Formulations with reduced degradation of polysorbate

Abstract

The invention provides methods for making such formulations and methods of using such formulations. The invention further provides methods of reducing polysorbate degradation, methods of reducing the amount of visible and sub-visible particles in an aqueous formulation, and methods of disaggregating polysorbate degradation products comprising adding a cyclodextrin to a formula comprising polysorbate and a polypeptide. The invention also provides aqueous formulations comprising a polypeptide, a polysorbate, and a cyclodextrin with reduced polysorbate degradation.

1 - 50 . (canceled) 
     
     
         51 . A method to produce an aqueous formulation of a polypeptide and a polysorbate, the method comprising adding a cyclodextrin to the formulation, wherein the resulting w/w ratio of cyclodextrin to polysorbate is greater than about 37.5:1, wherein degradation of the polysorbate is reduced compared to the formulation without polysorbate. 
     
     
         52 . The method of  claim 51 , wherein the polysorbate is polysorbate 20 or polysorbate 80. 
     
     
         53 . The method of  claim 51 , wherein the cyclodextrin is HP-β cyclodextrin, HP-γ cyclodextrin, or sulfobutyl ether β-cyclodextrin. 
     
     
         54 . The method of  claim 51 , wherein the concentration of polysorbate in the formulation is in the range of about 0.01% to 0.4%. 
     
     
         55 . The method of  claim 51 , wherein the concentration of cyclodextrin in the formulation is in the range of about 0.5 to 30%. 
     
     
         56 . The method of  claim 51 , wherein the polysorbate degradation is reduced by about 50%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99%. 
     
     
         57 . The method of  claim 51 , wherein the polypeptide is an antibody. 
     
     
         58 . The method of  claim 56 , wherein the antibody is a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, a multispecific antibody or an antibody fragment. 
     
     
         59 . The method of  claim 51 , wherein the polypeptide concentration in the formulation is about 1 mg/mL to about 250 mg/mL. 
     
     
         60 . A method of treating a mammal in need of treatment with a polypeptide, the method comprising administering an aqueous formulation to the mammal, wherein the aqueous formulation comprises the polypeptide, a polysorbate, and a cyclodextrin, wherein the w/w ratio of cyclodextrin to polysorbate is greater than about 37.5:1. 
     
     
         61 . The method of  claim 59 , wherein the polypeptide is an antibody. 
     
     
         62 . The method of  claim 59 , wherein the formulation is administered intravenously, subcutaneously, intramuscularly, or intravitreally. 
     
     
         63 . A kit for reducing polysorbate degradation, wherein the kit comprises an aqueous formulation of a polypeptide and a polysorbate, and a solution of a cyclodextrin, wherein the cyclodextrin is added to the formulation at a resulting w/w ratio of cyclodextrin to polysorbate of greater than about 37.5:1. 
     
     
         64 . The kit of  claim 62 , wherein the polysorbate is polysorbate 20 or polysorbate 80. 
     
     
         65 . The kit of  claim 62 , wherein the cyclodextrin is HP-β cyclodextrin, HP-γ cyclodextrin, or sulfobutyl ether β-cyclodextrin. 
     
     
         66 . The kit of  claim 62 , wherein the concentration of polysorbate in the formulation is in the range of about 0.01% to 0.4%. 
     
     
         67 . The kit of  claim 62 , wherein the concentration of cyclodextrin in the formulation is in the range of about 0.5 to 30%. 
     
     
         68 . The kit of  claim 51 , wherein the polysorbate degradation is reduced by about 50%, about 75%, about 80%, about 85%, about 90%, about 95% or about 99%. 
     
     
         69 . The kit of  claim 51 , wherein the polypeptide is an antibody. 
     
     
         70 . The kit of  claim 56 , wherein the antibody is a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody, a multispecific antibody or an antibody fragment. 
     
     
         71 . The kit of  claim 51 , wherein the polypeptide concentration in the formulation is about 1 mg/mL to about 250 mg/mL.