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Formulations of phosphoramidate derivatives of nucleoside drugs

A technology of pharmaceutical preparations and phosphate esters, applied in the direction of drug combination, drug delivery, medical preparations of non-active ingredients, etc., can solve problems such as limited development and poor water solubility

Pending Publication Date: 2018-10-23
NUCANA PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Unfortunately, phosphoramidate prodrugs are often extremely lipophilic and thus poorly water soluble, and the calculated pKa values ​​of the ionizable moiety are outside the pH range suitable for parenteral administration
Many phosphoramidate prodrugs are essentially insoluble in water regardless of salt content or pH within the physiological range, which limits the development of clinically acceptable methods for delivering the compound in sufficiently high doses for effective therapy

Method used

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  • Formulations of phosphoramidate derivatives of nucleoside drugs
  • Formulations of phosphoramidate derivatives of nucleoside drugs
  • Formulations of phosphoramidate derivatives of nucleoside drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0283] Example 1 - Solubility of NUC-3373

[0284] Table 1 shows the solubility of NUC-3373 (a mixture of diastereomers) in a range of solvents.

[0285] Table 1: Solubility of NUC-3373 in a range of pharmaceutically relevant solvents

[0286]

[0287]

[0288] It can be easily seen that the solubility of NUC-3373 in water is extremely low. Among the solvents tested, polar aprotic solvents, especially DMSO and DMA provided the best solubility.

Embodiment 2

[0289] Example 2 - Development of an aqueous formulation of NUC-3373.

[0290] The successful development of the diluent solution enabled the preparation of an aqueous formulation of NUC-1031, which prompted its development for an aqueous formulation of NUC-3373. Aqueous formulations of NUC-3373 were developed by adding 6.7 ml of a 250 mg / ml NUC-3373 solution in 80% DMA:20% 0.9% saline to 10 ml of diluent solution to produce a 100 mg / ml NUC-3373 surfactant solution (see Table 4), then diluted into the infusion bag.

[0291] The clinical dose of NUC-3373 has not been determined, but the estimated maximum dose may be as much as 3,000 mg, which sets an upper limit for formulation development studies. Table 2 shows the volume of 100 mg / ml NUC-3373 surfactant solution that needs to be added to a 250 ml infusion bag for various doses, and the composition of the resulting aqueous infusion solution.

[0292] Table 2: Composition of saline infusion solutions with various doses of N...

Embodiment 3

[0310] Example 3 - Illustrative Description of Formulation Process

[0311] Formulation methodology (see WO2015 / 198059 (PCT / GB2015 / 051858)) has been developed for intravenous administration of phosphoramidate prodrugs. This approach has been shown in clinical trials to be effective against NUC-1031, which has approximately the same solubility profile as NUC-3373 and NUC-7738. The method is as follows: A 250 mg / mL solution of the phosphoramidite ester prodrug (S-epimer, R-epimer, or a mixture thereof) is formed in an 80:20 (by volume) mixture of DMA and 0.9% saline. This stock solution formulation is generally sufficiently stable for long-term storage and transport of the phosphoramidate prodrug.

[0312] The stock solution formulation can be administered intravenously to the patient by CVAD (eg Hickman series, PICC series). The intravenous administration set is typically flushed with an 80:20 (by volume) mixture of DMA and 0.9% saline before and after administration of the...

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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 cancersuch as NUC-3373 (5-fluoro-2'-deoxyuridine-5'-0-[1-naphthyl (benzoxy-L-alaninyl)] phosphate) and NUC-7738 (3'-deoxyadenosine-5'-0-[phenyl(benzyloxy-L-alaninyl)] phosphate). In particular, the invention relates to formulations which comprise a polar aprotic solvent, for example dimethyl acetamide (DMA).

Description

technical field [0001] The present invention relates to phosphoramidate prodrugs (phosphoramidate derivatives of nucleosides), especially phosphoramidate prodrugs for the treatment of cancer, such as NUC-3373 (5-fluoro-2'-deoxyuridine-5' -O-[1-naphthyl(benzyloxy-L-alanyl)]phosphate), NUC-7738 (3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L- alanyl)]phosphate) and CPF-448 (2-chloro-2'-β-fluoro-2'-deoxyadenosine-5'-[phenyl-(benzyloxy-L-(alanyl) ]-phosphate esters) and formulation strategies. In particular, the present invention relates to formulations comprising polar aprotic solvents such as dimethylacetamide (DMA). Background technique [0002] Phosphoramidate prodrugs are phosphate derivatives of masked nucleosides. They have proven to be particularly effective therapeutic agents in the fields of antivirals and oncology. More specifically, phosphoramidate prodrugs are prodrugs of monophosphorylated nucleosides. These compounds appear to avoid many of the intrinsic and acqui...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/08A61K31/7072A61K31/7076A61P35/00
CPCA61K9/00A61K9/08A61K31/7072A61K31/7076A61P35/00A61K9/0019A61K47/18A61K47/20A61P31/12A61P35/02A61K47/22
Inventor 戈登·肯诺温休·格里菲斯
Owner NUCANA PLC
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