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 . An aqueous pharmaceutical composition comprising:
 (a) adalimumab;   (b) a sugar stabiliser that is a sugar polyol;   (c) an amino acid stabiliser;   (d) a non-buffering tonicifier that is the sugar polyol;   (e) polysorbate 80; and   (f) a buffer system;   wherein:   the composition comprises at most one sugar stabiliser, which is the sugar polyol;   the composition comprises only a single non-buffering tonicifier, which is the sugar polyol;   the composition is either free of surfactants, with the exception of polysorbate 80, or comprises one or more of said surfactants excluding polysorbate 80 in a collective concentration of at most 1 mM;   the buffer system comprises a combination of a buffering agent and its acid/base conjugate, the conjugate acid being a weak acid exhibiting a pKa 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 between 5.0 and pH 6.7; and   the composition is either free of phosphate buffering agents or comprises a phosphate buffer system in a concentration of at most 0.1 mM.   
     
     
         2 . The aqueous pharmaceutical composition of  claim 1 , wherein the sugar polyol is sorbitol. 
     
     
         3 . The aqueous pharmaceutical composition of  claim 1 , wherein the sugar polyol is present at a concentration of 190-300 mM. 
     
     
         4 . The aqueous pharmaceutical composition of  claim 1 , wherein the sugar polyol is present at a concentration of 250-300 mM. 
     
     
         5 . The aqueous pharmaceutical composition of  claim 1 , wherein the buffer system is present at a concentration of 5-14 mM. 
     
     
         6 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition comprises the adalimumab at a concentration of 45-55 mg/mL. 
     
     
         7 . The aqueous pharmaceutical composition of  claim 1 , wherein the polysorbate 80 is present at a concentration of 0.05-1.5 mg/mL. 
     
     
         8 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is a sugar polyol;   (c) 0.05-1.5 mg/mL polysorbate 80.   
     
     
         9 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is a sugar polyol;   (c) 0.05-1.5 mg/mL polysorbate 80;   (d) 5-14 mM buffer system.   
     
     
         10 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is sorbitol   (c) 0.05-1.5 mg/mL polysorbate 80.   
     
     
         11 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is sorbitol   (c) 0.05-1.5 mg/mL polysorbate 80;   (d) 5-14 mM buffer system.   
     
     
         12 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 the buffer system in a molar ratio of buffer system to adalimumab of from 5:1 to 145:1;   the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 145:1 to 1150:1;   the polysorbate 80 in a molar ratio of polysorbate 80 to adalimumab of from 1:3500 to 15:1.   
     
     
         13 . The aqueous pharmaceutical composition of  claim 1 , comprising:
 the buffer system in a molar ratio of buffer system to adalimumab of from 14:1 to 40:1;   the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 550:1 to 860:1;   the polysorbate 80 in a molar ratio of polysorbate 80 to adalimumab of from 1:35 to 3:1.   
     
     
         14 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition is isotonic with bodily fluids. 
     
     
         15 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition has an osmolality between 260 and 320 mOsm/kg. 
     
     
         16 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is a sugar polyol;   (c) 0.05-1.5 mg/mL polysorbate 80;   (d) the amino acid stabiliser;   (e) the buffer system; and   (f) water.   
     
     
         17 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 45-55 mg/mL adalimumab;   (b) 190-300 mM sugar stabiliser that is sorbitol   (c) 0.05-1.5 mg/mL polysorbate 80;   (d) 5-14 mM buffer system;   (e) the amino acid stabiliser; and   (f) water.   
     
     
         18 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) adalimumab;   (b) the sugar stabiliser that is a sugar polyol;   (c) the amino acid stabiliser;   (d) the polysorbate 80;   (e) the buffer system; and   (f) water.   
     
     
         19 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) adalimumab;   (b) the sugar stabiliser that is a sugar polyol;   (c) the amino acid stabiliser;   (d) the polysorbate 80;   (e) the buffer system; and   (f) water;   wherein:
 the buffer system in a molar ratio of buffer system to adalimumab of from 5:1 to 145:1; 
 the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 145:1 to 1150:1; 
 the polysorbate 80 in a molar ratio of polysorbate 80 to adalimumab of from 1:3500 to 15:1. 
   
     
     
         20 . The aqueous pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) adalimumab;   (b) the sugar stabiliser that is a sugar polyol;   (c) the amino acid stabiliser;   (d) the polysorbate 80;   (e) the buffer system; and   (f) water;   wherein:
 the buffer system in a molar ratio of buffer system to adalimumab of from 14:1 to 40:1; 
 the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 550:1 to 860:1; 
 the polysorbate 80 in a molar ratio of polysorbate 80 to adalimumab of from 1:35 to 3:1. 
   
     
     
         21 . A drug delivery device comprising the aqueous pharmaceutical composition of  claim 1 .