1
• Time in Patent Office: 389 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 vial comprising:

a vascular endothelial growth factor (VEGF) antagonist,

an organic co-solvent,

a buffer, and

a stabilizing agent,

wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component; and

wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5°

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

2. The vial of claim 1, wherein about 99% or more of the weight of the fusion protein is in native conformation.

3. The vial 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 the human Flt4.

4. The vial of claim 3, wherein the fusion protein comprises amino acids 27-457 of SEQ ID NO:

4.

5. The vial of claim 4, wherein the VEGF antagonist is a dimer of the fusion protein.

6. The vial of claim 5, wherein the organic co-solvent is selected for the group consisting of polysorbate 20, polysorbate 90, polyethylene glycol (PEG), PEG3350, and propylene glycol.

7. The vial of claim 6, wherein the stabilizing agent is selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol.

8. The vial of claim 1, wherein the organic co-solvent is polysorbate 20 and the stabilizing agent is sucrose.

9. The vial of claim 1, wherein the organic co-solvent is polysorbate 20, the buffer is phosphate, and the stabilizing agent is sucrose.

10. A formulation comprising:

a vascular endothelial growth factor (VEGF) antagonist,

an organic co-solvent,

a buffer, and

a stabilizing agent,

wherein the VEGF antagonist is a fusion protein produced in a Chinese Hamster Ovary (CHO) cell, the fusion protein comprising an immunoglobin-like (Ig) domain 2 of a first VEGF receptor and Ig domain 3 of a second VEGF receptor, and a multimerizing component; and

wherein at least 98% of the VEGF antagonist is present in native conformation following storage at 5°

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

11. The formulation of claim 10, wherein about 99%90% or more of the weight of the fusion protein is in native conformation.

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

13. The formulation of claim 12, wherein the fusion protein comprises amino acids 27-457 of SEQ ID NO:

4.

14. The formulation of claim 13, wherein the VEGF antagonist is a dimer of the fusion protein.

15. The formulation of claim 14, wherein the organic co-solvent is selected for the group consisting of polysorbate 20, polysorbate 90, polyethylene glycol (PEG), PEG3350, and propylene glycol.

16. The formulation of claim 15, wherein the stabilizing agent is selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol.

17. The formulation of claim 10, wherein the organic co-solvent is polysorbate 20 and the stabilizing agent is sucrose.

18. The formulation of claim 10, wherein the organic co-solvent is polysorbate 20, the buffer is phosphate, and the stabilizing agent is sucrose.