Stable Liquid Antibody Formulation

Abstract

The present invention relates generally to the field of pharmaceutical formulations of antibodies. Specifically, the present invention relates to a stable liquid antibody formulation and its pharmaceutical preparation and use. This invention is exemplified by a liquid formulation of a humanised anti-NGF antibody.

1 . A liquid composition comprising;
 at least one antibody,   at least one tonicity agent,   at least one buffer,   at least one chelating agent,   at least one surfactant,   wherein the pH of said composition is from 5.8 to 6.8.   
     
     
         2 . The liquid composition according to  claim 1  consisting essentially of;
 at least one antibody, 
 at least one tonicity agent, 
 at least one buffer, 
 at least one chelating agent, 
 at least one surfactant, 
 wherein the pH of said composition is from 5.8 to 6.8. 
 
     
     
         3 . The liquid composition according to  claim 1 , wherein the tonicity agent is a non reducing sugar. 
     
     
         4 . The liquid composition according to  claim 3 , wherein the reducing sugar is trehalose dihydrate at a concentration of about 1 mg/ml to about 100 mg/ml. 
     
     
         5 . The liquid composition according to  claim 1  wherein the surfactant is a polysorbate, preferably polysorbate 20. 
     
     
         6 . The liquid composition according to  claim 5  wherein the concentration of polysorbate is from about 0.01 to about 0.15 mg/ml. 
     
     
         7 . The liquid composition according to  claim 1  wherein the buffer is histidine buffer. 
     
     
         8 . The liquid composition according to  claim 7  wherein the concentration of histidine buffer is from about 1.0 to about 15 mM. 
     
     
         9 . The liquid composition according to  claim 1  wherein the chelating agent is disodium EDTA, preferably of a concentration from about 0.01 to about 0.1 mg/ml. 
     
     
         10 . The liquid composition according  claim 1  wherein the antibody concentration is less than or equal to about 50 mg/ml. 
     
     
         11 . The liquid composition according to  claim 10  wherein the antibody concentration is selected from about 2 mg/ml, about 2.5 mg/ml, about 5 mg/ml, about 10 mg/ml, about 20 mg/ml, about 22 mg/ml and about 50 mg/ml. 
     
     
         12 . The liquid composition according to  claim 1  which further comprises an antioxidant agent and/or a preservative agent. 
     
     
         13 . The liquid composition according to  claim 1  which does not comprise an antioxidant agent, a preservative agent or both. 
     
     
         14 . The liquid composition according to  claim 1  comprising;
 about 0.5 mg/ml to about 50 mg/ml of at least one antibody, 
 about 1.0 mM to about 15 mM histidine buffer, 
 about 1 mg/ml to about 100 mg/ml trehalose dihydrate, 
 about 0.01 to about 0.15 mg/ml PS20, 
 about 0.01 to about 0.1 mg/ml. disodium EDTA, 
 wherein said composition is of a pH from 5.8 to 6.8. 
 
     
     
         15 . The liquid composition according to  claim 13  consisting of;
 about 0.5 mg/ml to about 50 mg/ml of at least one antibody, 
 about 1.0 mM to about 15 mM histidine buffer, 
 about 1 mg/ml to about 100 mg/ml trehalose dihydrate, 
 about 0.01 to about 0.15 mg/ml PS20, 
 about 0.01 to about 0.1 mg/ml. disodium EDTA, 
 wherein said composition is of a pH from 5.8 to 6.8. 
 
     
     
         16 . The liquid composition according to  claim 14  comprising;
 about 2.5 mg/ml, 5 mg/ml, 10 mg/ml, 20 mg/ml, 22 mg/ml or about 50 mg/ml of at least one antibody, 
 about 10 mM histidine buffer, 
 about 84 mg/ml trehalose dihydrate, 
 about 0.1 mg/ml PS20, 
 about 0.05 mg/ml. disodium EDTA, 
 wherein said composition is of a pH 6.0+/−0.2. 
 
     
     
         17 . The liquid composition according to  claim 14  comprising;
 about 2.5 mg/ml, 5 mg/ml, 10 mg/ml, 20 mg/ml, 22 mg/ml or about 50 mg/ml of at least one antibody, 
 about 10 mM histidine buffer, 
 about 84 mg/ml trehalose dihydrate, 
 about 0.1 mg/ml PS20, 
 about 0.05 mg/ml disodium EDTA, 
 wherein said composition is of a pH from 5.8 to 6.5. 
 
     
     
         18 . The liquid composition according to  claim 1  wherein the at least one antibody is a human or humanised monoclonal antibody. 
     
     
         19 . The liquid composition according to  claim 1  wherein the at least one antibody is an IgG2 antibody 
     
     
         20 . The liquid composition according to  claim 1  wherein at least one antibody binds to human NGF with a Kd of less than or about 2 nM. 
     
     
         21 . The liquid composition according to  claim 1  wherein the at least one antibody comprises an amino acid sequence that is at least 90% identical to a heavy chain variable region amino acid sequence shown in SEQ ID NO: 1, and an amino acid sequence that is at least 90% identical to a light chain variable region amino acid sequence shown in SEQ ID NO: 2 
     
     
         22 . The liquid composition according to  claim 1  wherein the at least one antibody comprises an amino acid sequence that is at least 90% identical to a heavy chain amino acid sequence shown in SEQ ID NO: 16, and an amino acid sequence that is at least 90% identical to a light chain amino acid sequence shown in SEQ ID NO: 17. 
     
     
         23 . The liquid composition according to  claim 1  wherein the antibody comprises a variable heavy chain sequence of SEQ ID NO. 1 and a variable light chain sequence of SEQ ID NO. 2. 
     
     
         24 . The liquid composition according to  claim 1  wherein the composition is not lyophilized. 
     
     
         25 . The liquid composition according to  claim 1  wherein the composition is resistant to aggregation of the antibody after multiple freeze thaw cycles. 
     
     
         26 . The liquid composition according to  claim 1  wherein the composition can be stored for a period of at least about 26 weeks at a temperature of about 40° C. and wherein there is less than about 10% increase in aggregation of the antibody of the composition. 
     
     
         27 . The liquid composition according to  claim 1  wherein the composition can be stored for a period of at least about 26 weeks at a temperature of about 40° C. and wherein there is less than about 10% increase in oxidation of the antibody of the composition. 
     
     
         28 . The liquid composition according to  claim 1  wherein the composition can be stored for a period of at least about 26 weeks at a temperature of about 40° C. and wherein there is less than about 10% decrease in activity of the antibody of the composition. 
     
     
         29 . The liquid composition according to  claim 1  wherein the composition can stored for a period of at least about 26 weeks at a temperature of between 2 to 8° C. and wherein there is less than about 10% increase in aggregation of the antibody of the composition. 
     
     
         30 . A pharmaceutical composition for treating pain in a mammal comprising an effective amount of the liquid composition of  claim 1 . 
     
     
         31 . A method for treating pain in a mammal comprising administering an effective amount of the liquid composition of  claim 1  to said mammal once every eight weeks. 
     
     
         32 . The method according to  claim 31  wherein the volume of the effective amount of the liquid composition of  claim 1  is less than or equal to about 2.5 ml. 
     
     
         33 . The method according to  claim 31  wherein the effective amount of the liquid composition of  claim 1  contains less than or equal to 50 mg of antibody. 
     
     
         34 . The method according to  claim 31  wherein administration of the effective amount of the liquid composition of  claim 1  is administered either intravenously or subcutaneously intravenously.