Liquid Formalation of a VEGF Antagonist

Abstract

The present invention relates to liquid pharmaceutical compositions of a VEGF antagonist for intravitreal administration comprising a histidine buffer, an inorganic salt, a carbohydrate and a polysorbate.

1 . A method of treating an intraocular neovascular disease comprising administering a liquid pharmaceutical composition comprising
 a) a histidine containing buffer,   b) a non-ionic surfactant,   c) a VEGF antagonist,   d) an inorganic salt, and   e) a carbohydrate.   
     
     
         2 . The method of  claim 1 , wherein the pH of the composition is between 6.0 and 6.5, preferably between 6.2 and 6.5. 
     
     
         3 . The method of  claim 1 , wherein the histidine-containing buffer is L-histidine/histidine hydrochloride. 
     
     
         4 . The method of  claim 1 , wherein the histidine-containing buffer is present in a concentration of from 1 mM to 40 mM, preferably of 10 mM. 
     
     
         5 . The method of  claim 1 , wherein the non-ionic surfactant is polysorbate 20. 
     
     
         6 . The method of  claim 1 , wherein the non-ionic surfactant is present in a concentration of from 0.01 to 0.08% (w/v), preferably of 0.03% (w/v). 
     
     
         7 . The method of  claim 1 , wherein the inorganic salt is NaCl. 
     
     
         8 . The method of  claim 1 , wherein the inorganic salt is present in a concentration of from 20 to 100 mM. 
     
     
         9 . The method of  claim 1 , wherein the VEGF antagonist is an anti-VEGF antibody or an antigen-binding fragment of such antibody or a VEGF receptor fusion protein. 
     
     
         10 . The method of  claim 1 , wherein the VEGF antagonist is aflibercept or ranibizumab. 
     
     
         11 . The method of  claim 1 , wherein the VEGF antagonist is present in a concentration of 6 to 45 mg/ml. 
     
     
         12 . The method of  claim 1 , wherein the carbohydrate is sucrose. 
     
     
         13 . The method of  claim 1 , wherein the carbohydrate is present in a concentration of 3-20% (w/v). 
     
     
         14 . A method of treating an intraocular neovascular disease comprising administering a liquid pharmaceutical composition consisting of histidine hydrochloride/L-histidine, polysorbate 20, NaCl, aflibercept, sucrose and water and having a pH of 6.2 or 6.5. 
     
     
         15 . The method of  claim 14 , wherein the liquid pharmaceutical composition consists of 10 mM histidine hydrochloride/L-histidine, 0.03% polysorbate 20 (w/v), 40 mM NaCl, 40 mg/ml aflibercept, 5% sucrose and water and has a pH of 6.2 or 6.5. 
     
     
         16 . The method of  claim 1 , wherein the intraocular neovascular disease is age-related macular degeneration (AMD), visual impairment due to diabetic macular oedema (DME), visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO), or visual impairment due to choroidal neovascularisation (CNV) secondary to pathologic myopia. 
     
     
         17 . The method of  claim 1 , wherein the pharmaceutical composition is present in a prefilled syringe. 
     
     
         18 . The method of  claim 6 , wherein the non-ionic surfactant is present in a concentration of 0.03% (w/v). 
     
     
         19 . The method of  claim 8 , wherein the inorganic salt is present in a concentration of 40 mM. 
     
     
         20 . The method of  claim 13 , wherein the carbohydrate is present in a concentration of 5% (w/v).