Pharmaceutical Formulations

Abstract

The invention relates to a liquid pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof, cyclodextrin and methionine. In addition, it relates to a method for reducing precipitation of an antibody or an antigen-bindmg fragment thereof in a liquid pharmaceutical formulation through addition of methionine and cyclodextrin. In particular, the liquid pharmaceutical formulations comprises an anti-sclerostin antibody, hydroxypropyl-gamma cyclodextrin and methionine and may be used in the treatment of a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength, and especially for treating osteoporosis. Furthermore, the invention relates to a method of reducing inflammation at injection site in a mammalian subject comprising administering a therapeutically effective amount of a liquid pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof, cyclo dextrin and methionine.

1 . A liquid pharmaceutical formulation comprising:
 a. an antibody or an antigen-binding fragment thereof as an active ingredient;   b. cyclodextrin and   c. methionine.   
     
     
         2 . The liquid formulation according to  claim 1  comprising methionine at a concentration of from 7.5 mM to 200 mM. 
     
     
         3 . The liquid formulation according to  claim 1  comprising cyclodextrin at a concentration of from 7.5 mM to 250 mM. 
     
     
         4 . The liquid formulation according to  claim 1  comprising the antibody or the antigen-binding fragment thereof at a concentration of from 1 to 200 mg/ml, preferably from 90 to 180 mg/ml. 
     
     
         5 . The liquid formulation according to  claim 1 , wherein the antibody or the antigen-binding fragment thereof specifically binds human sclerostin. 
     
     
         6 . The liquid formulation according to  claim 1  wherein the antibody is a human or humanised antibody or antigen-binding fragment thereof. 
     
     
         7 . The liquid formulation according to  claim 1 , wherein:
 a. the antibody or the antigen-binding fragment thereof   i. comprises CDR-H1 having the sequence as defined in SEQ ID NO:1; CDR-H2 having the sequence as defined in SEQ ID NO:2; CDR-H3 having the sequence as defined in SEQ ID NO:3; CDR-L1 having the sequence as defined in SEQ ID NO:4; CDR-L2 having the sequence as defined in SEQ ID NO:5 and CDR-L3 having the sequence as defined in SEQ ID NO:6; or   ii. has a light variable region having the sequence as defined in SEQ ID NO: 7 and a heavy variable region having the sequence as defined in SEQ ID NO: 8; or   b. the antibody has   i. a light chain having the sequence as defined in SEQ ID NO: 9 and a heavy chain having the sequence as defined in SEQ ID NO: 10; or   ii. a light chain having the sequence as defined in SEQ ID NO: 11 and a heavy chain having the sequence as defined in SEQ ID NO: 12.   
     
     
         8 . The liquid formulation according to  claim 1 , wherein the antibody is romosozumab. 
     
     
         9 . The liquid formulation according to  claim 1  having a pH of from 4.0 to 7.5. 
     
     
         10 . The liquid formulation according to  claim 1  wherein the cyclodextrin is selected from alpha-cyclodextrin, beta-cyclodextrin, dimethyl-beta-cyclodextrin, trimethyl-beta-cyclodextrin, randomly methylated beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin (i.e. 2 hydroxypropyl-beta-cyclodextrin, 3-hydroxypropyl-beta-cyclodextrin or 2,3-dihydroxypropyl-beta-cyclodextrin), hydroxyisobutyl-beta-cyclodextrin sulfobutylether beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin (i.e. 2 hydroxypropyl-gamma-cyclodextrin, 3-hydroxypropyl-gamma-cyclodextrin or 2,3-dihydroxypropyl-gamma-cyclodextrin), cyclodextrin-containing polymers or combinations thereof. 
     
     
         11 . The liquid formulation according to  claim 10 , wherein the cyclodextrin is selected from hydroxypropyl-gamma-cyclodextrin. 
     
     
         12 . The liquid formulation according to  claim 1  wherein the formulation comprises from 1 mg/ml to 200 mg/ml of antibody, from 10 mM to 55 mM sodium acetate, from 0 to 14 mM calcium acetate, from 0 to 6% sucrose, from 0 to 0.006% polysorbate 20, from 55 mM to 80 mM hydroxypropyl-gamma-cyclodextrin, from 55 mM to 160 mM methionine at pH 5.2. 
     
     
         13 . The liquid formulation according to  claim 12 , wherein the formulation comprises from 90 mg/ml to 180 mg/ml, preferably from 120 mg/ml to 180 mg/ml of romosozumab. 
     
     
         14 . The liquid formulation according to  claim 1  wherein the liquid formulation is not a hydrogel. 
     
     
         15 . The liquid formulation according to  claim 1  wherein the liquid formulation comprises at least 2%, at least 5%, at least 10%, at least 25%, between 2% and 90%, between 2% and 75%, or between 2% and 50% water. 
     
     
         16 . The liquid formulation according to  claim 1  for use in the treatment of a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength. 
     
     
         17 . A method for treating a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength in a mammalian subject comprising administering a therapeutically effective amount of the formulation of  claim 1 . 
     
     
         18 . Use of the liquid formulation according to any one of  claims 1  in the manufacture of a medicament for the treatment of a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength. 
     
     
         19 . (canceled) 
     
     
         20 . A method for reducing precipitation of an antibody or an antigen-binding fragment thereof in a liquid pharmaceutical formulation, the method comprising providing a liquid formulation and adding to the formulation methionine and cyclodextrin, preferably hydroxypropyl-gamma-cyclodextrin. 
     
     
         21 . A method of reducing inflammation at injection site in a mammalian subject comprising administering a therapeutically effective amount of the formulation of  claim 1 .