Pharmaceutically acceptable salts of B-guanidinopropionic acid with improved properties and uses thereof
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.
1. A pharmaceutically acceptable salt of β-guanidinopropionic acid, wherein said pharmaceutically acceptable salt is a 2:1 fumarate salt wherein said salt is crystalline and has at least one peak at diffraction angle 2θ (°) selected from 27±0.5, 20±0.5, 20.5±0.5 or 23.5±0.5 as measured by X-ray diffractometry or calculated from X-ray diffractometry.
2. The pharmaceutically acceptable salt of claim 1 comprising less than 40% by weight of amorphous compound.
3. The pharmaceutically acceptable salt of claim 1 having an endothermic onset at about 187° C. and/or 251° C. in differential scanning calorimetry (DSC) profile.
4. The pharmaceutically acceptable salt of claim 1 having at least one peak at diffraction angle 2θ (°) of 27±0.5 as measured by X-ray diffractometry or calculated from X-ray diffractometry.
5. The pharmaceutically acceptable salt of claim 1 having at least one peak at diffraction angle 2θ (°) of 20±0.5 as measured by X-ray diffractometry or calculated from X-ray diffractometry.
6. The pharmaceutically acceptable salt of claim 1 having at least one diffraction angle 2θ (°) of 20.5±0.5 as measured by X-ray diffractometry or calculated from X-ray diffractometry.
7. The pharmaceutically acceptable salt of claim 1 having at least one diffraction angle 2θ (°) of 23±0.5 as measured by X-ray diffractometry or calculated from X-ray diffractometry.
8. The pharmaceutically acceptable salt of claim 1 , wherein the crystal has a unit cell of the space group P 2 1 /n, having dimensions of a=about 12.4541 Å, b=about 9.5447 Å, c=about 14.4013 Å and α=about 90°, β=about 100.5°, γ=about 90° and/or a cell volume of about 1683 Å 3 as measured by X-ray diffractometry.
9. The pharmaceutically acceptable salt of claim 1 in the form of plate-like crystals.
10. The pharmaceutically acceptable salt of claim 1 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 1 having at least one peak at 2941±1 cm−1 as measured by Raman spectroscopy.
12. The pharmaceutically acceptable salt of claim 1 having at least one peak at 1653±1 cm−1 as measured by Raman spectroscopy.
13. The pharmaceutically acceptable salt of claim 1 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 2:1 salt.
16. The composition of claim 14 , wherein said composition is substantially free of the 1:1 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-551a 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 2:1 fumarate salt of β-guanidinopropionic acid, said method comprising combining β-guanidinopropionic acid wherein said method further comprises dissolving said 2:1 fumarate salt of β-guanidinopropionic acid in a solvent wherein said 2:1 fumarate salt of β-guanidinopropionic acid precipitates from said solvent and fumaric acid in an amount sufficient to produce a pharmaceutically acceptable 2:1 fumarate salt of β-guanidinopropionic acid.