Liquid pharmaceutical composition

Abstract

The present invention relates to novel liquid pharmaceutical compositions of adalimumab, which include adalimumab or a biosimilar thereof, an acetate buffering agent/system such as sodium acetate/acetic acid, and a sugar stabiliser such as trehalose. Such a combination of components furnishes formulations having a stability (e.g. on storage and when exposed to stress) which is comparable to or an improvement upon those known in the art, and with fewer ingredients. Such advances will help adalimumab treatments to become more widely available at lower cost, and prolong the viability of pre-loaded delivery devices (e.g. pre-filled syringes) to reduce unnecessary waste of the drug.

1 . A buffered solution comprising:
 i) adalimumab;   ii) a sugar polyol;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) a surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH between 5.0 and 5.5; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         2 . The buffered solution of  claim 1 , wherein the buffered solution comprises:
 i) 45-55 mg/mL adalimumab;   ii) 100-300 mM sugar polyol;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) 0.05-1.5 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH between 5.1 and 5.3; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         3 . The buffered solution of  claim 1 , wherein the buffered solution comprises:
 i) 45-55 mg/mL adalimumab;   ii) 250-300 mM sorbitol;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) 0.9-1.1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         4 . The buffered solution of  claim 1 , wherein the buffered solution consists of:
 i) 45-55 mg/mL adalimumab;   ii) 250-300 mM sorbitol;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) 0.9-1.1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; and 
 has an osmolality between 260 and 320 mOsm/kg. 
 
     
     
         5 . The buffered solution of  claim 4 , wherein the buffered solution consists of:
 i) 45-55 mg/mL adalimumab;   ii) 250-300 mM sorbitol;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) 0.9-1.1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; and 
 is an aqueous buffered solution having a buffer system consisting of a combination of a buffering agent and its acid/base conjugate, the conjugate acid being a weak acid exhibiting a pK a  of 2.0 or more, such that together the buffering agent and its acid/base conjugate are present at a level and in a relative amount sufficient to provide the desired pH for the composition which is a pH of 5.2. 
 
     
     
         6 . The buffered solution of  claim 1 , wherein the buffered solution comprises:
 i) adalimumab;   ii) a sugar polyol present in a molar ratio of sugar polyol to adalimumab of from 290:1 to 860:1;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) a surfactant, which is polysorbate 80, present in a molar ratio of surfactant to adalimumab of from 1:35 to 3:1;   
       wherein the buffered solution:
 has a pH between 5.1 and 5.3; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         7 . The buffered solution of  claim 1 , wherein the buffered solution comprises:
 i) adalimumab;   ii) sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) a surfactant, which is polysorbate 80, present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         8 . The buffered solution of  claim 1 , wherein the buffered solution consists of:
 i) adalimumab;   ii) sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) a surfactant, which is polysorbate 80, present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1;   
       wherein the buffered solution has a pH of 5.2. 
     
     
         9 . The buffered solution of  claim 8 , wherein the buffered solution consists of:
 i) adalimumab;   ii) sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1;   iii) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine; and   iv) a surfactant, which is polysorbate 80, present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; and 
 is an aqueous buffered solution having a buffer system consisting of a combination of a buffering agent and its acid/base conjugate, the conjugate acid being a weak acid exhibiting a pK a  of 2.0 or more, such that together the buffering agent and its acid/base conjugate are present at a level and in a relative amount sufficient to provide the desired pH for the composition which is a pH of 5.2. 
 
     
     
         10 . The buffered solution of  claim 9 , wherein the buffer system is present in a molar ratio of buffer system to adalimumab of from 14:1 to 40:1. 
     
     
         11 . The buffered solution of  claim 1 , wherein the buffered solution consists of:
 i) 50 mg/mL adalimumab;   ii) 10-14 mM buffer system;   iii) about 45 mg/mL sorbitol;   iv) a stabiliser, which is an amino acid other than amino acid arginine, lysine, aspartic acid, and histidine;   v) 1 mg/mL surfactant, which is polysorbate 80; and   vi) water;   
       wherein the buffered solution:
 has a pH of 5.2; and 
 has an osmolality between 260 and 320 mOsm/kg. 
 
