Gemcitabine prodrugs
This invention relates to a prodrug of the monophosphate nucleotide of the well-known oncology drug gemcitabine. Specifically, it relates to gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate when present as a single phosphate diastereoisomer and, in particular, it relates to the (S)-phosphate diastereoisomer which offers a remarkable and unexpected increase in solubility relative to the (R)-diastereoisomer. The (S)-phosphate epimer is also preferentially taken up into cyclodextrin solutions over the (R)-diastereoisomer.
1. A pharmaceutical solution formulation, comprising water, gemcitabine[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate 3:
3 or a pharmaceutically acceptable salt or solvate thereof, and a further component, wherein said further component is selected from a polar organic solvent, a cyclodextrin, and both a polar organic solvent and a cyclodextrin; wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)- phosphate 3 has a diastereoisomeric purity of greater than about 90%, and the pharmaceutical solution is for intravenous administration.
2. The pharmaceutical solution of claim 1 , wherein the solution comprises the polar organic solvent.
3. The pharmaceutical solution of claim 2 , wherein the polar organic solvent is selected from the group consisting of propylene glycol, polyethylene glycol and ethanol.
4. The pharmaceutical solution of claim 3 , wherein the polar organic solvent is propylene glycol.
5. The pharmaceutical solution of claim 3 , wherein the polar organic solvent is polyethylene glycol.
6. The pharmaceutical solution of claim 5 , wherein the polyethylene glycol is PEG400.
7. The pharmaceutical solution of claim 3 , wherein the polar organic solvent is ethanol.
8. The pharmaceutical solution of claim 1 , wherein the solution comprises the cyclodextrin.
9. The pharmaceutical solution of claim 8 , wherein the cyclodextrin is selected from the group consisting of a-cyclodextrin, (3-cyclodextrin, y-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin, sulfobutylether (3-cyclodextrin sodium salt, and partially methylated 3-cyclodextrin.
10. The pharmaceutical solution of claim 1 , wherein the gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(S)-phosphate 3 is in the form of a free base.
11. The pharmaceutical solution of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(5)-phosphate 3 has a diastereoisomeric purity of greater than about 95%.
12. The pharmaceutical solution of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(5)-phosphate 3 has a diastereoisomeric purity of greater than about 98%.
13. The pharmaceutical solution of claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-(5)-phosphate 3 has a diastereoisomeric purity of greater than about 99.5%.