VEGF antagonist formulations suitable for intravitreal administration

Patent metadata

Field	Value
Publication number	US-9580489-B2
Application number	US-201615151776-A
Country	US
Kind code	B2
Filing date	May 11, 2016
Priority date	Jun 16, 2006
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

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 formulation comprising:
(a) 1-100 mg/mL of a VEGF-specific fusion protein antagonist;
(b) 5-40 mM of a buffer;
(c) 0.01-5% of an organic co-solvent; and
(d) a stabilizer or 30-150 mM of a tonicity agent,

wherein
the VEGF-specific fusion protein antagonist represents at least 90% of the total weight of protein in the composition,
at least 90% of the total weight of the VEGF-specific fusion protein antagonist is not present as an aggregate, and
the VEGF-specific fusion protein antagonist comprises an Ig domain 2 of human VEGF receptor 1, an Ig domain 3 of human VEGF receptor 2, and a multimerizing component.

2. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist represents at least 95% of the total weight of protein in the composition.

3. The formulation of claim 2 , wherein the VEGF-specific fusion protein antagonist represents at least 99% of the total weight of protein in the composition.

4. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist is present at a concentration of about 10 to about 80 mg/ml.

5. The formulation of claim 4 , where the VEGF-specific fusion protein antagonist is present at a concentration of about 10, about 20, about 30, about 40, about 50, about 60, about 70, or about 80 mg/ml.

6. The formulation of claim 1 , wherein the buffer comprises a phosphate buffer.

7. The formulation of claim 6 , wherein the buffer comprises sodium phosphate present at a concentration of 10 mM.

8. The formulation of claim 1 , wherein the pH of the composition is about pH 5.8-7.0.

9. The formulation of claim 1 , wherein the pH is about pH 6.2-6.3.

10. The formulation of claim 1 , wherein the pH is about pH 6.0.

11. The formulation of claim 1 , wherein the organic co-solvent comprises one or more of polysorbate 20, polysorbate 80, polyethylene glycol (PEG) 3350, and propylene glycol.

12. The formulation of claim 11 , wherein the organic co-solvent is present at a concentration of 0.01-3%.

13. The formulation of claim 12 , wherein the organic co-solvent is PEG 3350 or polypropylene glycol at a concentration of about 3%.

14. The formulation of claim 1 , wherein the organic co-solvent is present at a concentration of 0.01-0.15%.

15. The formulation of claim 14 , wherein the organic co-solvent is polysorbate 80 or polysorbate 20 present at a concentration of 0.015%, 0.03% or 0.1%.

16. The formulation of claim 1 , wherein the tonicity agent comprises sodium chloride or potassium chloride.

17. The formulation of claim 16 , wherein the tonicity agent comprises sodium chloride present at a concentration of 20-135 mM.

18. The formulation of claim 17 , wherein the sodium chloride is present at a concentration of 20 mM, 40 mM, 50 mM, 100 mM, or 135 mM.

19. The formulation of claim 1 , comprising a stabilizer comprising trehalose or sucrose.

20. The formulation of claim 19 , wherein the stabilizer comprises sucrose.

21. The formulation of claim 20 , wherein the sucrose is present at a concentration of 5%.

22. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist does not comprise amino acids 1-26 of SEQ ID NO:4.

23. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist is a dimer.

24. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist is expressed in a Chinese hamster ovary (CHO) cell.

25. The formulation of claim 1 , wherein the VEGF-specific fusion protein antagonist comprises glycosylated Asn residues corresponding to Asn residues at positions 62, 94, 149, 222, and 308 of SEQ ID NO:4.

26. A vial containing a formulation comprising:
(a) 1-100 mg/mL of a VEGF-specific fusion protein antagonist;
(b) 5-40 mM of a buffer;
(c) 0.01-5% of an organic co-solvent;
(d) a stabilizer or 30-150 mM of a tonicity agent,

wherein
the VEGF-specific fusion protein antagonist represents at least 90% of the total weight of protein in the composition,
at least 90% of the total weight of the VEGF-specific fusion protein antagonist is not present as an aggregate, and
the VEGF-specific fusion protein antagonist comprises an Ig domain 2 of human VEGF receptor 1, an Ig domain 3 of a human VEGF receptor 2, and a multimerizing component.

27. The vial of claim 26 , wherein the composition is stored under an inert gas, wherein the inert gas is nitrogen, helium or argon.

28. The vial of claim 27 , wherein the vial is stored at 5° C.

29. The vial of claim 28 , wherein the VEGF-specific fusion protein antagonist does not comprise amino acids 1-26 of SEQ ID NO:4.

Assignees

• Regeneron Pharma

Inventors

• Furfine Eric
• Dix Daniel B
• 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

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61K38/1793

  for cytokines; for lymphokines; for interferons · CPC title