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 liquid pharmaceutical composition comprising:
 (a) 75-150 mg/mL adalimumab;   (b) an acetate buffer system;   (c) a tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg; and   (d) a surfactant;   
       wherein the composition is free of phosphate buffering agents. 
     
     
         2 . The liquid pharmaceutical composition of  claim 1 , wherein the tonicifier comprises one or more tonicifiers selected from the group consisting of: stabilisers that act as osmolytes, water-soluble metal salts, water-soluble tonicifying sugars/sugar alcohols, water-soluble polyols, and any combination thereof. 
     
     
         3 . The liquid pharmaceutical composition of  claim 2 , wherein the tonicifier is or comprises a sugar stabiliser. 
     
     
         4 . The liquid pharmaceutical composition of  claim 3 , wherein the composition comprises only a single sugar stabiliser. 
     
     
         5 . The liquid pharmaceutical composition of  claim 4 , wherein the sugar stabiliser is a non-reducing sugar polyol or a non-reducing disaccharide without any aldehyde moieties and without the capability of forming an aldehyde moiety through isomerism. 
     
     
         6 . The liquid pharmaceutical composition of  claim 4 , wherein the sugar stabiliser is present at a concentration between 100 and 300 mM. 
     
     
         7 . The liquid pharmaceutical composition of  claim 4 , wherein the sugar stabiliser is present at a concentration between 15 and 140 mg/mL. 
     
     
         8 . The liquid pharmaceutical composition of  claim 6 , wherein the composition comprises 100-300 mM mannitol. 
     
     
         9 . The liquid pharmaceutical composition of  claim 6 , wherein the composition comprises 100-300 mM sorbitol. 
     
     
         10 . The liquid pharmaceutical composition of  claim 6 , wherein the composition comprises 100-300 mM trehalose. 
     
     
         11 . The liquid pharmaceutical composition of  claim 6 , wherein the composition comprises 100-300 mM sucrose. 
     
     
         12 . The liquid pharmaceutical composition of  claim 2 , wherein the tonicifier is or comprises a water-soluble metal salt. 
     
     
         13 . The liquid pharmaceutical composition of  claim 12 , wherein the tonicifier is or comprises sodium chloride. 
     
     
         14 . The liquid pharmaceutical composition of  claim 2 , wherein the tonicifier consists of a water-soluble metal salt and a single sugar stabiliser that is either a sugar polyol or a disaccharide. 
     
     
         15 . The liquid pharmaceutical composition of  claim 1 , wherein the acetate buffer system is the sole buffer system and is present at a concentration of 2-14 mM. 
     
     
         16 . The liquid pharmaceutical composition of  claim 1 , wherein the composition has a pH between pH 5.0 and 5.5. 
     
     
         17 . The liquid pharmaceutical composition of  claim 1 , wherein the composition is free of arginine. 
     
     
         18 . The liquid pharmaceutical composition of  claim 1 , wherein the composition is free of amino acids. 
     
     
         19 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 75-150 mg/mL adalimumab;   (b) an acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg; and   (d) a surfactant;   
       wherein the composition is free of phosphate buffering agents. 
     
     
         20 . The liquid pharmaceutical composition of in  claim 1 , wherein the composition comprises:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5 and is free of phosphate buffering agents. 
     
     
         21 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5 and is free of phosphate buffering agents. 
     
     
         22 . The liquid pharmaceutical composition of  claim 1 , wherein the composition comprises:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg, wherein the tonicifier consists of sugar stabiliser present at a concentration between 100 and 300 mM and optionally a water-soluble metal salt; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5 and is free of phosphate buffering agents. 
     
     
         23 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg, wherein the tonicifier consists of sugar stabiliser present at a concentration between 100 and 300 mM and optionally a water-soluble metal salt; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5 and is free of phosphate buffering agents. 
     
     
         24 . The liquid pharmaceutical composition of  claim 1 , wherein the composition comprises:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg, wherein the tonicifier consists of sugar stabiliser present at a concentration between 100 and 300 mM and optionally a water-soluble metal salt; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5, is free of phosphate buffering agents, and is free of amino acids. 
     
     
         25 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 200 and 400 mOsm/kg, wherein the tonicifier consists of sugar stabiliser present at a concentration between 100 and 300 mM and optionally a water-soluble metal salt; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5 to 5.5, is free of phosphate buffering agents, and is free of amino acids. 
     
     
         26 . The liquid pharmaceutical composition of  claim 1 , wherein the composition comprises:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 230 and 350 mOsm/kg, wherein the tonicifier comprises a water-soluble metal salt, and optionally a single sugar stabiliser that is a sugar polyol or a disaccharide; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5.0 to 5.5, is free of phosphate buffering agents, and is free of amino acids. 
     
     
         27 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 230 and 350 mOsm/kg, wherein the tonicifier comprises a water-soluble metal salt, and optionally a single sugar stabiliser that is a sugar polyol or a disaccharide; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5.0 to 5.5, is free of phosphate buffering agents, and is free of amino acids. 
     
     
         28 . The liquid pharmaceutical composition of  claim 1 , wherein the composition comprises:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 230 and 350 mOsm/kg, wherein the tonicifier comprises a water-soluble metal salt, and 100-300 mM single sugar stabiliser that is a sugar polyol or a disaccharide; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5.0 to 5.5, is free of phosphate buffering agents, and is free of amino acids. 
     
     
         29 . The liquid pharmaceutical composition of  claim 1 , wherein the composition consists of:
 (a) 75-150 mg/mL adalimumab;   (b) 2-14 mM acetate buffer system;   (c) tonicifier at a concentration sufficient for the composition to have an osmolality between 230 and 350 mOsm/kg, wherein the tonicifier comprises a water-soluble metal salt, and 100-300 mM single sugar stabiliser that is a sugar polyol or a disaccharide; and   (d) 0.01-2 mg/mL surfactant;   
       wherein the composition has a pH of 5.0 to 5.5, is free of phosphate buffering agents, and is free of amino acids.