Liquid pharmaceutical composition

Abstract

The present invention relates to novel liquid pharmaceutical compositions of adalimumab, which include adalimumab or a biosimilar thereof, a citrate buffering agent/system such as sodium citrate/citric 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 - 16 . (canceled) 
     
     
         17 . An aqueous pharmaceutical composition comprising:
 (a) adalimumab;   (b) a citrate buffer system in a molar ratio of citrate buffer system to adalimumab of from 14:1 to 40:1;   (c) a sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 290:1 to 860:1, wherein the sugar stabiliser is selected from the group consisting of trehalose, mannitol, sucrose, sorbitol, maltose, lactose, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol; and   (d) a surfactant in a molar ratio of surfactant to adalimumab of from 1:35 to 3:1;   
       wherein the composition:
 has a pH between 5.0 and 6.7; 
 is free of phosphate buffering agents 
 is free of arginine; and 
 comprises at most one sugar stabiliser. 
 
     
     
         18 . The aqueous pharmaceutical composition of  claim 17 , wherein the molecular weight of adalimumab is taken to be 144190.3 g/mol such that the number of moles in a known weight of adalimumab is calculated using this molecular weight. 
     
     
         19 . The aqueous pharmaceutical composition of  claim 17 , wherein adalimumab is present in the composition at a concentration of 45-55 mg/mL. 
     
     
         20 . The aqueous pharmaceutical composition of  claim 17 , wherein adalimumab is present in the composition at a concentration of 0.347 mM. 
     
     
         21 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition is free of amino acids selected from the group consisting of arginine, lysine, and aspartic acid. 
     
     
         22 . The aqueous pharmaceutical composition of  claim 17 , wherein the sugar stabiliser is selected from the group consisting of trehalose, sucrose, sorbitol, maltose, lactose, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. 
     
     
         23 . The aqueous pharmaceutical composition of  claim 17 , wherein the sugar stabiliser is a sugar polyol. 
     
     
         24 . The aqueous pharmaceutical composition of  claim 23 , wherein the sugar polyol is selected from the group consisting of sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol. 
     
     
         25 . The aqueous pharmaceutical composition as claimed in  claim 24 , wherein the sugar stabiliser is sorbitol. 
     
     
         26 . The aqueous pharmaceutical composition of  claim 17 , wherein the surfactant is selected from polysorbate 80 or polysorbate 20. 
     
     
         27 . The aqueous pharmaceutical composition of  claim 26 , wherein the surfactant is polysorbate 20. 
     
     
         28 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition comprises the sugar stabiliser in a molar ratio of sugar stabilizer to adalimumab of from 290:1 to 605:1. 
     
     
         29 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition comprises at most 1 mM of the surfactant. 
     
     
         30 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition comprises the surfactant in a molar ratio of surfactant to citrate buffer system of at most 1:10. 
     
     
         31 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition has a pH between 5.2 and 6.2. 
     
     
         32 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition further comprises a tonicifier. 
     
     
         33 . The aqueous pharmaceutical composition of  claim 32 , wherein the tonicifier is a single tonicifier. 
     
     
         34 . The aqueous pharmaceutical composition of  claim 32 , wherein the tonicifier is a buffering tonicifier. 
     
     
         35 . The aqueous pharmaceutical composition of  claim 32 , wherein the composition comprises the tonicifier in a molar ratio of tonicifier to adalimumab of from 115:1 to 175:1. 
     
     
         36 . The aqueous pharmaceutical composition of  claim 32 , wherein the tonicifier is present within the composition in a quantity or concentration sufficient for the composition to have an osmolality between 230 and 350 mOsm/kg. 
     
     
         37 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition consists of:
 (a) the adalimumab in an amount of 45-55 mg/mL   (b) the citrate buffer system, in a molar ratio of citrate buffer system to adalimumab of from 14:1 to 40:1   (c) the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 290:1 to 860:1, wherein the sugar stabilizer is a sugar polyol selected from the group consisting of mannitol, sorbitol, xylitol, arabitol, erythritol, lactitol, maltitol, and inositol;   (d) the surfactant in a molar ratio of surfactant to adalimumab of from 1:35 to 3:1, wherein the surfactant is selected from polysorbate 80 or polysorbate 20; and   (e) water;   
       wherein the composition has a pH between 5.0 and 6.0. 
     
