VEGF antagonist formulations suitable for intravitreal administration

Patent metadata

Field	Value
Publication number	US-10464992-B2
Application number	US-201816159269-A
Country	US
Kind code	B2
Filing date	Oct 12, 2018
Priority date	Jun 16, 2006
Publication date	Nov 5, 2019
Grant date	Nov 5, 2019

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.

First claim

We claim:

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.

Assignees

• Regeneron Pharma

Inventors

• Furfine Eric
• Dix Daniel
• Graham Kenneth
• Frye Kelly

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P27/02

  Ophthalmic agents · CPC title

• A61K9/0019

  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 title

• A61K38/1793

  for cytokines; for lymphokines; for interferons · CPC title