Pharmaceutical formulation

Abstract

A pharmaceutical composition suitable for oral administration comprising particles of 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide is provided. Also provided is a pharmaceutical composition suitable for parenteral administration wherein the composition comprises 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide. The compositions are useful in the treatment of fungal infection in a subject in need thereof.

1 . A pharmaceutical composition suitable for oral administration wherein the composition comprises spray-dried particles of a compound of Formula I or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide 
       
     
     
         2 . A pharmaceutical composition according to  claim 1  comprising spray-dried particles of a compound of Formula I. 
     
     
         3 . A pharmaceutical composition according to  claim 1  or  claim 2  wherein the compound of Formula I is substantially amorphous. 
     
     
         4 . A pharmaceutical composition according to any one of the preceding claims which further comprises one or more excipients. 
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein the composition comprises the excipient hydroxypropyl methyl cellulose acetate succinate (HPMCAS). 
     
     
         6 . A pharmaceutical composition according to any one of  claim 4  or  5  wherein the mass ratio of the compound of Formula I to excipient is from 1:100 to 1:1. 
     
     
         7 . A pharmaceutical composition according to any one of  claims 4  to  6  wherein the mass ratio of the compound of Formula I to excipient is from 1:15 to 1:2. 
     
     
         8 . A pharmaceutical composition according to any one of the previous claims wherein the particles are obtainable by spray-drying from a solution comprising an organic solvent selected from dichloromethane, methanol, and mixtures thereof. 
     
     
         9 . A pharmaceutical composition according to any one of the previous claims and further comprising one or more pharmaceutically acceptable binders and/or carriers and/or excipients and/or diluents and/or adjuvants. 
     
     
         10 . A pharmaceutical composition according to any one of the previous claims in the form of a solid oral dosage form. 
     
     
         11 . A pharmaceutical composition according to any one of the previous claims in the form of a liquid oral dosage form. 
     
     
         12 . A pharmaceutical composition according to  claim 11  wherein the liquid oral dosage form further comprises a pharmaceutically acceptable buffer having a pKa in the range 6.0 to 8.0. 
     
     
         13 . A pharmaceutical composition according to  claim 11  or  claim 12  wherein the buffer is from 1 mM to 200 mM phosphate buffer and wherein the composition is buffered to about pH 7. 
     
     
         14 . A pharmaceutical composition suitable for parenteral administration comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide 
       
       (ii) cyclodextrin or modified cyclodextrin, and (iii) polyethylene glycol. 
     
     
         15 . A pharmaceutical composition according to  claim 14  comprising:
 from 10 wt % to 40 wt % of cyclodextrin or modified cyclodextrin; and/or 
 from 10 wt % to 40 wt % of polyethylene glycol. 
 
     
     
         16 . A pharmaceutical composition according to  claim 14  or  claim 15  wherein the cyclodextrin or modified cyclodextrin is hydroxy propyl beta cyclodextrin. 
     
     
         17 . A pharmaceutical composition according to any of  claims 14  to  16  wherein the polyethylene glycol is PEG300 or PEG400. 
     
     
         18 . A pharmaceutical composition according to any one of  claims 14  to  17  which further comprises polyvinyl pyrrolidone (Povidone). 
     
     
         19 . A pharmaceutical composition according to any one of  claims 14  to  18  wherein the compound of Formula I or the pharmaceutically acceptable salt thereof is present at a concentration of from 1 mg/mL to 10 mg/mL. 
     
     
         20 . A pharmaceutical composition according to any one of  claims 14  to  19  which further comprises one or more pharmaceutically acceptable carriers and/or excipients and/or diluents and/or adjuvants. 
     
     
         21 . A pharmaceutical composition according to any one of  claims 14  to  20  comprising:
 4 mg/mL (relative to the final volume of the composition) of the compound of Formula I 
 25 wt % of hydroxy propyl beta cyclodextrin; 
 wt % of PEG400; 
 1 wt % of polyvinyl pyrrolidone (Povidone); 
 phosphoric acid in sufficient amount to adjust the pH of the pharmaceutical composition to pH 5.0; and 
 water to 100%. 
 
     
     
         22 . A pharmaceutical composition according to any one of the previous claims for use in a method of treatment of a human or animal subject in need thereof. 
     
     
         23 . A composition for use according to  claim 22  wherein the treatment comprises prevention of or treatment of fungal infection in the subject. 
     
     
         24 . A method of preventing or treating fungal infection in a human or animal subject in need thereof, said method comprising administering to the human or animal subject a therapeutically effective amount of a pharmaceutical composition according to any one of  claims 1  to  21 . 
     
     
         25 . Use of a pharmaceutical composition according to any one of  claims 1  to  21  in the manufacture of a medicament for use in the prevention or treatment of fungal infection in a human or animal subject in need thereof. 
     
     
         26 . A method of producing a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-(4-(4-(5-fluoropyrimidin-2-yl)piperazin-1-yl)phenyl)-2-oxoacetamide 
       
       wherein said method comprises spray-drying a solution of the compound of Formula (I) or salt thereof. 
     
     
         27 . A method according to  claim 26  comprising: 
       i) dissolving one or more excipients in a solvent; 
       ii) adding the compound of Formula I to the solution produced in step (i); and 
       iii) spray drying the solution produced in step (ii). 
     
     
         28 . A method according to  claim 27  wherein:
 the excipient is hydroxypropyl methyl cellulose acetate succinate (HPMCAS); 
 the solvent is a mixture of dichloromethane and methanol, wherein the volume ratio of dichloromethane to methanol is from 5:1 to 1:1; 
 the concentration of the excipient in the solvent is from 5% to 20% w/v; and 
 the compound of Formula I is added to the solution of the excipient in the solvent to give a concentration of 0.5% to 10% by mass. 
 
     
     
         29 . A pharmaceutical composition suitable for oral administration wherein the composition comprises substantially amorphous particles of a compound of Formula I or a pharmaceutically acceptable salt thereof.