Compositions of tolperisone

Abstract

The present disclosure is directed to methods for providing tolperisone having extremely low levels of 4-MMPPO (2-methyl-1-(4-methylphenyl)-propenone), as well as related compositions. The invention further relates to methods of treating a subject with tolperisone under conditions that limit exposure of the subject to tolerable levels of 4-MMPPO, among other features.

1 . Tolperisone comprising less than about 1.5 ppm 2-methyl-1-(4-methylphenyl)-propanone (4-MMPPO). 
     
     
         2 . The tolperisone of  claim 1  comprising less than about 1 ppm 4-MMPPO. 
     
     
         3 . A stabilized composition comprising the tolperisone of  claim 1 , wherein said composition, when stored under dry conditions for a period of 3 months exhibits substantially no change in its level of 4-MMPPO over said period. 
     
     
         4 . The stabilized composition of  claim 3 , further comprising one or more pharmaceutically acceptable excipients. 
     
     
         5 . The stabilized composition of  claim 4 , wherein said one or more pharmaceutically acceptable excipients comprises an acid. 
     
     
         6 . The stabilized composition of  claim 5 , wherein said acid is a di-acid or greater. 
     
     
         7 . The stabilized composition of  claim 6 , wherein said acid is citric acid or succinic acid. 
     
     
         8 . A method of preparing a purified composition of tolperisone, said method comprising:
 (i) providing tolperisone comprising an initial level of 4-MMPPO greater than 10 ppm, and optionally additional impurities, and   (ii) purifying said tolperisone to form a purified tolperisone having a level of 4-MMPPO that is less than about 1.5 ppm.   
     
     
         9 . The method of  claim 8 , wherein said purifying is effective to form a purified tolperisone having a level of 4-MMPPO that is less than about 1 ppm. 
     
     
         10 . The method of  claim 8 , wherein said purifying is effective to reduce the level of 4-MMPPO by at least five-fold over its initial level. 
     
     
         11 . The method of  claim 8 , further comprising, prior to said providing step, identifying the presence of 4-MMPPO as a contaminant in said tolperisone. 
     
     
         12 . The method of  claim 11 , further comprising, in addition to said identifying, determining the initial level of 4-MMPPO in said tolperisone. 
     
     
         13 . The method of  claim 8 , further comprising the step of washing the purified tolperisone of step (ii) with a non-ketonic solvent to provide washed tolperisone. 
     
     
         14 . The method of  claim 13 , wherein said non-ketonic solvent is low boiling. 
     
     
         15 . The method of  claim 14 , wherein said solvent is methyl tert-butyl ether or a low boiling hydrocarbon solvent. 
     
     
         16 . The method of  claim 13 , wherein said purifying comprises recrystallization from a single solvent or a combination of solvents, and collecting the purified tolperisone resulting from said recrystallization. 
     
     
         17 . The method of  claim 16 , wherein said recrystallization is carried out in a mixed solvent system comprising a lower ketone and a lower alcohol. 
     
     
         18 . The method of  claim 17 , wherein said solvent system comprises methyl ethyl ketone and isopropanol. 
     
     
         19 . The method of  claim 8 , wherein said purified tolperisone is dried at a temperature that is less than about 40° C. 
     
     
         20 . The method of  claim 19 , wherein said purified tolperisone is dried at a temperature ranging from about 30° C. to 40° C. 
     
     
         21 . The method of  claim 20 , wherein said purified tolperisone is dried under reduced pressure. 
     
     
         22 . The method of  claim 8 , wherein said purifying comprises
 (i) treating a solution of tolperisone with an adsorbing agent to thereby remove 4-MMPPO, and   (ii) isolating tolperisone from the solution in (i).   
     
     
         23 . The method of  claim 22 , wherein the adsorbing agent is selected from activated charcoal, diatomaceous earth, or a combination thereof. 
     
     
         24 . In a method of purifying tolperisone wherein said purifying comprises recrystallization of tolperisone from a ketonic solvent to provide purified tolperisone, the improvement comprising washing said purified tolperisone with a non-ketonic solvent to thereby minimize formation of 4-MMPPO. 
     
     
         25 . A purified tolperisone produced by the method of  claim 17 . 
     
     
         26 . A pharmaceutical composition comprising the tolperisone of  claim 1 . 
     
     
         27 . The pharmaceutical composition of  claim 26 , wherein said tolperisone is bound to a cationic exchange resin. 
     
     
         28 . In a method of administering tolperisone to a subject in need thereof, the improvement comprising administering a composition of tolperisone comprising less than about 1.5 ppm 2-methyl-1-(4-methylphenyl)-propanone (4-MMPPO). 
     
     
         29 . The method of  claim 28 , whereby as a result of said administering, genotoxic effects of said composition related to the presence of 4-MMPPO upon said subject are minimized. 
     
     
         30 . The tolperisone of  claim 1  packaged in a suitable container, and combined with a dessicant. 
     
     
         31 . A stabilized composition comprising the tolperisone of  claim 1 , wherein said composition, when stored under ambient, dry conditions for a period of three months exhibits substantially no change in its level of 4-MMPPO over said period. 
     
     
         32 . A method of preparing a pharmaceutical formulation comprising tolperisone according to  claim 1  in tablet form, said method comprising a wet granulation step absent a ketonic or aldehydic solvent. 
     
     
         33 . A method of preparing a pharmaceutical formulation comprising tolperisone according to  claim 1  in tablet form, wherein said method is absent a wet granulation step and comprises a dry granulation step. 
     
     
         34 . A method of detecting levels of 4-MMPPO in a composition comprising tolperisone, said method comprising:
 (a) providing a composition comprising tolperisone and optionally one or more excipients,   (b) dissolving said composition in acidified alcohol to thereby prevent formation of additional 4-MMPPO, to form an acidified solution of tolperisone,   (c) separating said tolperisone from said one or more excipients, if present, by extraction with an organic solvent to provide an acidified extract of tolperisone,   (d) adding to the solution of (b) or (c) an internal standard to quantify the amount of 4-MMPPO to provide a sample solution, and   (e) analyzing the amount of 4-MMPPO in said sample solution by liquid chromatography/mass spectrometry, wherein at least one eluent employed in said liquid chromatography is acidified, to thereby detect levels of 4-MMPPO in said sample that may be below 500 ppm.   
     
     
         35 . The method of  claim 34 , wherein said acidified alcohol is acidified with an acid selected from hydrochloric acid, hydrobromic acid, trifluoroacetic acid, and methane sulfonic acid. 
     
     
         36 . The method of  claim 35 , wherein said acidified alcohol is methanolic hydrochloric acid. 
     
     
         37 . The method of  claim 34 , wherein said organic solvent in (c) is an ether or a lipophilic ester. 
     
     
         38 . The method of  claim 37 , wherein said solvent is diisopropyl ether. 
     
     
         39 . The method of  claim 34 , wherein said internal standard is deuterated 4-MMPPO. 
     
     
         40 . In a method of preparing, processing, or purifying tolperisone, the improvement comprising replacing one or more ketonic solvents with a non-ketonic solvent to thereby minimize formation of 4-MMPPO.