Formulation comprising a gemcitabine-prodrug
This invention relates to pharmaceutical formulations of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate, a monophosphate derivative of the well-known oncology drug gemcitabine. In particular, the invention relates to formulations which comprise a polar aprotic solvent, preferably dimethyl acetamide (DMA). Formulations comprising these solvent provide therapeutically effective treatments of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. The invention also relates to methods of using said formulations and kits comprising said formulations.
1. A pharmaceutical formulation comprising:
from 10% to 60% by volume DMA;
from 10% to 80% by volume solubilizer or solubilizers;
from 1% to 15% by volume aqueous vehicle; and
from 50 mg to 150 mg per mL gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate,
wherein each solubilizer is a non-ionic surfactant or a mixture thereof; and
wherein the aqueous vehicle is selected from saline, glucose solution and water for infusion (WFI).
2. The pharmaceutical formulation according to claim 1 , wherein the aqueous vehicle is saline.
3. The pharmaceutical formulation according to claim 1 , wherein the aqueous vehicle is WFI.
4. The pharmaceutical formulation according to claim 1 , wherein each solubilizer is a polyethoxylated fatty acid or a mixture thereof.
5. The pharmaceutical formulation according to claim 1 , wherein each solubilizer is a polyoxyl castor oil or a mixture thereof.
6. The pharmaceutical formulation according to claim 1 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer with a diastereoisomeric purity of greater than 95%.
7. The pharmaceutical formulation according to claim 1 for dilution with an aqueous vehicle to form a formulation for intravenous administration.
8. A method of preparing a pharmaceutical formulation according to claim 1 , the method comprising:
diluting a first formulation with a second formulation;
wherein the first formulation comprises:
from 200 mg to 300 mg per mL gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate;
from 70% to 90% by volume dimethyl acetamide (DMA); and
from 10% to 30% by volume aqueous vehicle; and
the second formulation comprises:
from 20% to 70% by volume DMA;
from 10% to 60% by volume a first solubilizer; and
from 10% to 60% by volume a second solubilizer,
wherein each solubilizer is a non-ionic surfactant or a mixture thereof; and
wherein the aqueous vehicle is selected from saline, glucose solution and water for infusion (WFI).
9. The method according to claim 8 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer with a diastereoisomeric purity of greater than 95%.
10. A method of treating cancer, the method comprising:
diluting a solution comprising:
from 10% to 60% by volume DMA;
from 30% to 80% by volume solubilizer or solubilizers;
from 1% to 15% by volume aqueous vehicle; and
from 50 mg to 150 mg per mL gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate,
with an aqueous vehicle to provide a formulation for infusion or injection; and
administering the formulation for infusion or injection to the subject by infusion or injection,
wherein each solubilizer is a non-ionic surfactant or a mixture thereof; and
wherein the aqueous vehicle is selected from saline, glucose solution and water for infusion (WFI).
11. The method according to claim 10 , wherein gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate is in the form of the (S)-phosphate epimer with a diastereoisomeric purity of greater than 95%.