Stable formulations

• US 20080112953A1
• Filed: 10/05/2007
• Published: 05/15/2008
• Est. Priority Date: 10/06/2006
• Status: Abandoned Application

• Current Assignee: Amgen Inc.
• Original Assignee: Amgen Inc.
• Inventors: Rehder, Douglas, Matsumura, Masazumi, McAuley, Arnold
• Application Number:
  US11/973,200
• Publication Number:
  US 20080112953A1
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• 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: A61K 9/19 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 Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 2317/21 from primates, e.g. man

Abstract

The invention provides a formulation including an acetic acid buffer, a glutamic acid buffer or a succinic acid buffer with a pH from about 4.5-7.0, at least one excipient comprising a sugar or a polyol and an effective amount of a therapeutic antibody. The buffer can include a salt of acetate, glutamate or succinate and the sugar or polyol can include glycerol, sucrose, trehalose or sorbitol. The therapeutic antibody can include a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

Claims

1. A formulation comprising a glutamic acid buffer with a pH from about 4.5-7.0, at least one excipient comprising a sugar or a polyol and an effective amount of a therapeutic antibody having specific binding activity to human epidermal growth factor receptor (EGFR), wherein said therapeutic antibody retains at least about 80% stability for up to two months in solution.

2. The formulation of claim 1, wherein said buffer comprises a sodium salt of glutamic acid.

3. The formulation of claim 1, wherein said glutamic acid buffer comprises a concentration of about 1-50 mM.

4. The formulation of claim 3, wherein said glutamic acid buffer comprises a concentration of about 5-10 mM.

5. The formulation of claim 1, wherein said pH comprises a pH of about 4.8-5.2.

6. The formulation of claim 1, wherein said sugar or polyol is selected from glycerol, sucrose, trehalose or sorbitol.

7. The formulation of claim 6, wherein said glycerol, sucrose, trehalose or sorbitol comprises a concentration selected from between about 1-20%.

8. The formulation of claim 6, wherein said glycerol comprises a concentration of about 2.6%.

9. The formulation of claim 6, wherein said sucrose comprises a concentration selected from about 9.3% or 20%.

10. The formulation of claim 6, wherein said trehalose comprises a concentration selected from about 9.3% or 20%.

11. The formulation of claim 6, wherein said sorbitol comprises a concentration of about 5%.

12. The formulation of claim 1, further comprising a surfactant.

13. The formulation of claim 12, wherein said surfactant comprises a polysorbate.

14. The formulation of claim 12, wherein said surfactant comprises a concentration selected from between about 0.001-0.10% (w/v).

15. The formulation of claim 1, further comprising a second excipient.

16. The formulation of claim 15, wherein said second excipient is selected from a buffer, stabilizer, tonicity agent, bulking agent, surfactant, cryoprotectant, lyoprotectant, anti-oxidant, metal ion, chelating agent and preservative.

17. The formulation of claim 1, wherein said therapeutic antibody having specific binding activity to human EGFR comprises a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

18. The formulation of claim 17, wherein said human antibody is panitumumab.

19. The formulation of claim 17, wherein said chimeric antibody is Erbitux (cetuximab).

20. The formulation of claim 17, wherein said human antibody is selected from IMC-11F8 or HUMAX-EGFR.

21. The formulation of claim 17, wherein said humanized antibody is selected from matuzumab (EMD-7200) or nimotuzumab (TheraCIM hR3).

22. The formulation of claim 17, wherein said functional fragment thereof comprises a Fd, Fv, Fab, F(ab′

), F(ab)₂, F(ab′

)₂, single chain Fv (scFv) or chimeric antibody.

23. The formulation of claim 1, wherein said therapeutic antibody comprises a concentration selected from between about 10-200 mg/ml.

24. A liquid formulation comprising 10 mM glutamic acid buffer having a pH of about 4.8-5.2, at least one excipient comprising about 2.6% glycerol and an effective amount of panitumumab, wherein said panitumumab retains at least about 80% stability for up to two months in solution.

25. A formulation comprising an acetic acid buffer with a pH from about 4.5-7.0, at least one excipient comprising a sugar or a polyol and an effective amount of a therapeutic antibody having specific binding activity to human epidermal growth factor receptor (EGFR), wherein said therapeutic antibody retains at least about 80% stability for up to two months in solution.

26. The formulation of claim 25, wherein said buffer comprises a sodium salt of acetic acid.

27. The formulation of claim 25, wherein said acetic acid buffer comprises a concentration selected from between about 1-50 mM.

28. The formulation of claim 27, wherein said acetic acid buffer comprises a concentration of about 5-10 mM.

29. The formulation of claim 25, wherein said pH comprises a pH of about 4.8-5.2.

30. The formulation of claim 25, wherein said sugar or polyol is selected from glycerol, sucrose, trehalose or sorbitol.

31. The formulation of claim 30, wherein said glycerol, sucrose, trehalose or sorbitol comprises a concentration selected from between about 1-20%.

