PHARMACEUTICALLY ACCEPTABLE SALTS OF beta-GUANIDINOPROPIONIC ACID WITH IMPROVED PROPERTIES AND USES THEREOF

Abstract

The present invention relates to new pharmaceutical salts of β-GPA which exhibit improved physical properties. In particular, the invention relates to salts of β-GPA with improved flow properties (e.g., improved Carr's index and/or Hausner ratio) such as fumarate salts, succinate salts, and oxalate salts. The invention also relates to pharmaceutical compositions including a pharmaceutically effective amount of one or more salts of β-GPA, as well as methods of treating cancer including administration of a formulation including a β-GPA salt of the invention to a subject in need thereof.

What is claimed is: 
     
         1 . A pharmaceutically acceptable salt of β-guanidinopropionic acid, wherein said pharmaceutically acceptable salt is a 1:1 fumarate salt. 
     
     
         2 . The pharmaceutically acceptable salt of  claim 1 , wherein said salt is crystalline. 
     
     
         3 . The pharmaceutically acceptable salt of  claim 2  comprising less than 40% by weight of amorphous compound. 
     
     
         4 . The pharmaceutically acceptable salt of  claim 2  having an endothermic onset at about 171° C. in differential scanning calorimetry (DSC) profile. 
     
     
         5 . The pharmaceutically acceptable salt of  claim 2  having at least one peak at diffraction angle 2θ (°) of 27±0.5 as measured by X-ray powder diffractometry. 
     
     
         6 . The pharmaceutically acceptable salt of  claim 2  having at least one peak at diffraction angle 2θ (°) of 20±0.5 as measured by X-ray powder diffractometry. 
     
     
         7 . The pharmaceutically acceptable salt of  claim 2  having at least one diffraction angle 2θ (°) of 20.5±0.5 as measured by X-ray powder diffractometry. 
     
     
         8 . The pharmaceutically acceptable salt of  claim 2  having at least one diffraction angle 2θ (°) of 23±0.5 as measured by X-ray powder diffractometry. 
     
     
         9 . The pharmaceutically acceptable salt of  claim 2  in the form of rod-like crystals. 
     
     
         10 . The pharmaceutically acceptable salt of  claim 2  having a loss of weight from 31° C. to 140° C. of less than 1% as measured by thermal gravimetric analysis. 
     
     
         11 . The pharmaceutically acceptable salt of  claim 2  having at least one peak at 2941±1 cm-1 as measured by Raman spectroscopy. 
     
     
         12 . The pharmaceutically acceptable salt of  claim 2  having at least one peak at 1653±1 cm-1 as measured by Raman spectroscopy. 
     
     
         13 . The pharmaceutically acceptable salt of  claim 2  having at least one peak at 997±1 cm-1 as measured by Raman spectroscopy. 
     
     
         14 . A composition comprising a pharmaceutically acceptable salt of  claim 1  which contains less than 10% by weight of amorphous compound and a pharmaceutically acceptable excipient. 
     
     
         15 . A composition comprising a pharmaceutically acceptable salt of  claim 1 , wherein at least 80% of the fumarate salt of β-guanidinopropionic acid in said composition is a 1:1 salt. 
     
     
         16 . The composition of  claim 15 , wherein said composition is substantially free of the 2:1 fumarate salt of β-guanidinopropionic acid. 
     
     
         17 . A pharmaceutical composition in unit dosage form comprising a pharmaceutically acceptable salt of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically acceptable salt of  claim 1  and a pharmaceutically acceptable excipient, wherein said pharmaceutical composition is formulated for intravenous infusion. 
     
     
         19 . A method of treating cancer in a subject in need thereof, said method comprising administering an effective amount of a pharmaceutically acceptable salt of  claim 1  to said subject. 
     
     
         20 . The method of  claim 19 , wherein said cancer is metastatic cancer. 
     
     
         21 . The method of  claim 20 , wherein said effective amount comprises an amount effective to suppress metastatic colonization of said cancer. 
     
     
         22 . The method of  claim 21 , wherein said cancer is gastrointestinal cancer. 
     
     
         23 . The method of  claim 19 , wherein said subject is identified to have, or to be at risk of having, metastatic cancer on the basis of the expression level of miR-483-5p and/or miR-551 a is below a predetermined reference value or the expression level of CKB and/or SLC6a8 is above a predetermined reference value. 
     
     
         24 . A method for treating metastatic cancer in a subject in need thereof, comprising injecting into the subject an aqueous composition comprising a pharmaceutically acceptable salt of  claim 1  and a pharmaceutically acceptable excipient in an amount effective to suppress metastatic colonization of said cancer. 
     
     
         25 . The method of  claim 24 , wherein said metastatic cancer is gastrointestinal cancer. 
     
     
         26 . A method of treating cancer in a subject in need thereof comprising:
 (a) providing a subject identified to have, or to be at risk of having, metastatic cancer on the basis of the expression level of miR-483-5p and/or miR-551a is below a predetermined reference value or the expression level of CKB and/or SLC6a8 is above a predetermined reference value; and   (b) administering to the subject an effective amount of a pharmaceutically acceptable salt of  claim 1 .   
     
     
         27 . The method of  claim 26 , wherein said metastatic cancer is gastrointestinal cancer. 
     
     
         28 . A method of producing a pharmaceutically acceptable 1:1 fumarate salt of β-guanidinopropionic acid, said method comprising combining β-guanidinopropionic acid and fumaric acid in an amount sufficient to produce a pharmaceutically acceptable 1:1 fumarate salt of β-guanidinopropionic acid. 
     
     
         29 . The method of  claim 28 , wherein said method comprises dissolving said β-guanidinopropionic acid and said fumaric acid in a solvent and wherein said 1:1 fumarate salt of β-guanidinopropionic acid precipitates from said solvent. 
     
     
         30 . The method of  claim 28 , wherein said method further comprises recrystallization of said 1:1 fumarate salt of β-guanidinopropionic acid.