Bupivacaine enantiomers and levobupivacaine

Abstract

The prevent invention describes a new method for the separation of bupivacaine enantiomers consisting in a continous separation process performed without heating, by the selective precipitation of their diastereomeric salts with tartaric acid. This heatless process avoids the degradation of the reagents granting a continuous process feature to the procedure. Another embodiment of the present invention is related to the enantiomeric manipulation of bupivacaine enantiomers in order to obtain pharmaceutical compositions presenting several enantiomeric excess of levobupivacaine to quantify and determinate the role of the dextrobupivacaine on its anesthetic and cardiotoxic effects. These enantiomeric manipulated compositions showed to present an expressive improvement on its anesthetic properties that has shown to be similar to racemic bupivacaine presenting a cardiotoxic profile similar to enantiomeric pure levobupivacaine.

1 . Process for obtainment of bupivacaine enantiomers, characterized by reacting to racemic bipuvicaine with a resolution agent within a medium of organic solvent a low concentration and at room temperature, wherein said resolution agent is used in an amount not lower to 0.6 molar equivalent per racemic bupivacaine molar equivalent.  
     
     
         2 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized in that the organic solvent employed is acetone.  
     
     
         3 . Process for obtainment of bupivicaine enantiomers according to  claim 1 , characterized in that the resolution agent is the acid (R,R)-tartaric.  
     
     
         4 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized in that the resolution agent is the acid (S,S)-tartaric.  
     
     
         5 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized inn that the resolution agent used is in amounts ranging from 0.6 to 1.2 molar equivalent in relation to racemic bupivacaine.  
     
     
         6 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized by being carried out without heating employment, at a temperature ranging from 15° C. to 30° C.  
     
     
         7 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized in that the reaction medium of the resolution phase is considerably diluted, with a concentration ranging from 0.1M to 0.4M in relation to the base bupivacaine.  
     
     
         8 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized in that the free bases of bupivacaine enantiomers are directly obtained from tartrate salts, by means of the treatment of the solutions from such salts with alkali.  
     
     
         9 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , characterized by the fact that the free bases of its enantiomers being converted into its chlorohydrate salts.  
     
     
         10 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , for preparation of the levobupivacaine and/or an appropriate pharmaceutical salt thereof.  
     
     
         11 . Process for obtainment of bupivacaine enantiomers according to  claim 1 , for preparation of the dextrobupivacaine and/or an appropriate pharmaceutical salt thereof.  
     
     
         12 . Process for obtainment of pharmaceutical compositions based on levobupivacaine and/or suitably pharmaceutical salts therof, characterized by the manipulation of enantiomeric excesses aiming at obtaining enantiomeric excess inferior to 90% of levobupivacaine by means of the adequate combination of two pure enantiomers in its solid forms or in solution, or by mixing the racemic bupivacaine with the pure levobupivacaine in its solid forms or in solution, or by manipulation of the enantiomeric excess of the enriched levobupivacaine, obtained in the process with dextrobupivacaine or racemic bupivacaine in its solid forms or in solution.  
     
     
         13 . Pharmaceutical compositions based on levobupivacaine, formulated in its free bases forms, and/or in its adequate pharmaceutical forms, obtained according to  claim 12 , characterized by the presence of enantiomeric excess, preferably comprised between 90% and 20%, and more preferably, comprised between 80% to 30% of levobupivacaine.  
     
     
         14 . Pharmaceutical compositions based on levobupivacaine according to  claim 12 , characterized by the fact of presenting enantiomeric excess of 80% of levobupivacaine.  
     
     
         15 . Pharmaceutical compositions based on levobupivacaine according to  claim 12 , characterized by the fact of presenting enantiomeric excess of 50% of levobupivacaine.  
     
     
         16 . Pharmaceutical compositions based on levobupivacaine according to  claim 12 , characterized by the fact of being used in medicine and veterinary.  
     
     
         17 . Pharmaceutical compositions based on levobupivacaine according to  claim 12 , characterized by being employed in anesthesia.