Protide Formulations With Polar Aprotic Solvents for Infusion Stability

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Solution Overview

Problem

Protides, being highly lipophilic and poorly water-soluble, face challenges in stable parenteral administration due to insolubility and pH limitations, limiting effective dosage and stability during infusion.

Innovation Solution

Formulations incorporating polar aprotic solvents like dimethylacetamide (DMA) and dimethylsulfoxide (DMSO) enhance solubility and stability, allowing for effective intravenous delivery of protides through CVAD or peripheral veins, with optional solubilizers and aqueous vehicles to maintain stability and reduce osmolarity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If protides are used as therapeutic agents, then potency and ability to overcome resistance mechanisms are improved, but water solubility deteriorates due to high lipophilicity

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidwater solubility

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent uses polar aprotic solvents (DMA, DMSO, NMP) as intermediary substances to bridge the solubility gap. These solvents act as mediators that can dissolve both the lipophilic protide molecules and are compatible with intravenous administration, thereby resolving the contradiction between maintaining therapeutic potency and achieving adequate water solubility for parenteral delivery

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent changes the solvent parameter from purely aqueous to polar aprotic solvents, which fundamentally alters the solubility characteristics. This parameter change enables the formulation to achieve both high protide solubility and compatibility with intravenous administration, resolving the contradiction between therapeutic effectiveness and solubility

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If protides are formulated for parenteral administration, then therapeutic delivery is improved, but stability deteriorates due to pH limitations and precipitation

Engineering Contradiction:

Improveparenteral deliverabilityVSAvoidformulation stability

Core Design Contradiction:

Ease of operationVSStability of the object's composition

Solution Approach 1:

The polar aprotic solvents serve as stabilizing intermediaries that prevent protide precipitation and degradation. These solvents create a stable formulation environment that maintains protide integrity during storage and infusion, while still allowing for safe parenteral administration, thus resolving the contradiction between deliverability and stability

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates composite formulations combining polar aprotic solvents with protides and optional co-solvents. This composite approach provides both the stability needed to prevent precipitation and the compatibility required for intravenous administration, resolving the contradiction between formulation stability and parenteral deliverability

Inventive Principle:

Principle #40Composite materials

3Quantity of substance

If higher dosages are administered to overcome solubility limitations, then therapeutic effect is improved, but formulation stability deteriorates due to precipitation

Engineering Contradiction:

ImprovedosageVSAvoidformulation stability

Core Design Contradiction:

Quantity of substanceVSStability of the object's composition

Solution Approach 1:

The patent changes the solvent parameter to polar aprotic solvents, which fundamentally increases the solubility capacity of the formulation. This enables administration of higher therapeutic dosages while maintaining formulation stability and preventing precipitation, thereby resolving the contradiction between dosage and stability

Inventive Principle:

Principle #35Parameter changes

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The formulations provide stable, effective, and tolerable intravenous delivery of protides, overcoming solubility and stability issues, enabling therapeutic doses for various cancers.

Implementation Method 1

Formulations incorporating polar aprotic solvents like dimethylacetamide (DMA) and dimethylsulfoxide (DMSO) enhance solubility and stability

Methodology Applied

Scientific EffectSolvation: Solvation

Data Source

PatentUS20250302859A1Formulations of phosphoramidate derivatives of nucleoside drugs

Publication Date: 2025.10.02 NUCANA PLC

AI summary

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 which comprise a polar aprotic solvent, for example dimethyl acetamide (DMA).