US2018344717A1PendingUtilityA1

Compositions of tolperisone

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Assignee: SANOCHEMIA PHARMAZEUTIKA AGPriority: Apr 26, 2007Filed: Jul 26, 2018Published: Dec 6, 2018
Est. expiryApr 26, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:Federico GaetaKlaus GerdesStefan WelzigBeate KaelzJan RothenburgerJozsef Gungl
A61P 7/00A61P 9/00A61P 25/04A61P 25/28A61P 25/00A61P 29/00Y10T436/145555C07D 295/108A61P 21/00A61K 9/20A61K 31/4453A61K 9/0053A61P 21/02A61P 15/00A61P 19/02
62
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Claims

Abstract

The present disclosure relates to tolperisone, or a pharmaceutically acceptable salt or hydrate thereof, with 10 ppm 2-methyl-1-(4-methylphenyl)-propenone (4-MMPPO) or less, methods of producing the same, as well as compositions related thereto. The disclosure further relates to methods of treating a subject with tolperisone under conditions that limit exposure of the subject to tolerable levels of 4-MMPPO.

Claims

exact text as granted — not AI-modified
1 .- 22 . (canceled) 
     
     
         23 . A pharmaceutical composition, comprising:
 tolperisone free base or a pharmaceutically acceptable salt thereof,   wherein the pharmaceutical composition contains from about 50 mg to about 200 mg of tolperisone free base or a pharmaceutically acceptable salt thereof and   wherein the pharmaceutical composition contains less than about 1.5 μg of 2-methyl-1-(4-methylphenyl)-propenone (4-MMPPO).   
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the pharmaceutical composition contains less than about 0.5 μg of 4-MMPPO. 
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition contains about 50 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition contains about 100 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition contains about 150 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition contains about 200 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition is an oral dosage form. 
     
     
         30 . The pharmaceutical composition of  claim 29 , wherein the oral dosage form is a tablet. 
     
     
         31 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition comprises tolperisone hydrochloride. 
     
     
         32 . The pharmaceutical composition of  claim 24 , wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. 
     
     
         33 . Tolperisone free base or a pharmaceutically acceptable salt thereof, with less than about 1.5 μg of 2-methyl-1-(4-methylphenyl)-propenone (4-MMPPO) in about 50 mg to about 200 mg of the tolperisone free base or a pharmaceutically acceptable salt. 
     
     
         34 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 33 , with less than about 0.5 μg of 4-MMPPO in about 50 mg to about 200 mg of the tolperisone free base or a pharmaceutically acceptable salt. 
     
     
         35 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 34 , with less than about 0.5 μg of 4-MMPPO in about 50 mg of the tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         36 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 34 , with less than about 0.5 μg of 4-MMPPO in about 100 mg of the tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 34 , with less than about 0.5 μg of 4-MMPPO in about 150 mg of the tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         38 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 34 , with less than about 0.5 μg of 4-MMPPO in about 200 mg of the tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The tolperisone free base or a pharmaceutically acceptable salt thereof of  claim 34 , wherein the tolperisone free base or a pharmaceutically acceptable salt thereof comprises tolperisone hydrochloride. 
     
     
         40 . A pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof, with 5 ppm 2-methyl-1-(4-methylphenyl)-propenone (4-MMPPO) or less. 
     
     
         41 . A pharmaceutical composition comprising the pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof, of  claim 40  and one or more pharmaceutically acceptable excipients. 
     
     
         42 . A kit comprising the pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof, of  claim 40  packaged in a container and a dessicant. 
     
     
         43 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 40 , with 4 ppm 4-MMPPO or less. 
     
     
         44 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 43 , with 3 ppm 4-MMPPO or less. 
     
     
         45 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 44 , with 2 ppm 4-MMPPO or less. 
     
     
         46 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 40 , wherein the acid addition salt of tolperisone comprises tolperisone hydrochloride. 
     
     
         47 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 43 , wherein the acid addition salt of tolperisone comprises tolperisone hydrochloride. 
     
     
         48 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 44 , wherein the acid addition salt of tolperisone comprises tolperisone hydrochloride. 
     
     
         49 . The pharmaceutically acceptable acid addition salt of tolperisone or hydrate thereof of  claim 45 , wherein the acid addition salt of tolperisone comprises tolperisone hydrochloride. 
     
     
         50 . A method of treating muscle spasms or spasticity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising:
 tolperisone free base or a pharmaceutically acceptable salt thereof;   wherein the pharmaceutical composition contains from about 50 mg to about 200 mg of tolperisone free base or a pharmaceutically acceptable salt thereof and   wherein the pharmaceutical composition contains less than about 1.5 μg of 4-MMPPO.   
     
     
         51 . The method of  claim 50 , wherein the pharmaceutical composition contains less than about 0.5 μg of 4-MMPPO. 
     
     
         52 . The method of  claim 51 , wherein the pharmaceutical composition contains about 50 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         53 . The method of  claim 51 , wherein the pharmaceutical composition contains about 100 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method of  claim 51 , wherein the pharmaceutical composition contains about 150 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         55 . The method of  claim 51 , wherein the pharmaceutical composition contains about 200 mg of tolperisone free base or a pharmaceutically acceptable salt thereof. 
     
     
         56 . The method of  claim 51 , wherein the pharmaceutical composition is an oral dosage form. 
     
     
         57 . The method of  claim 56 , wherein the oral dosage form is a tablet. 
     
     
         58 . The method of  claim 51 , wherein the pharmaceutical composition comprises tolperisone hydrochloride. 
     
     
         59 . The method of  claim 51 , wherein the subject is treated for muscle spasms. 
     
     
         60 . The method of  claim 51 , wherein the subject is treated for spasticity. 
     
     
         61 . The method of  claim 51 , wherein the pharmaceutical composition is administered to the subject three times per day. 
     
     
         62 . The method of  claim 51 , wherein the composition further comprises one or more pharmaceutically acceptable excipients. 
     
     
         63 . A method of preparing a pharmaceutical composition, comprising:
 (i) recrystallizing tolperisone free base or a pharmaceutically acceptable salt thereof containing greater than 10 ppm of 4-MMPPO, to provide tolperisone free base or a pharmaceutically acceptable salt thereof containing less than about 10 ppm of 4-MMPPO; and   (ii) combining the tolperisone free base or a pharmaceutically acceptable salt thereof from Step (i) with one or more pharmaceutically acceptable excipients to provide a pharmaceutical composition,   wherein the pharmaceutical composition contains from about 50 mg to about 200 mg of the tolperisone free base or a pharmaceutically acceptable salt thereof, and   wherein the pharmaceutical composition contains less than about 1.5 μg of 4-MMPPO.   
     
     
         64 . The method of  claim 63 , wherein the pharmaceutical composition contains less than about 0.5 μg of 4-MMPPO. 
     
     
         65 . The method of  claim 64 , wherein the recrystallization takes place in the presence of one or more acids. 
     
     
         66 . The method of  claim 65 , wherein the recrystallization takes place in the presence of hydrochloric acid. 
     
     
         67 . The method of  claim 63 , wherein the recrystallization Step (i) is repeated one or more times before Step (ii) takes place. 
     
     
         68 . The method of  claim 63 , wherein the recrystallization takes place in an organic solvent system comprising a lower alkyl alcohol. 
     
     
         69 . The method of  claim 68 , wherein the organic solvent system comprises isopropanol and hydrochloric acid. 
     
     
         70 . The method of  claim 69 , wherein the organic solvent system further comprises a lower alkyl ketone.

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