     
         38 . The aqueous pharmaceutical composition of  claim 17 , wherein the composition consists of:
 (a) the adalimumab in an amount of 45-55 mg/mL;   (b) the citrate buffer system and a histidine buffer system, wherein the citrate buffer system is present in the composition in a molar ratio of citrate buffer system to adalimumab of from 14:1 to 40:1;   (c) the sugar stabilizer in a molar ratio of sugar stabilizer to adalimumab of from 290:1 to 860:1, wherein the sugar stabilizer is sorbitol;   (d) the surfactant in a molar ratio of surfactant to adalimumab of from 1:35 to 3:1, wherein the surfactant is polysorbate 20; and   (e) water;   
       wherein the composition has a pH between 5.0 and 6.0. 
     
     
         39 . An aqueous pharmaceutical composition consisting of:
 (a) adalimumab;   (b) a citrate buffer system;   (c) a single sugar stabiliser which is a sugar polyol or a disaccharide; [00103/00104]   (d) a tonicifier;   (e) a surfactant; and   (f) water;   wherein the composition contains adalimumab, citrate buffer system, sugar stabiliser, tonicifier, and surfactant in a molar ratio of 1:14-40: 288-865:28-576:0.1-3.2 respectively; and   wherein the composition is free of phosphate buffering agents and free of arginine.   
     
     
         40 . An aqueous pharmaceutical composition consisting of:
 (a) adalimumab,   (b) citrate buffer system,   (c) sugar stabiliser,   (d) tonicifier, and   (e) surfactant in a molar ratio of 1:14-40: 288-865:28-576:0.1-3.2 respectively,   
       wherein the composition is free of phosphate buffering agents. 
     
     
         41 . An aqueous pharmaceutical composition consisting of:
 (a) adalimumab;   (b) citrate buffer system;   (c) a sugar stabiliser;   (d) a tonicifier;   (e) a surfactant; and   (f) water;   wherein the composition is free of arginine and is free of phosphate buffering agents.   
     
     
         42 . An aqueous pharmaceutical composition consisting of:
 (a) adalimumab;   (b) a citrate buffer system;   (c) a sugar stabiliser that is a sugar polyol or a disaccharide;   (d) a tonicifier;   (e) a surfactant; and   (f) water;   wherein the composition comprises the adalimumab, the citrate buffer system, the sugar stabiliser, the tonicifier, and the surfactant in a molar ratio of 1:14-40:288-865:28-576:0.1-3.2 respectively; and   wherein the composition:   has only a single sugar stabiliser;   has only a single tonicifier that is either a buffering or non-buffering tonicifier;   has a pH between 5.2 and 6.2;   is free of arginine;   is free of amino acids selected from the group consisting of arginine, lysine, and aspartic acid; and   is free of phosphate buffering agents.   
     
     
         43 . An aqueous pharmaceutical composition consisting of:
 (a) adalimumab;   (b) a citrate buffer system;   (c) sorbitol;   (d) a tonicifier;   (e) polysorbate 20; and   (f) water;   wherein the composition has a pH greater than or equal to 5.0 and a pH less than or equal to 6.0, and   the composition contains adalimumab, citrate buffer system, sugar stabiliser, tonicifier, and surfactant in a molar ratio of 1:14-40: 288-865:28-576:0.1-3.2 respectively.   
     
     
         44 . An aqueous pharmaceutical composition consisting of:
 (a) 0.347 mM adalimumab;   (b) a citrate buffer system;   (c) a sugar stabiliser that is sorbitol;   (d) a tonicifier;   (e) a surfactant that is polysorbate 20; and   (f) water;   wherein the composition contains the adalimumab, the citrate buffer system, the sugar stabiliser, the tonicifier, and the surfactant in a molar ratio of 1:14-40:288-865:28-576:0.1-3.2 respectively; and   wherein the composition:   has only a single sugar stabiliser;   has only a single tonicifier that is either a buffering or non-buffering tonicifier;   has a pH between 5.2 and 6.2;   is free of arginine;   is free of amino acids selected from the group consisting of arginine, lysine, and aspartic acid; and   is free of phosphate buffering agents.   
     
     
         45 . An aqueous pharmaceutical composition consisting of:
 (a) 50 mg/mL adalimumab;   (b) a citrate buffer system;   (c) a sugar stabiliser which is a sugar polyol or a disaccharide;   (d) a tonicifier present within the composition in a concentration sufficient for the composition to have an osmolarity of 230 and 350 mOsm/kg; and   (e) at most 1 mM surfactant;   wherein the composition has a pH of 5.2-6.2;   the composition contains adalimumab, citrate buffer system, sugar stabiliser, tonicifier, and surfactant in a molar ratio of 1:14-40:288-865:28-576:0.1-3.2 respectively; and   the composition is free of phosphate buffering agents and free of arginine.   
     
     
         46 . A drug delivery device comprising the aqueous pharmaceutical composition of  claim 17 . 
     
     
         47 . 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 aqueous pharmaceutical composition of  claim 17 .