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Last Updated: January 26, 2022

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Claims for Patent: 6,267,958

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Summary for Patent: 6,267,958
Title: Protein formulation
Abstract:A stable lyophilized protein formulation is described which can be reconstituted with a suitable diluent to generate a high protein concentration reconstituted formulation which is suitable for subcutaneous administration. For example, anti-IgE and anti-HER2 antibody formulations have been prepared by lyophilizing these antibodies in the presence of a lyoprotectant. The lyophilized mixture thus formed is reconstituted to a high protein concentration without apparent loss of stability of the protein.
Inventor(s): Andya; James (Millbrae, CA), Cleland; Jeffrey L. (San Carlos, CA), Hsu; Chung C. (Los Altos Hills, CA), Lam; Xanthe M. (San Francisco, CA), Overcashier; David E. (El Granada, CA), Shire; Steven J. (Belmont, CA), Yang; Janet Yu-Feng (San Mateo, CA), Wu; Sylvia Sau-Yan (San Francisco, CA)
Assignee: Genentech, Inc. (South San Francisco, CA)
Application Number:08/615,369
Patent Claims:1. A stable isotonic reconstituted formulation comprising an antibody in an amount of about 50 mg/mL to about 400 mg/mL and a diluent, which reconstituted formulation has been prepared from a lyophilized mixture of the antibody and a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant:antibody is about 100-510 mole lyoprotectant:1 mole of antibody, and wherein the antibody concentration in the reconstituted formulation is about 2-40 times greater than the antibody concentration in the mixture before lyophilization.

2. The formulation of claim 1 wherein the lyoprotectant is sucrose.

3. The formulation of claim 1 wherein the lyoprotectant is trehalose.

4. The formulation of claim 1 which further comprises a buffer.

5. The formulation of claim 4 wherein the buffer is histidine or succinate.

6. The formulation of claim 1 which farther comprises a surfactant.

7. The formulation of claim 1 which is sterile.

8. A stable reconstituted formulation comprising an antibody in an amount of about 50 mg/mL to about 400 mg/mL and a diluent, which reconstituted formulation has been prepared from a lyophilized mixture of an antibody and a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant:antibody is about 100-510 mole lyoprotectant:1 mole of antibody, and wherein the antibody concentration in the reconstituted formulation is about 2-40 times greater than the antibody concentration in the mixture before lyophilization.

9. The formulation of claim 8 wherein the antibody is an anti-IgE antibody.

10. The formulation of claim 8 wherein the antibody is an anti-HER2 antibody.

11. The formulation of claim 8 wherein the antibody is a full length humanized antibody.

12. The formulation of claim 8 which is isotonic.

13. A method for preparing a stable isotonic reconstituted formulation comprising reconstituting a lyophilized mixture of an antibody and a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant:antibody is about 100-510 mole lyoprotectant:1 mole of antibody in a diluent such that the antibody concentration in the reconstituted formulation is at least 50 mg/mL, wherein the antibody concentration in the reconstituted formulation is about 2-40 times greater than the antibody concentration in the mixture before lyophilization.

14. The method of claim 13 wherein the lyoprotectant is sucrose.

15. The method of claim 13 wherein the lyoprotectant is trehalose.

16. The method of claim 13 wherein the lyophilized mixture further comprises a bulking agent which is added in an amount which adds mass to the lyophilized mixture and contributes to the physical structure of the lyophilized cake.

17. A method for preparing a formulation comprising the steps of:

(a) lyophilizing a mixture of an antibody and a lyoprotecting amount of a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant:antibody is about 100-510 mole lyoprotectant:1 mole of antibody; and

(b) reconstituting the lyophilized mixture of step (a) in a diluent such that the reconstituted formulation is isotonic and stable and has an antibody concentration of about 80 mg/mL to about 400 mg/mL.

18. The method of claim 17 wherein the protein concentration in the reconstituted formulation is from about 80 mg/mL to about 300 mg/mL.

19. The method of claim 17 wherein the protein concentration in the reconstituted formulation is about 2-40 times greater than the protein concentration in the mixture before lyophilization.