32. The formulation of claim 30, wherein said glycerol comprises a concentration of about 2.6%.

33. The formulation of claim 30, wherein said sucrose comprises a concentration selected from about 9.3% or 20%.

34. The formulation of claim 30, wherein said trehalose comprises a concentration selected from about 9.3% or 20%.

35. The formulation of claim 30, wherein said sorbitol comprises a concentration of about 5%.

36. The formulation of claim 25, further comprising a surfactant.

37. The formulation of claim 35, wherein said surfactant comprises a polysorbate.

38. The formulation of claim 36, wherein said surfactant comprises a concentration selected from between about 0.001-0.10% (w/v).

39. The formulation of claim 25, further comprising a second excipient.

40. The formulation of claim 39, wherein said second excipient is selected from a buffer, stabilizer, tonicity agent, bulking agent, surfactant, cryoprotectant, lyoprotectant, anti-oxidant, metal ion, chelating agent and preservative.

41. The formulation of claim 25, wherein said therapeutic antibody having specific binding activity to human EGFR comprises a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

42. The formulation of claim 41, wherein said human antibody is panitumumab.

43. The formulation of claim 41, wherein said chimeric antibody is Erbitux (cetuximab).

44. The formulation of claim 41, wherein said human antibody is selected from IMC-11F8 or HUMAX-EGFR.

45. The formulation of claim 41, wherein said humanized antibody is selected from matuzumab (EMD-7200) or nimotuzumab (TheraCIM hR3).

46. The formulation of claim 41, wherein said functional fragment thereof comprises a Fd, Fv, Fab, F(ab′

), F(ab)₂, F(ab′

)₂, single chain Fv (scFv) or chimeric antibody.

47. The formulation of claim 25, wherein said therapeutic antibody comprises a concentration selected from between about 10-200 mg/ml.

48. A formulation comprising a succinic acid buffer with a pH from about 4.5-7.0, at least one excipient comprising a sugar or a polyol and an effective amount of a therapeutic antibody having specific binding activity to human epidermal growth factor receptor (EGFR), wherein said therapeutic antibody retains at least about 80% stability for up to two months in solution.

49. The formulation of claim 48, wherein said buffer comprises a sodium salt of succinic acid.

50. The formulation of claim 48, wherein said succinic acid buffer comprises a concentration of about 1-50 mM.

51. The formulation of claim 50, wherein said succinic acid buffer comprises a concentration of about 5-10 mM.

52. The formulation of claim 48, wherein said pH comprises a pH of about 4.8-5.2.

53. The formulation of claim 48, wherein said sugar or polyol is selected from glycerol, sucrose, trehalose or sorbitol.

54. The formulation of claim 53, wherein said glycerol, sucrose, trehalose or sorbitol comprises a concentration selected from between about 1-20%.

55. The formulation of claim 53, wherein said glycerol comprises a concentration of about 2.6%.

56. The formulation of claim 53, wherein said sucrose comprises a concentration selected from about 9.3% or 20%.

57. The formulation of claim 53, wherein said trehalose comprises a concentration selected from about 9.3% or 20%.

58. The formulation of claim 53, wherein said sorbitol comprises a concentration of about 5%.

59. The formulation of claim 48, further comprising a surfactant.

60. The formulation of claim 59, wherein said surfactant comprises a polysorbate.

61. The formulation of claim 59, wherein said surfactant comprises a concentration selected from between about 0.001-0.10% (w/v).

62. The formulation of claim 48, further comprising a second excipient.

63. The formulation of claim 62, wherein said second excipient is selected from a buffer, stabilizer, tonicity agent, bulking agent, surfactant, cryoprotectant, lyoprotectant, anti-oxidant, metal ion, chelating agent and preservative.

64. The formulation of claim 48, wherein said therapeutic antibody having specific binding activity to human EGFR comprises a human antibody, a humanized antibody, a chimeric antibody, or a functional fragment thereof.

65. The formulation of claim 64, wherein said human antibody is panitumumab.

66. The formulation of claim 64, wherein said chimeric antibody is Erbitux (cetuximab).

67. The formulation of claim 64, wherein said human antibody is selected from IMC-11F8 or HUMAX-EGFR.

68. The formulation of claim 64, wherein said humanized antibody is selected from matuzumab (EMD-7200) or nimotuzumab (TheraCIM hR3).

69. The formulation of claim 64, wherein said functional fragment thereof comprises a Fd, Fv, Fab, F(ab′

), F(ab)₂, F(ab′

)₂, single chain Fv (scFv) or chimeric antibody.

70. The formulation of claim 48, wherein said therapeutic antibody comprises a concentration selected from between about 10-200 mg/ml.