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).

Description

[0001]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), NUC-7738 (3′-deoxyadenosine-5′-O-[phenyl(benzyloxy-L-alaninyl)] phosphate) and CPF-448 (2-chloro-2′-beta-fluoro-2′-deoxyadenosine-5′-[phenyl-(benzoxy-L-(alaninyl)]-phosphate). In particular, the invention relates to formulations which comprise a polar aprotic solvent, for example dimethyl acetamide (DMA).BACKGROUND[0002]Protides are masked phosphate derivatives of nucleosides. They have been shown to be particularly potent therapeutic agents in the fields of both antivirals and oncology. Protides, more specifically, are prodrugs of monophosphorylated nucleosides. These compounds appear to avoid many of the inherent and acquired resistance mechanisms which limit the utility of the parent ...

AI Technical Summary

Benefits of technology

The present invention provides a pharmaceutical formulation comprising a protide, a polar aprotic solvent, and optionally one or more pharmaceutically acceptable excipients. The use of a polar aprotic solvent, such as DMA or NMP, as the solvent for the protide is advantageous because it helps to dissolve the protide in a stable solution at a concentration sufficient for therapeutic effect. The formulation may be for dilution before administration or may be ready for injection. It may also contain other solubilizers, such as polyethoxylated fatty acids or fatty acid esters, to improve the solubility of the protide. The formulation may be for intravenous, subcutaneous or intramuscular administration. The total dose of protide in the formulation may range from 250 mg to 5 g. The formulation may also be administered orally.

Problems solved by technology

Unfortunately, protides are often extremely lipophilic and thus poorly water soluble, and the ionisable moieties, tend to have calculated pKa values which lie outside the pH range suitable for parenteral administration.

Many are essentially insoluble in water, regardless of salt content or pH within physiological ranges, and this puts limitations on the development of clinically acceptable methods for delivering the compounds at sufficiently high dosages for effective treatment.

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