Reduced-viscosity concentrated protein formulations

• US 20020045571A1
• Filed: 10/04/2001
• Published: 04/18/2002
• Est. Priority Date: 10/12/2000
• Status: Active Grant

• Current Assignee: Novartis Ag, Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Liu, Jun, Shire, Steven J.
• Granted Patent: US 6,875,432 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 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 Class Codes: A61K 9/0019 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 Class Codes: Y10S 435/80 Elimination or reduction of contamination by undersired ferments, e.g. aseptic cultivation

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.

Claims

1. A stable liquid formulation comprising a protein in an amount of at least about 80 mg/ml and a salt and/or buffer in an amount of at least about 50 mM, and having a kinematic viscosity of about 50 cs or less.

2. The formulation of claim 1 comprising said salt and/or buffer in an amount of at least about 100 mM.

3. The formulation of claim 2 comprising said salt and/or buffer in an amount of about 50-200 mM.

4. The formulation of claim 2 comprising said salt and/or buffer in an amount of about 100-200 mM.

5. The formulation of claim 2 comprising said salt and/or buffer in an amount of about 200 mM.

6. The formulation of claim 1 wherein said salt and/or buffer are derived from:

a) an organic or inorganic acid and a base forming metal or amine;

or

b) an amino acid.

7. The formulation of claim 1 wherein the base forming metal is selected from the group consisting of alkali metals, alkaline earth metals, Al, Zn and Fe.

8. The formulation of claim 1 wherein the base forming amine is NR₄⁻

, wherein R is independently H or C_1-4 alkyl.

9. The formulation of claim 1 wherein the salt and/or buffer is derived from an amino acid.

10. The formulation of claim 1 wherein said salt is selected from the group consisting of sodium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride, calcium chloride, arginine hydrochloride, zinc chloride and sodium acetate.

11. The formulation of claim 1 which has a viscosity of about 40 cs or less.

12. The formulation of claim 11 which has a viscosity of about 30 cs or less.

13. The formulation of claim 12 which has a viscosity of about 20 cs or less.

14. The formulation of claim 13 having a viscosity of about 10 to 30 cs.

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

16. The formulation of claim 15 wherein said lyoprotectant is a sugar.

17. The formulation of claim 16 wherein said sugar is sucrose or trehalose.

18. The formulation of claim 16 comprising said sugar in an amount of about 60-300 mM.

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

20. The formulation of claim 1 which is hypertonic.

21. The formulation of claim 1 which is a reconstituted formulation.

22. The formulation of claim 21 wherein the protein concentration in the reconstituted formulation is about 2-40 times greater than the protein concentration in the mixture before lyophilization.

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

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

25. The formulation of claim 24 wherein said protein is an immunoglobulin.

26. The formulation of claim 25 wherein said immunoglobulin is an antibody directed against a specific antigen.

27. The formulation of claim 26 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.

28. The formulation of claim 27 wherein the antibody is rhuMAb-E25, rhuMAb-E26 or rhuMAb-E27.

29. The formulation of claim 1 which is a liquid pharmaceutical formulation.

30. The formulation of claim 29 which is for subcutaneous administration.

43. An article of manufacture comprising a container containing the formulation of claim 1.

44. The article of manufacture of claim 43 further comprising directions for administration of said formulation.

46. The formulation of claim 45 comprising said acid, base and/or buffer in an amount of at least about 100 mM.

47. The formulation of claim 45 comprising said acid, base and/or buffer in an amount of about 50-200 mM.

48. The formulation of claim 45 comprising said acid, base and/or buffer in an amount of about 100-200 mM.

49. The formulation of claim 45 comprising said acid, base and/or buffer in an amount of about 200 mM.

50. The formulation of claim 45 wherein said acid, base and/or buffer are selected from the group consisting of:

acetic acid, hydrochloric acid, arginine and histidine.

51. The formulation of claim 45 wherein the base is derived from a base forming metal selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, aluminum, zinc, iron, copper.

52. The formulation of claim 45 wherein the base forming amine is NR₄⁻

, wherein R is independently H or C_1-4 alkyl.

