Pharmaceutical compositions and methods for producing low impurity concentrations of the same

Abstract

A composition having clevidipine as an active ingredient is described. The composition includes clevidipine as an active ingredient and an amount of the impurity H168/79 that is no greater than about 1.5%, or where the ratio between clevidipine and H168/79 is equal or above 60 to 1.

1 . A pharmaceutical composition for treating or preventing hypertension in a subject in need thereof, comprising clevidipine or any of its pharmaceutically acceptable salts as an active ingredient, wherein the composition is stored at an effective temperature so that the level of a degradant is approximately equal to or less than 0.2% on a weight-by-weight basis, wherein the degradant is selected from a group having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         2 . The composition of  claim 1 , wherein the effective temperature is approximately equal to or less than about 25° C. 
     
     
         3 . The composition of  claim 1 , wherein the effective temperature is approximately equal to or less than about 5° C. 
     
     
         4 . A pharmaceutical composition for treating or preventing hypertension in a subject in need thereof, comprising clevidipine or any of its pharmaceutically acceptable salt as an active ingredient, wherein the composition is stored at an effective temperature so that the level of a degradant, H168/79, is approximately equal to or less than 1.5% on a weight-by-weight basis, wherein H168/79 having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The composition of  claim 4 , wherein the effective temperature is approximately equal to or less than about 25° C. 
     
     
         6 . The composition of  claim 4 , wherein the effective temperature is approximately equal to or less than about 5° C. 
     
     
         7 . A pharmaceutical composition comprising clevidipine and a degradant having the formula: 
       
         
           
           
               
               
           
         
         prepared by a process comprising:
 storing the pharmaceutical composition at an effective temperature wherein the amount of degradant is approximately equal to or less than about 0.2%. 
 
       
     
     
         8 . The composition of  claim 7 , wherein the effective temperature is approximately equal to or less than about 25° C. 
     
     
         9 . The composition of  claim 7 , wherein the effective temperature is approximately equal to or less than about 5° C. 
     
     
         10 . A pharmaceutical composition comprising an effective amount of clevidipine and Substance 23, wherein the ratio of the HPLC peak areas between clevidipine and Substance 23 is equal or above 500 to 1. 
     
     
         11 . A pharmaceutical composition comprising an effective amount of clevidipine and Substance 24, wherein the ratio of the HPLC peak areas between clevidipine and Substance 24 is equal or above 500 to 1. 
     
     
         12 . A pharmaceutical composition comprising an effective amount of clevidipine and Substance 25, wherein the ratio of the HPLC peak areas between clevidipine and Substance 23 is equal or above 500 to 1. 
     
     
         13 . A pharmaceutical composition comprising clevidipine and a degradant having the following formula: 
       
         
           
           
               
               
           
         
         wherein the amount of degradant is approximately equal to or less than about 1.5% on a weight by weight basis. 
       
     
     
         14 . The composition of  claim 13 , wherein the amount of degradant is approximately equal to or less than about 1.0%. 
     
     
         15 . The composition of  claim 13 , wherein the amount of degradant is approximately equal to or less than about 0.5%. 
     
     
         16 . A method of reducing impurities in a composition, comprising:
 heating an oil to between to about 70° C. to about 82° C.;   adding to the heated oil clevidipine and heating the mixture to about 78° C.;   adding to the mixture egg yolk phospholipids; and   adding an aqueous phase;   wherein the pH is adjusted to about 6 to about 8.8;   homogenizing the emulsion; and   wherein the amount of degradant with the formula of:   
       
         
           
           
               
               
           
         
         is approximately equal to or less than about 1.5%. 
       
     
     
         17 . The composition of  claim 16 , wherein the amount of degradant is approximately equal to or less than about 1.0%. 
     
     
         18 . The composition of  claim 16 , wherein the amount of degradant is approximately equal to or less than about 0.5%. 
     
     
         19 . The composition of  claim 16 , wherein the aqueous phase consists essentially of glycerin. 
     
     
         20 . The method of  claim 16 , wherein the pH is about 9.8. 
     
     
         21 . The method of  claim 16 , wherein the mixture is homogenized at about 25° C. 
     
     
         22 . The method of  claim 16 , wherein the mixture is homogenized at about 15° C. 
     
     
         23 . The method of  claim 16 , wherein the mixture is homogenized at about 10° C. 
     
     
         24 . The method of  claim 16 , wherein the mixture is homogenized at about 5° C. 
     
     
         25 . A pharmaceutical composition comprising an effective amount of clevidipine prepared by a process comprising:
 heating an oil to between to about 70° C.;   adding to the heated oil clevidipine and heating the mixture to about 78° C.;   adding to the mixture egg yolk phospholipids; and   adding an aqueous phase;   wherein the aqueous phase consists essentially of glycerin and the pH is adjusted to about 9.5; and   wherein the amount of degradant with the formula of:   
       
         
           
           
               
               
           
         
         is approximately equal to or less than about 1.5%. 
       
     
     
         26 . The composition of  claim 25 , wherein the amount of degradant is approximately equal to or less than about 1.0%. 
     
     
         27 . The composition of  claim 25 , wherein the amount of degradant is approximately equal to or less than about 0.5%. 
     
     
         28 . Method of detecting Substance 24, comprising optimizing an HPLC method to detect Substance 24 wherein the ratio of the HPLC peak areas between clevidipine and Substance 24 is equal or above 500 to 1.