Methods for reducing the viscosity of liquid pharmaceutical formulations comprising therapeutic proteins
A method for reducing the viscosity of a pharmaceutical formulation is provided that utilizes a viscosity-reducing concentration of an excipient selected from the group consisting of the n-acetyl arginine, n-acetyl lysine, n-acetyl proline and mixtures thereof in combination with a therapeutiv protein. A stable pharmaceutical formulation is also provided.
1. A method for reducing the viscosity of a liquid pharmaceutical formulation comprising an antibody at a concentration of at least 70 mg/ml, comprising combining the antibody with a viscosity-reducing concentration of an excipient selected from the group consisting of the n-acetyl arginine, n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof, wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 5% versus a control formulation.
2. The method of claim 1 wherein the excipient is n-acetyl arginine.
3. The method of claim 1 wherein the excipient is n-acetyl lysine.
4. The method of claim 1 wherein the excipient is n-acetyl histidine.
5. The method of claim 1 wherein the excipient is n-acetyl proline.
6. The method of claim 1 wherein viscosity of the formulation is reduced by at least 25%.
7. The method of claim 1 wherein viscosity of the formulation is reduced by at least 50%.
8. The method of claim 1 wherein viscosity of the formulation is reduced by at least 80%.
9. A pharmaceutical formulation produced by the method of claim 1 .
10. The method of claim 1 , comprising combining the excipient with the therapeutic protein at an excipient concentration of at least 50 mM.
11. The method of claim 1 , comprising combining the excipient with the therapeutic protein at an excipient concentration of 50 mM to 300 mM.
12. The method of claim 1 , comprising combining the excipient with the therapeutic protein at an excipient concentration of 100 mM to 400 mM.
13. The method of claim 1 , comprising combining the excipient with the therapeutic protein at an excipient concentration of less than 200 mM.
14. The method of claim 2 , wherein the concentration of the antibody is at least 140 mg/mL.
15. A pharmaceutical composition comprising an antibody at a concentration of at least 70 mg/ml and an excipient selected from the group consisting of n-acetyl arginine, n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof at a viscosity-reducing concentration, wherein the viscosity is reduced by at least 5% versus a control formulation and the concentration of the excipient is less than about 200 mM.
16. The pharmaceutical composition of claim 15 , wherein the excipient is n-acetyl arginine.
17. The pharmaceutical composition of claim 15 , wherein the excipient is n-acetyl lysine.
18. The pharmaceutical composition of claim 15 , wherein the excipient is n-acetyl histidine.
19. The pharmaceutical composition of claim 15 , wherein the excipient is n-acetyl proline.
20. The pharmaceutical composition of claim 15 having a pH between about 4.0 to about 8.0.
21. The pharmaceutical composition of claim 20 having a pH of about 4.6 to about 5.4.
22. A method of preparing a lyophilized powder comprising the step of lyophilizing the pharmaceutical composition of claim 15 .
23. The pharmaceutical composition of claim 16 , wherein the concentration of the antibody is at least 140 mg/mL.
24. The method of any one of claim 1 or 22 wherein the antibody is an IgG2 monoclonal antibody.
25. The pharmaceutical formulation or pharmaceutical composition of claim 9 or 15 wherein the antibody is an IgG2 monoclonal antibody.
26. A method for reducing the viscosity of a liquid pharmaceutical formulation comprising a therapeutic protein at a concentration of at least 70 mg/ml, comprising combining the therapeutic protein with a viscosity-reducing concentration of an excipient selected from the group consisting of the n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof, wherein the viscosity of the liquid pharmaceutical formulation is reduced by at least 5% versus a control formulation.
27. The method of claim 26 , wherein the excipient is n-acetyl lysine.
28. The method of claim 26 , wherein the excipient is n-acetyl histidine.
29. The method of claim 26 , wherein the excipient is n-acetyl proline.
30. The method of claim 26 , comprising combining the excipient with the therapeutic protein at an excipient concentration of at least 50 mM.
31. A pharmaceutical composition comprising a therapeutic protein at a concentration of at least 70 mg/ml and an excipient selected from the group consisting of n-acetyl lysine, n-acetyl histidine, n-acetyl proline and mixtures thereof at a viscosity-reducing concentration, wherein the viscosity is reduced by at least 5% versus a control formulation and the concentration of the excipient is less than about 200 mM.
32. The pharmaceutical composition of claim 31 , wherein the excipient is n-acetyl lysine.
33. The pharmaceutical composition of claim 31 , wherein the excipient is n-acetyl histidine.
34. The pharmaceutical composition of claim 31 , wherein the excipient is n-acetyl proline.
35. The pharmaceutical composition of claim 31 , having a pH of about 4.6 to about 5.4.