20. The method of claim 17 wherein lyophilization is performed at a shelf temperature maintained at about 15-30.degree. C. throughout the entire lyophilization process.

21. An article of manufacture comprising:

(a) a container which holds a lyophilized mixture of an antibody and a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant: antibody is about 100-510 mole lyoprotectant:1 mole of antibody; and

(b) instructions for reconstituting the lyophilized mixture with a diluent to an antibody concentration in the reconstituted formulation of about 80 mg/mL to about 400 mg/mL.

22. The article of manufacture 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 article of manufacture of claim 21 further comprising a second container which holds a diluent.

24. The article of manufacture of claim 23 wherein the diluent is bacteriostatic water for injection (BWFI) comprising an aromatic alcohol.

25. A formulation comprising a lyophilized mixture of an antibody and a lyoprotectant which prevents or reduces chemical or physical instability of the antibody upon lyophilization and subsequent storage, wherein the molar ratio of lyoprotectant:antibody is about 100-510 mole lyoprotectant:1 mole antibody.

26. A formulation comprising anti-HER2 antibody in amount from about 5-40 mg/mL, sucrose or trehalose in an amount from about 10-100 mM, a buffer and a surfactant.

27. The formulation of claim 26 further comprising a bulking agent which adds mass to the lyophilized mixture and contributes to the physical structure of the lyophilized cake.

28. The formulation of claim 27 wherein the bulking agent is mannitol or glycine.

29. The formulation of claim 26 which is lyophilized and stable at 30.degree. C. for at least 6 months.

30. The formulation of claim 29 which is reconstituted with a diluent such that the anti-HER2 antibody concentration in the reconstituted formulation is from about 10-30 mg/mL, wherein the reconstituted formulation is stable at 2-8.degree. C. for at least about 30 days.

31. The formulation of claim 30 wherein the diluent is bacteriostatic water for injection (BWFI) comprising an aromatic alcohol.

32. A formulation comprising anti-IgE antibody in amount from about 5-40 mg/ML, sucrose or trehalose in an amount from about 80-300 mM, a buffer and a surfactant.

33. The formulation of claim 32 which is lyophilized and stable at about 30.degree. C. for at least 1 year.

34. The formulation of claim 1 wherein the antibody in the formulation is a monoclonal antibody.

35. The formulation of claim 1 wherein the reconstituted formulation fails to display significant or unacceptable levels of chemical or physical instability of the antibody upon storage at 2-8.degree. C. for at least 30 days.

36. The formulation of claim 1 wherein less than about 10% of the antibody is present as an aggregate in the reconstituted formulation.

37. The formulation of claim 1 wherein less than about 5% of the antibody is present as an aggregate in the reconstituted formulation.

38. The formulation of claim 1 wherein the lyoprotectant is a non-reducing sugar.

39. The formulation of claim 1 wherein the lyoprotectant is a disaccharide.

40. The formulation of claim 39 wherein the lyoprotectant is a non-reducing disaccharide.

41. The formulation of claim 1 wherein the molar ratio of lyoprotectant:antibody is about 200-510 mole lyoprotectant:1 mole of antibody.

42. The article of manufacture of claim 23 wherein the diluent is sterile water.

43. The article of manufacture of claim 23 wherein the diluent is sterile saline solution.

44. The formulation of claim 25 wherein the antibody is a monoclonal antibody.

45. The formulation of claim 44 wherein the lyoprotectant is sucrose.

46. The formulation of claim 44 wherein the lyoprotectant is trehalose.

47. A stable reconstituted formulation comprising a monoclonal antibody in an amount of about 50 mg/mL to about 400 mg/mL and a diluent, which reconstituted formulation has been prepared from a lyophilized mixture of the monoclonal antibody and a sugar selected from the group consisting of sucrose and trehalose, wherein the molar ratio of sugar:monoclonal antibody is about 100-510 mole sugar:1 mole of monoclonal antibody, and wherein the monoclonal antibody concentration in the reconstituted formulation is about 2-40 times greater than the monoclonal antibody concentration in the mixture before lyophilization.

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