US2014094499A1PendingUtilityA1

Formulations of (r)-1-(2,2-difluorobenzo[d] [1,3] dioxol-5-yl)-n-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl)cyclopropanecarboxamide

Assignee: VERTEX PHARMAPriority: Jun 8, 2010Filed: Sep 16, 2013Published: Apr 3, 2014
Est. expiryJun 8, 2030(~3.9 yrs left)· nominal 20-yr term from priority
A61P 27/02A61K 45/06A61K 9/0095A61P 19/10A61K 31/404A61K 47/10A61P 11/00
48
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Claims

Abstract

The present invention relates to formulations of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1), pharmaceutical packs or kits thereof, and methods of treatment therewith.

Claims

exact text as granted — not AI-modified
1 - 37 . (canceled) 
     
     
         38 . A method of treating a CFTR mediated disease selected from male infertility and pancreatic insufficiency in a subject comprising administering to the subject an effective amount of a formulation comprising (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (Compound 1), water, a surfactant which is vitamin E TPGS, and a polyethylene glycol (PEG) which is PEG 400. 
     
     
         39 - 42 . (canceled) 
     
     
         43 . The method of  claim 38 , wherein the concentration of Compound 1 in the formulation is from about 0.05 to about 3% by weight. 
     
     
         44 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is from about 0.1 to about 2% by weight. 
     
     
         45 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is about 0.12, 0.25, or 0.50% by weight. 
     
     
         46 . The method of  claim 43 , wherein the concentration of polyethylene glycol in the formulation is from about 40 to about 60% by weight. 
     
     
         47 . The method of  claim 43 , wherein the concentration of polyethylene glycol in the formulation is from about 45 to about 55% by weight. 
     
     
         48 . The method of  claim 43 , wherein the concentration of polyethylene glycol in the formulation is about 50% by weight. 
     
     
         49 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is from about 0.05 to about 3% by weight; and the concentration of polyethylene glycol is from about 40 to about 60% by weight. 
     
     
         50 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is from about 0.1 to about 2% by weight; and the concentration of polyethylene glycol is from about 45 to about 55% by weight. 
     
     
         51 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is about 0.12, 0.25, or 0.50% by weight; and the concentration of polyethylene glycol is about 50% by weight. 
     
     
         52 . The method of  claim 43 , wherein the concentration of surfactant in the formulation is from about 5 to about 15% by weight. 
     
     
         53 . The method of  claim 43 , wherein the concentration of surfactant in the formulation is from about 10 to about 12% by weight. 
     
     
         54 . The method of  claim 43 , wherein the concentration of surfactant in the formulation is about 11% by weight. 
     
     
         55 . The method of  claim 43 , wherein the concentration of Compound 1 in the formulation is from about 0.05 to about 3% by weight, the concentration of polyethylene glycol is from about 40 to about 60% by weight, and the concentration of surfactant is from about 5 to about 15% by weight. 
     
     
         56 . The method of  claim 55 , wherein the concentration of Compound 1 in the formulation is from about 0.05 to about 3% by weight, the polyethylene glycol is PEG 400 at about 40 to about 60% by weight, and the surfactant is vitamin E TPGS at about 5 to 15% by weight. 
     
     
         57 . The method of  claim 43 , wherein the formulation is about 30 to 50 g. 
     
     
         58 . The method of  claim 43 , wherein the formulation is about 35 to 45 g. 
     
     
         59 . The method of  claim 43 , wherein the formulation is about 40 g. 
     
     
         60 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (g) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.05 
                 
                     
                   PEG 400 
                   19.95 
                 
                     
                   Vitamin E TPGS 
                   4.48 
                 
                     
                   Water 
                   15.52 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         61 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (g) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.10 
                 
                     
                   PEG 400 
                   19.90 
                 
                     
                   Vitamin E TPGS 
                   4.48 
                 
                     
                   Water 
                   15.52 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         62 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (g) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.20 
                 
                     
                   PEG 400 
                   19.80 
                 
                     
                   Vitamin E TPGS 
                   4.48 
                 
                     
                   Water 
                   15.52 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         63 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (g) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.30 
                 
                     
                   PEG 400 
                   19.70 
                 
                     
                   Vitamin E TPGS 
                   4.48 
                 
                     
                   Water 
                   15.52 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         64 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (% by weight) 
                 
                     
                     
                 
                     
                   Compound 1 
                   0.10-0.80 
                 
                     
                   PEG 400 
                   48-51 
                 
                     
                   Vitamin E TPGS 
                   10-12 
                 
                     
                   Water 
                   37-40 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         65 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (% by weight) 
                 
                     
                     
                 
                     
                   Compound 1 
                   0.20-0.60 
                 
                     
                   PEG 400 
                   49-50 
                 
                     
                   Vitamin E TPGS 
                   10-12 
                 
                     
                   Water 
                   37-40 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
               
            
           
         
       
     
     
         66 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (% by weight) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.25 
                 
                     
                   PEG 400 
                   49.75 
                 
                     
                   Vitamin E TPGS 
                   11.20 
                 
                     
                   Water 
                   38.80 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         67 . The method of  claim 43 , wherein the formulation comprises the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Component 
                   Amount (% by weight) 
                 
                     
                     
                 
                     
                 
                 
                 
                 
               
                     
                   Compound 1 
                   0.50 
                 
                     
                   PEG 400 
                   49.50 
                 
                     
                   Vitamin E TPGS 
                   11.20 
                 
                     
                   Water 
                   38.80 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         68 . The method of  claim 43 , wherein the formulation further comprises a taste masker. 
     
     
         69 . The method of  claim 43 , wherein the formulation further comprises an additional therapeutic agent. 
     
     
         70 . The method of  claim 43 , wherein the additional therapeutic agent is selected from a mucolytic agent, bronchodialator, an anti-biotic, an anti-infective agent, an anti-inflammatory agent, a CFTR modulator other than Compound 1, or a nutritional agent.

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