Combination drug substance of polyamine transport inhibitor and DFMO
Provided herein are combinations comprising difluoromethylornithine (DFMO), or an ionic form thereof, and a compound of the following structural formula: or a protonated form thereof, wherein values for the variables (e.g., a, b, c, d, e, n, R 1 , R 2 , X) are described herein. The combinations can provide combination drug therapy in a single pharmaceutical dosage form, and be used, for example, for the treatment of cancer.
1. A salt of a deprotonated form of difluoromethylornithine (DFMO) and a protonated form of a compound of the following structural formula:
and optionally an anion of a pharmaceutically acceptable acid or base, a cation of a pharmaceutically acceptable acid or base, or both.
2. A crystalline solid form of a deprotonated form of DFMO and a protonated form of a compound of the following structural formula:
and optionally a coformer, one or more additional ionic species, or a coformer and one or more additional ionic species.
3. The crystalline solid form of claim 2 , characterized by an x-ray diffraction pattern in accordance with that depicted in FIG. 5 or one of those depicted in FIG. 11 .
4. The crystalline solid form of claim 2 , wherein a coformer is present.
5. The crystalline solid form of claim 2 , wherein the molar ratio of the deprotonated form of DFMO and the protonated form of AMXT 1501 is from about one to one (1:1) to about 10 to one (10:1).
6. A pharmaceutical composition comprising a crystalline solid form of claim 2 , and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6 , formulated for oral administration.
8. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline solid form of claim 3 .
9. The crystalline solid form of claim 4 , wherein the coformer is water.
10. The crystalline solid form of claim 2 , wherein one or more additional ionic species are present.
11. The crystalline solid form of claim 10 , wherein the one or more additional ionic species are anionic.
12. The salt of claim 1 , wherein an anion and a cation of a pharmaceutically acceptable acid are present.
13. The salt of claim 12 , wherein the pharmaceutically acceptable acid is an inorganic acid.
14. The salt of claim 12 , wherein the pharmaceutically acceptable acid has a pK a difference of greater than or equal to 2 compared to DFMO or AMXT 1501.
15. A hydrate of the salt of claim 1 .
16. A method of making a crystalline solid form of claim 2 , comprising:
combining the AMXT 1501, or a salt thereof, and DFMO, or a salt thereof, in a solvent to provide a solution having a pH of about 6 to about 8, wherein the solvent is a polar protic solvent or mixture of solvents comprising a polar protic solvent; and
inducing precipitation of the crystalline solid form from the solution.
17. The method of claim 16 , wherein the solution has a pH of near 7.
18. The method of claim 16 , wherein the polar protic solvent is water.
19. The method of claim 16 , further comprising adding a non-solvent to the solution, thereby inducing precipitation of the crystalline solid form from the solution.
20. The method of claim 19 , wherein the non-solvent is acetonitrile.
21. A solvate of the salt of claim 1 .
22. The crystalline solid form of claim 2 , wherein a coformer and one or more additional ionic species are present.