Bupivacaines

Abstract

The present invention describes a new method for the separation of bupivacaine enantiomers consisting in a continuous 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 had shown to be similar to racemic bupivacaine presenting a cardiotoxic profile similar to enantiomeric pure levobupivacaine.

1 . A continuous process for preparing bupivacaine enantiomers in a high yield with a minimum of impurities, characterized by reacting racemic bupivacaine with a resolution agent within a medium of organic solvent at low concentration and at room temperature, wherein said resolution agent is used in an amount not lower than 0.6 molar equivalent per racemic bupivacaine molar equivalent.  
   
   
       2 . The process of  claim 1 , characterized in that the organic solvent employed is acetone.  
   
   
       3 . The process of  claim 1 , characterized in that the resolution agent is (R,R)-tartaric acid.  
   
   
       4 . The process of  claim 1 , characterized in that the resolution agent is (S,S)-tartaric acid.  
   
   
       5 . The process of  claim 1 , characterized in that the resolution agent used is in amounts ranging from 0.6 to 1.2 molar equivalent in relation to racemic bupivacaine.  
   
   
       6 . The process of  claim 1 , characterized by being carried out without heating employment, at a temperature ranging from 15° C. to 30° C.  
   
   
       7 . The process of  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 . The process of  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 . The process of  claim 1 , characterized by the fact that the free bases of its enantiomers being converted to its hydrochloride salts.  
   
   
       10 . The process of  claim 1 , for preparation of the levobupivacaine and/or an appropriate pharmaceutical salt thereof.  
   
   
       11 . The process of  claim 1 , for preparation of the dextrobupivacaine and/or an appropriate pharmaceutical salt thereof.  
   
   
       12 . Pharmaceutical compositions comprising levobupivacaine and dextrobupivacaine in a weight ratio of from 60:40 to less than 90:10.  
   
   
       13 . Pharmaceutical compositions of  claim 13  characterized by the fact of being used in medicine and veterinary.  
   
   
       14 . Pharmaceutical compositions of  claim 13 , characterized by being employed in anesthesia.  
   
   
       15 . A pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of from 65:35 to less than 90:10.  
   
   
       16 . A pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of less than 90:10.  
   
   
       17 . A pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of about 75:25.  
   
   
       18 . A continuous process for producing levobupivacaine from racemic bupivacaine comprising the steps of: 
 (I) providing a first solution comprising acetone and having 0.1 to 0.4 moles of racemic bupivacaine per liter and 0.6 to about 1.2 moles of (R,R)-tartaric acid per mole of racemic bupivacaine; and then    (II) seeding the first solution at about 15 to about 30° C. with a small amount of dextrobupivacaine (R,R) tartrate thereby producing a precipitate of dextrobupivacaine (R,R) tartrate; and then    (III) removing the precipitate of dextrobupivacaine (R,R) tartrate from the first solution thereby producing a dextro-free solution; and then    (IV) seeding the dextro-free solution at about 15 to about 30° C. with levobupivacaine (R,R) tartrate thereby producing a precipitate of levobupivacaine (R,R) tartrate; and then    (V) recovering levobupivacaine from the levobupivacaine (R,R) tartrate.    
   
   
       19 . A method for blocking a nerve by contacting the nerve with a pharmacologically effective amount of a pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of from 65:35 to less than 90:10.  
   
   
       20 . A method for blocking a nerve by contacting the nerve with a pharmacologically effective amount of a pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of less than 90:10.  
   
   
       21 . A method for blocking a nerve by contacting the nerve with a pharmacologically effective amount of a pharmaceutical composition comprising levobupivacaine and dextrobupivacaine in a weight ratio of about 75:25.