Formulations for intravenous administration

Abstract

The present invention relates to an improved formulation of danirixin in its hydrobromide salt form. This improved formulation can be an aqueous intravenous formulation containing danirixin or a lyophilized pharmaceutical solid composition containing danirixin to be reconstituted to provide a solution for intravenous administration.

What is claimed is: 
     
         1 - 18 . (canceled) 
     
     
         19 . A pharmaceutical composition for intravenous administration comprising a hydrobromide salt of N-(4-chloro-2-hydroxy-3-((3S)-3-piperidinylsulfonyl]phenyl)-N′-(3-fluoro-2-methylphenyl)urea and one or more pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipient is selected from the group consisting of sulfobutyl ether-β-cyclodextrin (Captisol®), mannitol, and a citrate buffer. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the composition is an aqueous composition. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the composition has a pH that ranges from 3.5 to 4.5. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein the pH is about 4. 
     
     
         23 . The pharmaceutical composition according to  claim 19 , wherein the composition is freeze-dried to form a lyophilized powder. 
     
     
         24 . The pharmaceutical composition according to  claim 19 , wherein the composition comprises about 4% Captisol and the composition does not comprise surfactant. 
     
     
         25 . The pharmaceutical composition according to  claim 19  has the amount in Table C below: 
       
         
           
                 
                 
                 
                 
               
                     
                   TABLE C 
                 
                     
                     
                 
                     
                   COMPOSITION 
                   Formula 
                   Unit Formula, 
                 
                     
                   (HBr lyophilized 
                   (mg/mL) 
                   Nominal Fill 
                 
                     
                   formulation) 
                   2 mg/mL 
                   (mg/13 mL) 
                 
                     
                     
                 
                     
                   Danirixin, HBr. 
                    2.46 mg* 
                   31.98 mg 
                 
                     
                   ACTIVE SUBSTANCE 
                 
                     
                   B-CYCLODEXTRIN 
                    40.0 mg 
                   520.0 mg 
                 
                     
                   SULFOBUTYLETHER, 
                 
                     
                   CAPTISOL* 
                 
                     
                   MANNITOL 
                     50 mg 
                   650.0 mg 
                 
                     
                   CITRIC ACID 
                   0.655 mg 
                   8.515 mg 
                 
                     
                   SODIUM CITRATE 
                   0.555 mg 
                   7.215 mg 
                 
                     
                   SODIUM HYDROXIDE 
                   QS 
                   QS 
                 
                     
                   HYDROCHLORIC 
                   QS 
                   QS 
                 
                     
                   ACID 
                 
                     
                   pH 
                   3.9 
                   — 
                 
                     
                     
                 
                     
                   *QS refers to “quantity sufficient” to fill the vial to the nominal fill (or volume). 
                 
                     
                   *indicates 2 mg/mL that has been adjusted for the salt factor of 1.228 = 2.46 mg/mL 
                 
             
                
                
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         26 . A method of treating an infectious disease comprising administering to a subject the pharmaceutical composition for intravenous administration comprising a hydrobromide salt of N-(4-chloro-2-hydroxy-3-((3S)-3-piperidinylsulfonyl]phenyl)-N′-(3-fluoro-2-methylphenyl)urea and one or more pharmaceutically acceptable excipients, wherein the pharmaceutical acceptable excipient is selected from the group consisting of sulfobutyl ether-β-cyclodextrin (Captisol®), mannitol, and a citrate buffer. 
     
     
         27 . The method according to  claim 26 , wherein the infectious disease is a viral disease. 
     
     
         28 . The method according to  claim 26 , wherein the infectious disease is influenza or respiratory syncytial virus. 
     
     
         29 . The method according to  claim 26 , wherein the infectious disease is influenza. 
     
     
         30 . The method according to  claim 29 , wherein the composition comprises about 4% Captisol and the composition does not comprise surfactant. 
     
     
         31 . The method according to  claim 29 , wherein the composition has the amount of Table C below: 
       
         
           
                 
                 
                 
                 
               
                     
                   TABLE C 
                 
                     
                     
                 
                     
                   COMPOSITION 
                   Formula 
                   Unit Formula, 
                 
                     
                   (HBr lyophilized 
                   (mg/mL) 
                   Nominal Fill 
                 
                     
                   formulation) 
                   2 mg/mL 
                   (mg/13 mL) 
                 
                     
                     
                 
                     
                   Danirixin, HBr. 
                    2.46 mg* 
                   31.98 mg 
                 
                     
                   ACTIVE SUBSTANCE 
                 
                     
                   B-CYCLODEXTRIN 
                    40.0 mg 
                   520.0 mg 
                 
                     
                   SULFOBUTYLETHER, 
                 
                     
                   CAPTISOL ® 
                 
                     
                   MANNITOL 
                     50 mg 
                   650.0 mg 
                 
                     
                   CITRIC ACID 
                   0.655 mg 
                   8.515 mg 
                 
                     
                   SODIUM CITRATE 
                   0.555 mg 
                   7.215 mg 
                 
                     
                   SODIUM HYDROXIDE 
                   QS 
                   QS 
                 
                     
                   HYDROCHLORIC 
                   QS 
                   QS 
                 
                     
                   ACID 
                 
                     
                   pH 
                   3.9 
                   — 
                 
                     
                     
                 
                     
                   *QS refers to “quantity sufficient” to fill the vial to the nominal fill (or volume). 
                 
                     
                   *indicates 2 mg/mL that has been adjusted for the salt factor of 1.228 = 2.46 mg/mL