Reduced-viscosity concentrated protein formulations

Patent metadata

Field	Value
Publication number	US-10166293-B2
Application number	US-201414201346-A
Country	US
Kind code	B2
Filing date	Mar 7, 2014
Priority date	Oct 12, 2000
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present application concerns concentrated protein formulations with reduced viscosity, which are particularly suitable for subcutaneous administration. The application further concerns a method for reducing the viscosity of concentrated protein formulations.

First claim

What is claimed is:

1. A stable liquid formulation comprising a protein in an amount of at least about 80 mg/ml and a pharmaceutically acceptable acid, base or buffer in an amount of at least about 50 mM, so as to have either a pH of about 4.2 to about 4.9 or about 7.1 to about 12.0 and having a kinematic viscosity of about 50 cs or less at 25° C.

2. An article of manufacture comprising a syringe containing a stable liquid formulation comprising a monoclonal antibody in an amount of about 80-300 mg/ml and a pharmaceutically acceptable acid, base, or buffer in an amount of about 150-200 mM, wherein the acid, base, or buffer is comprised of arginine or histidine, and wherein the formulation has a kinematic viscosity of about 50 cs or less at 25° C.

3. The article of manufacture of claim 2 , wherein the syringe is further contained within an injection device.

4. The article of manufacture of claim 2 , wherein the acid, base, or buffer is arginine hydrochloride.

5. The article of manufacture of claim 2 , wherein the acid, base, or buffer is in an amount of about 150 mM.

6. The article of manufacture of claim 2 , wherein the acid, base, or buffer is in an amount of about 200 mM.

7. The article of manufacture of claim 2 , wherein the antibody is in an amount of about 90-150 mg/ml.

8. The article of manufacture of claim 2 , wherein the antibody is in an amount of about 150 mg/ml.

9. The article of manufacture of claim 2 , wherein the formulation has a viscosity of about 40 cs or less.

10. The article of manufacture of claim 2 , wherein the formulation has a viscosity of about 30 cs or less.

11. The article of manufacture of claim 2 , wherein the formulation has a viscosity of about 20 cs or less.

12. The article of manufacture of claim 2 , wherein the formulation has a viscosity of about 10 to 30 cs.

13. The article of manufacture of claim 2 , wherein the formulation further comprises a lyoprotectant.

14. The article of manufacture of claim 13 , wherein the lyoprotectant is a sugar.

15. The article of manufacture of claim 14 , wherein the sugar is sucrose or trehalose.

16. The article of manufacture of claim 14 , wherein the formulation comprises said sugar in an amount of about 60-300 mM.

17. The article of manufacture of claim 2 , wherein the formulation further comprises a surfactant.

18. The article of manufacture of claim 2 , wherein the formulation is hypertonic.

19. The article of manufacture of claim 2 , wherein the formulation is a reconstituted formulation.

20. The article of manufacture of claim 19 , wherein the antibody concentration in the reconstituted formulation is about 2-40 times greater than the antibody concentration in the mixture before lyophilization.

21. The article of manufacture of claim 2 , wherein the antibody is directed against IgE.

22. The article of manufacture of claim 21 , wherein the antibody is rhuMAb-E25, rhuMAb-E26 or rhuMAb-E27.

23. The article of manufacture of claim 2 , further comprising directions for administration of said formulation.

24. The article of manufacture of claim 23 , wherein the directions indicate use for the treatment or prophylaxis of an IgE-mediated disorder.

25. The article of manufacture of claim 24 , wherein the disorder is asthma.

26. A stable liquid formulation comprising a monoclonal antibody in an amount of about 80-300 mg/ml and a pharmaceutically acceptable acid, base, or buffer in an amount of about 150-200 mM, wherein the acid, base, or buffer is comprised of arginine or histidine, wherein the formulation has a kinematic viscosity of about 50 cs or less at 25° C.

27. The formulation of claim 26 , wherein the acid, base, or buffer is in an amount of about 150 mM.

28. The formulation of claim 26 , wherein the acid, base, or buffer is in an amount of about 200 mM.

29. The formulation of claim 1 comprising said acid, base or buffer in an amount of at least about 100 mM.

30. The formulation of claim 1 comprising said acid, base or buffer in an amount of about 50-200 mM.

31. The formulation of claim 1 comprising said acid, base or buffer in an amount of about 100-200 mM.

32. The formulation of claim 1 comprising said acid, base or buffer in an amount of about 200 mM.

33. The formulation of claim 1 wherein said acid, base or buffer is selected from the group consisting of: acetic acid, hydrochloric acid, arginine and histidine.

34. The formulation of claim 1 , wherein the base is derived from a base forming metal selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, aluminum, zinc, iron, and copper.

35. The formulation of claim 1 , wherein the base forming amine is NR 4 + wherein R 4 is independently H or C 1-4 alkyl.

36. The formulation of claim 1 wherein the base or buffer is derived from an amino acid.

37. The formulation of claim 1 , wherein the formulation has a viscosity of about 40 cs or less.

38. The formulation of claim 1 , wherein the formulation has a viscosity of about 30 cs or less.

39. The formulation of claim 1 , wherein the formulation has a viscosity of about 20 cs or less.

40. The formulation of claim 1 , wherein the formulation has a viscosity of about 10 to 30 cs.

41. The formulation of claim 1 further comprising a lyoprotectant.

42. The formulation of claim 41 wherein said lyoprotectant is a sugar.

43. The formulation of claim 42 wherein said sugar is sucrose or trehalose.

44. The formulation of claim 42 comprising said sugar in an amount of about 60-300 mM.

45. The formulation of claim 1 further comprising a surfactant.

46. The formulation of claim 1 , wherein the formulation is hypertonic.

47. The formulation of claim 1 , wherein the formulation is a reconstituted formulation.

48. The formulation of claim 47 wherein the protein concentration in the reconstituted formulation is about 2-40 times greater than the protein concentration in the mixture before lyophilization.

49. The formulation of claim 1 wherein said protein has a molecular weight of at least about 15-20 kD.

50. The formulation of claim 1 wherein said protein is a member of the immunoglobulin gene superfamily.

51. The formulation of claim 50 wherein said protein is an immunoglobulin.

52. The formulation of claim 51 wherein said immunoglobulin is an antibody directed against a specific antigen.

53. The formulation of claim 52 wherein said antibody is directed against IgE, a member of the HER receptor family, a cell adhesion molecule or a subunit thereof, or a growth factor.

54. The formulation of claim 53 wherein the antibody is rhuMAb-E25, rhuMAb-E26 or rhuMAb-E27.

55. The formulation of claim 1 , wherein the formulation is a liquid pharmaceutical formulation.

56. The formulation of claim 55 , wherein the formulation is for subcutaneous administration.

57. The formulation of claim 1 , whe

Assignees

• Genentech Inc
• Novartis Ag

Inventors

• Liu Jun
• Shire Steven J

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61K39/39591 Primary

  Stabilisation, fragmentation · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K39/39566

  against immunoglobulins, e.g. anti-idiotypic antibodies · CPC title

• A61P11/06

  Antiasthmatics · CPC title