VEGF antagonist formulations suitable for intravitreal administration

Patent metadata

Field	Value
Publication number	US-12331099-B2
Application number	US-202418924707-A
Country	US
Kind code	B2
Filing date	Oct 23, 2024
Priority date	Jun 16, 2006
Publication date	Jun 17, 2025
Grant date	Jun 17, 2025

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 liquid ophthalmic formulation comprising:
40 mg/ml of a glycosylated vascular endothelial growth factor (VEGF) antagonist fusion protein comprising amino acids 27-457 of SEQ ID NO: 4;
water;
an organic co-solvent comprising polysorbate; and
a stabilizing agent,
wherein the liquid ophthalmic formulation has a pH of between 5.8 to 7.0,
wherein the liquid ophthalmic formulation is suitable for intravitreal administration,
wherein 90% or more of the weight of the VEGF antagonist fusion protein is not present as an aggregate, and
wherein the VEGF antagonist fusion protein is at least 95% free of protein contaminants.

2. The liquid ophthalmic formulation of claim 1 , wherein the polysorbate is polysorbate 80, and wherein the stabilizing agent is sucrose and trehalose.

3. The liquid ophthalmic formulation of claim 2 , wherein the liquid ophthalmic formulation comprises 0.01% to 3% polysorbate 80.

4. The liquid ophthalmic formulation of claim 3 , wherein the liquid ophthalmic formulation comprises 0.03% to 0.1% polysorbate 80.

5. The liquid ophthalmic formulation of claim 4 , wherein the liquid ophthalmic formulation comprises 0.1% polysorbate 80.

6. The liquid ophthalmic formulation of claim 4 , wherein the liquid ophthalmic formulation comprises 0.03% polysorbate 80.

7. The liquid ophthalmic formulation of claim 2 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% stabilizing agent.

8. The liquid ophthalmic formulation of claim 2 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% sucrose.

9. The liquid ophthalmic formulation of claim 8 , wherein the liquid ophthalmic formulation comprises 5% sucrose.

10. The liquid ophthalmic formulation of claim 1 , wherein the liquid ophthalmic formulation has a pH of between 6.2 to 6.3.

11. A liquid ophthalmic formulation comprising:
40 mg/ml of a glycosylated vascular endothelial growth factor (VEGF) antagonist fusion protein comprising amino acids 27-457 of SEQ ID NO: 4;
water;
an organic co-solvent comprising polysorbate; and
a stabilizing agent,
wherein the liquid ophthalmic formulation has a pH of between 5.8 to 7.0,
wherein the liquid ophthalmic formulation is suitable for intravitreal administration,
wherein at least 98% of the VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

12. The liquid ophthalmic formulation of claim 11 , wherein the polysorbate is polysorbate 80, and wherein the stabilizing agent is sucrose and trehalose.

13. The liquid ophthalmic formulation of claim 12 , wherein the liquid ophthalmic formulation comprises 0.01% to 3% polysorbate 80.

14. The liquid ophthalmic formulation of claim 13 , wherein the liquid ophthalmic formulation comprises 0.03% to 0.1% polysorbate 80.

15. The liquid ophthalmic formulation of claim 14 , wherein the liquid ophthalmic formulation comprises 0.1% polysorbate 80.

16. The liquid ophthalmic formulation of claim 14 , wherein the liquid ophthalmic formulation comprises 0.03% polysorbate 80.

17. The liquid ophthalmic formulation of claim 16 , wherein at least 99% of the VEGF antagonist fusion protein is present in native conformation after 2 month storage at 5° C. as measured by size exclusion chromatography.

18. The liquid ophthalmic formulation of claim 12 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% stabilizing agent.

19. The liquid ophthalmic formulation of claim 12 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% sucrose.

20. The liquid ophthalmic formulation of claim 19 , wherein the liquid ophthalmic formulation comprises 5% sucrose.

21. The liquid ophthalmic formulation of claim 11 , wherein the liquid ophthalmic formulation has a pH of between 6.2 to 6.3.

22. A liquid ophthalmic formulation comprising:
40 mg/ml of a glycosylated vascular endothelial growth factor (VEGF) antagonist fusion protein comprising amino acids 27-457 of SEQ ID NO: 4;
water;
an organic co-solvent comprising polysorbate 80; and
a stabilizing agent comprising sucrose and trehalose,
wherein the liquid ophthalmic formulation has a pH of about 6.2 to 6.3,
wherein the liquid ophthalmic formulation is suitable for intravitreal administration,
wherein 90% or more of the weight of the VEGF antagonist fusion protein is not present as an aggregate, and
wherein the VEGF antagonist fusion protein is at least 95% free of protein contaminants.

23. The liquid ophthalmic formulation of claim 22 , wherein the liquid ophthalmic formulation comprises 0.01% to 3% polysorbate 80.

24. The liquid ophthalmic formulation of claim 22 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% stabilizing agent.

25. The liquid ophthalmic formulation of claim 22 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% sucrose.

26. A liquid ophthalmic formulation comprising:
40 mg/ml of a glycosylated vascular endothelial growth factor (VEGF) antagonist fusion protein comprising amino acids 27-457 of SEQ ID NO: 4;
water;
an organic co-solvent comprising polysorbate 80; and
a stabilizing agent comprising sucrose and trehalose,
wherein the liquid ophthalmic formulation has a pH of about 6.2 to 6.3,
wherein the liquid ophthalmic formulation is suitable for intravitreal administration,
wherein at least 98% of the VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

27. The liquid ophthalmic formulation of claim 26 , wherein the liquid ophthalmic formulation comprises 0.01% to 3% polysorbate 80.

28. The liquid ophthalmic formulation of claim 27 , wherein the liquid ophthalmic formulation comprises 0.03% polysorbate 80, and wherein at least 99% of the VEGF antagonist fusion protein is present in native conformation after 2 month storage at 5° C. as measured by size exclusion chromatography.

29. The liquid ophthalmic formulation of claim 26 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% stabilizing agent.

30. The liquid ophthalmic formulation of claim 26 , wherein the liquid ophthalmic formulation comprises 1.0% to 7.5% sucrose.

Assignees

• Regeneron Pharma

Inventors

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

Classifications

• C07K2319/00

  Fusion polypeptide · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• A61K47/26

  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 title

• A61K38/179

  for growth factors; for growth regulators · CPC title