     
     
         12 . A buffered solution, wherein at least 99 wt % of the buffered solution consists of:
 i) adalimumab;   ii) a sugar polyol;   iii) a surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH between 5.0 and 5.5; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         13 . The buffered solution of  claim 12 , wherein at least 99 wt % of the buffered solution consists of:
 i) 45-55 mg/mL adalimumab;   ii) 100-300 mM sugar polyol;   iii) 0.05-1.5 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH between 5.1 and 5.3; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         14 . The buffered solution of  claim 12 , wherein at least 99 wt % of the buffered solution consists of:
 i) 45-55 mg/mL adalimumab;   ii) 250-300 mM sorbitol;   iii) 0.9-1.1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         15 . The buffered solution of  claim 12 , wherein at least 99 wt % of the buffered solution consists of:
 i) 45-55 mg/mL adalimumab;   ii) 250-300 mM sorbitol; and   iii) 0.9-1.1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is an aqueous buffer solution having a buffer system consisting of a combination of a buffering agent and its acid/base conjugate, the conjugate acid being a weak acid exhibiting a pK a  of 2.0 or more, such that together the buffering agent and its acid/base conjugate are present at a level and in a relative amount sufficient to provide the desired pH for the composition which is a pH of 5.2; and 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         16 . The buffered solution of  claim 12 , wherein
 the sugar polyol is present in a molar ratio of sugar polyol to adalimumab of from 290:1 to 860:1;   the surfactant, which is polysorbate 80, is present in a molar ratio of surfactant to adalimumab of from 1:35 to 3:1; and   the buffered solution has a pH between 5.1 and 5.3.   
     
     
         17 . The buffered solution of  claim 12 , wherein
 the sugar polyol is sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1;   the surfactant, which is polysorbate 80, is present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1; and   the buffered solution has a pH of 5.2.   
     
     
         18 . The buffered solution of  claim 12 , wherein
 the sugar polyol is sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1;   the surfactant, which is polysorbate 80, is present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1; and   the buffered solution has a pH of 5.2.   
     
     
         19 . The buffered solution of  claim 18 , wherein the sugar polyol is sorbitol present in a molar ratio of sorbitol to adalimumab of from 720:1 to 860:1; and
 the surfactant, which is polysorbate 80, is present at a molar ratio of surfactant to adalimumab of from 2.1:1 to 2.3:1;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is an aqueous buffered solution having a buffer system consisting of a combination of a buffering agent and its acid/base conjugate, the conjugate acid being a weak acid exhibiting a pK a  of 2.0 or more, such that together the buffering agent and its acid/base conjugate are present at a level and in a relative amount sufficient to provide the desired pH for the composition which is a pH of 5.2. 
 
     
     
         20 . The buffered solution of  claim 19 , wherein the buffer system is present in a molar ratio of buffer system to adalimumab of from 14:1 to 40:1. 
     
     
         21 . The buffered solution of  claim 12 , wherein at least 99 wt % of the buffered solution consists of:
 i) 50 mg/mL adalimumab;   ii) about 45 mg/mL sorbitol; and   iii) 1 mg/mL surfactant, which is polysorbate 80;   
       wherein the buffered solution:
 has a pH of 5.2; 
 has an osmolality between 260 and 320 mOsm/kg; 
 is an aqueous buffered solution having a buffer system present in an amount of 10-14 mM; 
 is free of arginine, lysine, aspartic acid, and histidine; 
 is free of surfactants with the exception of polysorbate 80; and 
 is free of phosphate buffering agents. 
 
     
     
         22 . A drug delivery device comprising the buffered solution of  claim 1 . 
     
     
         23 . A drug delivery device comprising the buffered solution of  claim 12 . 
     
     
         24 . A method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and/or juvenile idiopathic arthritis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of the buffered solution of  claim 1 . 
     
     
         25 . The method of treating of  claim 24 , wherein the method is for treating psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and/or juvenile idiopathic arthritis in a patient in need of such treatment. 
     
     
         26 . A method of treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and/or juvenile idiopathic arthritis in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of the buffered solution of  claim 12 . 
     
     
         27 . The method of treating of  claim 26 , wherein the method is for treating psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and/or juvenile idiopathic arthritis in a patient in need of such treatment.