Formulations of phosphoramidate derivatives of nucleoside drugs

Abstract

This invention relates to pharmaceutical formulations and formulation strategies of protides (phosphoramidate derivatives of nucleosides) and, in particular, protides useful in the treatment of cancer, such as NUC-3373 (5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L-alaninyl)] phosphate) and NUC-7738 (3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate). In particular, the invention relates to formulations that comprise a polar aprotic solvent, for example, dimethyl acetamide (DMA).

1 . A pharmaceutical formulation comprising:
 a protide;   a polar aprotic solvent; and   optionally one or more pharmaceutically acceptable excipients;   
       wherein the protide is not gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031). 
     
     
         2 . The formulation of  claim 1 , wherein the polar aprotic solvent is selected from the group consisting of dimethyl acetamide (DMA), dimethylsulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP). 
     
     
         3 . The formulation of  claim 1 , wherein the polar aprotic solvent is DMA. 
     
     
         4 . The formulation of  claim 1 , wherein the formulation further comprises an aqueous vehicle. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The formulation of  claim 1 , wherein the formulation further comprises a solubilizer. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The formulation of  claim 1 , wherein the formulation comprises:
 from 30% to 95% by volume DMA;   from 5% to 50% by volume aqueous vehicle; and   from 100 mg to 400 mg per mL protide.   
     
     
         11 . (canceled) 
     
     
         12 . The formulation of  claim 1 , wherein the formulation comprises
 from 0.1% to 10% by volume DMA;   from 0.1% to 10% by volume solubilizer or solubilizers;   from 85% to 99% by volume aqueous vehicle; and   from 2.0 mg to 12.0 mg per mL protide.   
     
     
         13 . (canceled) 
     
     
         14 . The formulation of  claim 1 , wherein the protide is 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L-alaninyl)] phosphate (NUC-3373). 
     
     
         15 . The formulation of  claim 1 , wherein the protide is 3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate (NUC-7738). 
     
     
         16 . The formulation of  claim 1 , wherein the protide is 2-chloro-2′-beta-fluoro-2′-deoxyadenosine-5′-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF-448). 
     
     
         17 . (canceled) 
     
     
         18 . A method of treating cancer, the method comprising administering to a subject in need thereof a pharmaceutical formulation comprising:
 a protide;   a polar aprotic solvent; and   optionally one or more pharmaceutically acceptable excipients;   wherein the protide is not gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031).   
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 18 , wherein the polar aprotic solvent is DMA. 
     
     
         22 . The method of  claim 18 , wherein the protide is 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L-alaninyl)] phosphate (NUC-3373). 
     
     
         23 . The method of  claim 18 , wherein the protide is 3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate (NUC-7738). 
     
     
         24 . The method of  claim 18 , wherein the protide is 2-chloro-2′-beta-fluoro-2′-deoxyadenosine-5′-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF-448). 
     
     
         25 . A kit, comprising:
 a first formulation comprising the polar aprotic and the protide and optionally an aqueous vehicle;   a second formulation comprising the polar aprotic solvent and one or more solubilizers;   wherein the protide is not gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate (NUC-1031).   
     
     
         26 . (canceled) 
     
     
         27 . The kit of  claim 25 , wherein the polar aprotic solvent is DMA. 
     
     
         28 . The kit of  claim 25 , wherein the protide is NUC-3373 5-fluoro-2′-deoxyuridine-5′-O-[1-naphthyl (benzoxy-L-alaninyl)] phosphate (NUC-3373). 
     
     
         29 . The kit of  claim 25 , wherein the protide is 3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate (NUC-7738). 
     
     
         30 . The kit of  claim 25 , wherein the protide is 2-chloro-2′-beta-fluoro-2′-deoxyadenosine-5′-[phenyl-(benzoxy-L-alaninyl)]-phosphate (CPF-448).