Voriconazole inclusion complexes

Abstract

The present invention relates to new voriconazole formulations comprising 2-hydroxypropyl-□-cyclodextrins and the preparation thereof.

1 . A stabilized pharmaceutical formulation comprising voriconazole and a substituted β-cyclodextrin characterized by a molar substitution of the β-cyclodextrin by hydroxypropyl groups of more than 0.8, provided that the formulation does not comprise lactose. 
     
     
         2 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the substituent on the β-cyclodextrin is a 2-hydroxypropyl group. 
     
     
         3 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the molar substitution of the 2-hydroxypropyl β-cyclodextrin is 0.8-1.1. 
     
     
         4 . The stabilized pharmaceutical formulation according to  claim 3 , wherein the molar substitution of the 2-hydroxypropyl β-cyclodextrin is 0.8-1.0. 
     
     
         5 . The stabilized pharmaceutical formulation according to  claim 4 , wherein the molar substitution of the 2-hydroxypropyl β-cyclodextrin is 0.9. 
     
     
         6 . The stabilized pharmaceutical formulation according to  claim 1 , having a pH in the range of about 4-7. 
     
     
         7 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the formulation further comprises a pH adjusting agent. 
     
     
         8 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the formulation further comprises an acidification agent. 
     
     
         9 . The stabilized pharmaceutical formulation according to  claim 8 , wherein the formulation further comprises one or more organic carboxylic acids. 
     
     
         10 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the formulation further comprises citrate, acetate, tartrate and/or succinate buffers. 
     
     
         11 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the formulation further comprises citric, acetic, tartaric and/or succinic acids. 
     
     
         12 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the said formulation is further lyophilized. 
     
     
         13 . The stabilized pharmaceutical formulation according to  claim 12 , comprising 4-10% w/w voriconazole in a solid state. 
     
     
         14 . The stabilized pharmaceutical formulation according to  claim 12 , comprising 6% w/w voriconazole in a solid state. 
     
     
         15 . The stabilized pharmaceutical formulation according to  claim 12 , comprising about 90-96% w/w β-cyclodextrin in a solid state. 
     
     
         16 . The stabilized pharmaceutical formulation according to  claim 15 , comprising about 94% w/w β-cyclodextrin in the solid state. 
     
     
         17 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the said formulation comprises voriconazole and 2-hydroxypropyl-β-cyclodextrin in a molar ratio of up to 1:5. 
     
     
         18 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the said formulation comprises voriconazole and 2-hydroxypropyl-β-cyclodextrin in a molar ratio of 1:3.6. 
     
     
         19 . The stabilized pharmaceutical formulation according to  claim 1 , wherein the said formulation comprises voriconazole and 2-hydroxypropyl-β-cyclodextrin in a weight ratio of 1:22 to 1:10. 
     
     
         20 . The stabilized pharmaceutical formulation according to  claim 19 , wherein the formulation comprises voriconazole and 2-hydroxypropyl-β-cyclodextrin in a weight ratio of 1:18 to 1:14. 
     
     
         21 . The stabilized pharmaceutical formulation according to  claim 20 , wherein the formulation comprises voriconazole and 2-hydroxypropyl-β-cyclodextrin in a weight ratio of 1:16 
     
     
         22 . A reconstituted formulation, consisting of a solution of a formulation according to  claim 1  dissolved in a diluent suitable for injection or intravenous infusion. 
     
     
         23 . The reconstituted formulation according to  claim 22 , comprising 1-20 mg/ml voriconazole. 
     
     
         24 . The reconstituted formulation according to  claim 22 , comprising 50-300 mg/ml 2-hydroxypropyl-β-cyclodextrin. 
     
     
         25 . A stabilized pharmaceutical formulation consisting of:
 i. voriconazole;   ii. a substituted β-cyclodextrin characterized by a molar substitution of the β-cyclodextrin by 2-hydroxypropyl groups of more than 0.8;   iii. optionally pH adjusting agents; and   iv. optionally pharmaceutically acceptable diluents or solvents.   
     
     
         26 . The stabilized pharmaceutical formulation according to  claim 25 , having a pH in the range of 4-7. 
     
     
         27 . A stabilized pharmaceutical formulation comprising voriconazole and a substituted β-cyclodextrin having a pH of 4-7 when dissolved in a suitable diluent. 
     
     
         28 . The stabilized pharmaceutical formulation according to  claim 27 , wherein the formulation further comprises citrate, acetate, tartrate and/or succinate buffers. 
     
     
         29 . The stabilized pharmaceutical formulation according to  claim 27 , wherein the formulation further comprises citric, acetic, tartaric and/or succinic acids. 
     
     
         30 . A method for stabilizing a composition comprising voriconazole, wherein the method comprises the steps of:
 a. providing an aqueous solution of 2-hydroxypropyl-β-cyclodextrin having a molar substitution of the β-cyclodextrin by hydroxypropyl groups of more than 0.8;   b. adding voriconazole;   c. optionally adjusting the pH; and   d. optionally lyophilizing the obtained stabilized composition.   
     
     
         31 . The method according to  claim 28 , provided that the composition does not comprise lactose. 
     
     
         32 . (canceled) 
     
     
         33 . (canceled)