Gemcabene, pharmaceutically acceptable salts thereof, compositions thereof and methods of use therefor

Abstract

This present invention provides gemcabene pharmaceutically acceptable salts having a PSD90 of 35 μm to about 90 μm, methods for purifying crude gemcabene, pharmaceutically acceptable salts of purified gemcabene, pharmaceutical compositions of a gemcabene pharmaceutically acceptable salt and therapeutic and prophylactic methods useful for various conditions, including dyslipidemia.

What is claimed is: 
     
         1 . A pharmaceutically acceptable salt of gemcabene, the pharmaceutically acceptable salt having a PSD90 ranging from 40 μm to about 75 μm as measured by laser light diffraction and providing a plasma gemcabene AUC (0-24)  ranging from about 200 μg·hr/mL at steady state to about 6000 μg·hr/mL at steady state when administered to a human subject at a dose of about 50 mg to about 900 mg. 
     
     
         2 . The pharmaceutically acceptable salt of  claim 1 , wherein the pharmaceutically acceptable salt has a dissolution profile characterized by a % dissolution value of (1) at least 80% in pH 5.0 potassium acetate buffer at 37° C.±5° C. in no more than 45 minutes as measured by high-performance liquid chromatography using a detection wavelength of 210 nm or (2) at least 70% in pH 5.0 potassium acetate buffer at 37° C.±5° C. in no more than 30 minutes as measured by high-performance liquid chromatography using a detection wavelength of 210 nm. 
     
     
         3 . The pharmaceutically acceptable salt of  claim 1 , wherein the pharmaceutically acceptable salt is a calcium salt. 
     
     
         4 . A pharmaceutically acceptable salt of gemcabene, the pharmaceutically acceptable salt having a PSD90 ranging from 40 μm to about 75 μm as measured by laser light diffraction and providing a plasma gemcabene AUC last  ranging from about 50 μg·hr/mL to about 7500 μg·hr/mL after a single dose administration of about 50 mg to about 900 mg to a human subject. 
     
     
         5 . The pharmaceutically acceptable salt of  claim 4 , wherein the pharmaceutically acceptable salt has a dissolution profile characterized by a % dissolution value of (1) at least 80% in pH 5.0 potassium acetate buffer at 37° C.±5° C. in no more than 45 minutes as measured by high-performance liquid chromatography using a detection wavelength of 210 nm or (2) at least 70% in pH 5.0 potassium acetate buffer at 37° C.±5° C. in no more than 30 minutes as measured by high-performance liquid chromatography using a detection wavelength of 210 nm. 
     
     
         6 . The pharmaceutically acceptable salt of  claim 4 , wherein the pharmaceutically acceptable salt is a calcium salt. 
     
     
         7 . A method for purifying crude gemcabene, wherein the crude gemcabene comprises no more than 3% w/w of 2,2,7,7-tetramethyl-octane-1,8-dioic acid as determined by high-performance liquid chromatography, comprising:
 dissolving the crude gemcabene in heptane to provide a heptane solution of the crude gemcabene; and   cooling the heptane solution to a temperature ranging from 10° C. to 15° C. to precipitate gemcabene, wherein the gemcabene comprises 0.5% w/w or less of 2,2,7,7-tetramethyl-octane-1,8-dioic acid as determined by high-performance liquid chromatography.   
     
     
         8 . The method of  claim 7 , further comprising:
 dissolving the gemcabene in heptane to provide a heptane solution of the gemcabene; and   cooling the heptane solution to a temperature ranging from 10° C. to 15° C. to precipitate recrystallized gemcabene.   
     
     
         9 . The method of  claim 7 , further comprising:
 allowing two or more molar equivalents of an enolate of an alkali metal salt of isobutyric acid to react with one molar equivalent of a bis-(4-halobutyl)ether to provide crude gemcabene salt and   acidifying the crude gemcabene salt to provide the crude gemcabene.   
     
     
         10 . Gemcabene made by the method of  claim 7 . 
     
     
         11 . A pharmaceutically acceptable salt of the gemcabene of  claim 10 . 
     
     
         12 . The pharmaceutically acceptable salt of  claim 11 , wherein the pharmaceutically acceptable salt is a calcium salt. 
     
     
         13 . A composition comprising an effective amount of the pharmaceutically acceptable salt of  claim 1  and a pharmaceutically acceptable carrier or vehicle. 
     
     
         14 . A composition comprising an effective amount of the pharmaceutically acceptable salt of  claim 4  and a pharmaceutically acceptable carrier or vehicle. 
     
     
         15 . A composition comprising an effective amount of the pharmaceutically acceptable salt of  claim 11  and a pharmaceutically acceptable carrier or vehicle.