53. The formulation of claim 45 wherein the base and/or buffer is derived from an amino acid.

54. The formulation of claim 45 which has a viscosity of about 40 cs or less.

55. The formulation of claim 45 which has a viscosity of about 30 cs or less.

56. The formulation of claim 45 which has a viscosity of about 20 cs or less.

57. The formulation of claim 45 having a viscosity of about 10 to 30 cs.

58. The formulation of claim 45 further comprising a lyoprotectant.

59. The formulation of claim 58 wherein said lyoprotectant is a sugar.

60. The formulation of claim 59 wherein said sugar is sucrose or trehalose.

61. The formulation of claim 59 comprising said sugar in an amount of about 60-300 mM.

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

63. The formulation of claim 45 which is hypertonic.

64. The formulation of claim 45 which is a reconstituted formulation.

65. The formulation of claim 64 wherein the protein concentration in the reconstituted formulation is about 2-40 times greater than the protein concentration in the mixture before lyophilization.

66. The formulation of claim 45 wherein said protein has a molecular weight of at least about 15-20 kD.

67. The formulation of claim 45 wherein said protein is a member of the immunoglobulin gene superfamily.

68. The formulation of claim 67 wherein said protein is an immunoglobulin.

69. The formulation of claim 68 wherein said immunoglobulin is an antibody directed against a specific antigen.

70. The formulation of claim 69 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.

71. The formulation of claim 70 wherein the antibody is rhuMAb-E25, rhuMAb-E26 or rhuMAb-E27.

72. The formulation of claim 45 which is a liquid pharmaceutical formulation.

73. The formulation of claim 72 which is for subcutaneous administration.

84. An article of manufacture comprising a container containing the formulation of claim 45.

85. The article of manufacture of claim 84 further comprising directions for administration of said formulation.

31. A method of reducing the viscosity of a formulation containing high concentration of a protein comprising the addition of a salt in an amount of at least about 50 mM.

32. The method of claim 31 wherein said protein is present in an amount of at least about 80 mg/ml.

33. The method of claim 31 wherein said salt is selected from the group consisting of sodium chloride, sodium thiocyanate, ammonium thiocyanate, ammonium sulfate, ammonium chloride and calcium chloride.

34. The method of claim 31 wherein said protein is a member of the immunoglobulin gene superfamily.

35. The method of claim 31 wherein said protein is an immunoglobulin.

36. The method of claim 35 wherein said immunoglobulin is an antibody directed against a specific antigen.

37. The method of claim 36 wherein said antibody is directed against IgE.

38. The method of claim 37 wherein the antibody is rhuMAb-E25, rhuMAbE26 or rhuMAb-E27.

39. The method of claim 31 wherein said formulation is a reconstituted formulation.

40. The method of claim 31 wherein the formulation is hypertonic.

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

42. The method of claim 41 wherein the viscosity of said formulation is reduced to about 50 cs or less.

45. A stable liquid formulation comprising a protein in an amount of at least about 80 mg/ml and a pharmaceutically acceptable acid, base and/or buffer in an amount of at least about 50 mM, so as to have either a pH of about 4.2 to about 5.3 or about 6.5 to about 12.0 and having a kinematic viscosity of about 50 cs or less.

74. A method of reducing the viscosity of a formulation containing high concentration of a protein comprising either lowering the pH to about 4.2 to about 5.3 or lowering the pH to about 6.5 to about 12.0.

75. The method of claim 74 wherein said protein is present in an amount of at least about 80 mg/ml.

76. The method of claim 74 wherein said protein is a member of the immunoglobulin gene superfamily.

77. The method of claim 76 wherein said protein is an immunoglobulin.

78. The method of claim 77 wherein said immunoglobulin is an antibody directed against a specific antigen.

79. The method of claim 78 wherein said antibody is directed against IgE.

80. The method of claim 79 wherein the antibody is rhuMAb-E25, rhuMAbE-26 or rhuMAb-E27.

81. The method of claim 80 wherein said formulation is a reconstituted formulation.

82. The method of claim 81 wherein the protein concentration in said reconstituted formulation is about 2-40 times greater than the protein concentration in the mixture before lyophilization.

83. The method of claim 82 wherein the viscosity of said formulation is reduced to about 50 cs or less.