VEGF antagonist formulations suitable for intravitreal administration

Patent metadata

Field	Value
Publication number	US-11066458-B2
Application number	US-201916582486-A
Country	US
Kind code	B2
Filing date	Sep 25, 2019
Priority date	Jun 16, 2006
Publication date	Jul 20, 2021
Grant date	Jul 20, 2021

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 glass vial comprising an ophthalmic formulation suitable for intravitreal administration comprising:
a vascular endothelial growth factor (VEGF) antagonist fusion protein,
an organic co-solvent,
a buffer, and
a stabilizing agent;
wherein said VEGF antagonist fusion protein is glycosylated and comprises an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor that is human Flt1 and Ig domain 3 of a second VEGF receptor selected from the group consisting of human Flk1 and human Flt4, and a multimerizing component; and
wherein at least 98% of said VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

2. The glass vial of claim 1 , wherein the concentration of said VEGF antagonist fusion protein is 40 mg/ml, and wherein said organic co-solvent comprises polysorbate.

3. The glass vial of claim 2 , wherein said organic co-solvent comprises 0.01% to 3% polysorbate.

4. The glass vial of claim 2 , wherein said organic co-solvent comprises about 0.03% to about 0.1% polysorbate 20.

5. The glass vial of claim 2 , wherein said organic co-solvent comprises 0.01% to 3% polysorbate 20.

6. The glass vial of claim 5 , wherein said buffer comprises a phosphate buffer.

7. The glass vial of claim 5 , wherein said buffer comprises 5-25 mM buffer.

8. The glass vial of claim 5 , wherein said buffer comprises a pH between about 5.8-7.0.

9. The glass vial of claim 5 , wherein said buffer comprises a pH about 6.2-6.3.

10. The glass vial of claim 5 , wherein said stabilizing agent comprises a sugar.

11. The glass vial of claim 10 , wherein said sugar is selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol.

12. The glass vial of claim 5 , wherein said stabilizing agent comprises 1.0-7.5% of sucrose.

13. The glass vial of claim 5 , wherein said formulation further comprises a tonicity agent.

14. The glass vial of claim 5 , wherein said VEGF antagonist fusion protein is glycosylated at asparagine residues corresponding to asparagine residues 62, 94, 149, 222 and 308 of SEQ ID NO: 4.

15. The glass vial of claim 5 , wherein said formulation is capable of providing a turbidity of 0.01 or lower at OD 405 after 2 month storage at 5° C.

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

17. The glass vial of claim 5 , wherein at least 98% of said VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for 24 months as measured by size exclusion chromatography.

18. The glass vial of claim 5 , wherein said formulation does not contain phosphate.

19. The glass vial of claim 5 , wherein said formulation does not contain trehalose.

20. The glass vial of claim 5 , wherein said stabilizing agent comprises 1.0-10% of sucrose.

21. The glass vial of claim 20 , wherein said formulation further comprises a tonicity agent.

22. The glass vial of claim 20 , wherein said VEGF antagonist fusion protein is glycosylated at asparagine residues corresponding to asparagine residues 62, 94, 149, 222 and 308 of SEQ ID NO: 4.

23. The glass vial of claim 20 , wherein said formulation is capable of providing a turbidity of 0.01 or lower at OD 405 after 2 month storage at 5° C.

24. The glass vial of claim 20 , wherein at least 99% of said VEGF antagonist fusion protein is present in native conformation after 2 month storage at 5° C. as measured by size exclusion chromatography.

25. The glass vial of claim 20 , wherein at least 98% of said VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for 24 months as measured by size exclusion chromatography.

26. The glass vial of claim 1 , wherein said stabilizing agent comprises sucrose.

27. The glass vial of claim 26 , wherein said stabilizing agent comprises 1.0-10% of sucrose.

28. The glass vial of claim 26 , wherein the organic co-solvent is polysorbate 20.

29. The glass vial of claim 28 , wherein said Ig domain 3 of human VEGF receptor 2 comprises amino acids 131-230 of SEQ ID NO:4.

30. The glass vial of claim 29 , wherein said formulation further comprises a tonicity agent.

31. The glass vial of claim 30 , wherein said tonicity agent comprises sodium chloride.

32. The glass vial of claim 28 , wherein said formulation comprises 10 mg/mL VEGF antagonist fusion protein.

33. The glass vial of claim 28 , wherein said formulation does not contain phosphate.

34. A pre-filled syringe comprising an ophthalmic formulation suitable for intravitreal administration comprising:
a vascular endothelial growth factor (VEGF) antagonist fusion protein,
an organic co-solvent,
a buffer, and
a stabilizing agent;
wherein said VEGF antagonist fusion protein is glycosylated and comprises an immunoglobulin-like (Ig) domain 2 of a first VEGF receptor that is human Flt1 and Ig domain 3 of a second VEGF receptor selected from the group consisting of human Flk1 and human Flt4, and a multimerizing component; and
wherein at least 98% of said VEGF antagonist fusion protein is present in native conformation following storage at 5° C. for two months as measured by size exclusion chromatography.

35. The pre-filled syringe of claim 34 , wherein the concentration of said VEGF antagonist fusion protein is 40 mg/ml, and wherein said organic co-solvent comprises polysorbate.

36. The pre-filled syringe of claim 35 , wherein said organic co-solvent comprises 0.01% to 3% polysorbate.

37. The pre-filled syringe of claim 35 , wherein said organic co-solvent comprises about 0.03% to about 0.1% polysorbate 20.

38. The pre-filled syringe of claim 35 , wherein said organic co-solvent comprises 0.01% to 3% polysorbate 20.

39. The pre-filled syringe of claim 38 , wherein said buffer comprises 5-25 mM buffer.

40. The pre-filled syringe of claim 38 , wherein said buffer comprises a pH between about 5.8-7.0.

41. The pre-filled syringe of claim 38 , wherein said buffer comprises a pH about 6.2-6.3.

42. The pre-filled syringe of claim 38 , wherein said buffer comprises a phosphate buffer.

43. The pre-filled syringe of claim 38 , wherein said stabilizing agent comprises a sugar.

44. The pre-filled syringe of claim 43 , wherein said sugar is selected from the group consisting of sucrose, sorbitol, glycerol, trehalose, and mannitol.

45. The pre-filled syringe of claim 38 , wherein said stabilizing agent comprises 1.0-10% of sucrose.

46. The pre-filled syringe of claim 45 , wherein said formulation further comprises a tonicity agent.

47. The pre-filled syringe of claim 45 , wherein said VEGF antagonist fusion protein is glycosylated at asparagine residues corresponding to asparagine residues 62, 94, 149, 222 and 308 of SEQ ID NO: 4.

48. The pre-filled syringe of claim 45 , wherein said formulation is capable of providing a turbidity of 0.0

Assignees

• Regeneron Pharma

Inventors

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

Classifications

• A61K9/19 Primary

  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 title

• A61K9/0048 Primary

  Eye, e.g. artificial tears · CPC title

• C07K14/47

  from mammals · CPC title

• A61P43/00

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

• A61K38/1793

  for cytokines; for lymphokines; for interferons · CPC title