Phosphoramidate Protide Formulations With Polar Aprotic Solvents
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Solution Overview
Problem
Protides, being highly lipophilic and poorly water-soluble, face challenges in stable parenteral administration due to limitations in solubility and pH range, which hinders effective dosage delivery and causes potential precipitation and degradation.
Innovation Solution
The use of polar aprotic solvents like dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) in pharmaceutical formulations to enhance solubility and stability of protides, combined with pharmaceutically acceptable excipients and solubilizers, allows for stable intravenous delivery through CVAD or peripheral veins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If protides are used as therapeutic agents, then therapeutic efficacy is improved, but water solubility deteriorates due to high lipophilicity
Solution Approach 1:
The patent uses polar aprotic solvents (DMA, NMP) as intermediary substances to bridge the gap between lipophilic protides and aqueous administration systems. These solvents act as mediators that can dissolve both the lipophilic drug and mix with water, enabling parenteral administration without compromising therapeutic efficacy or solubility
2Productivity
If protides are administered parenterally, then delivery efficiency is improved, but formulation stability deteriorates due to precipitation and degradation
Solution Approach 1:
The patent changes the physical and chemical parameters of the formulation system by introducing polar aprotic solvents with specific properties (high polarity, aprotic nature, water miscibility). This parameter change enables the formulation to maintain stability across the required pH and temperature ranges for parenteral administration, preventing precipitation and degradation while ensuring efficient delivery
3Ease of manufacture
If conventional solvents are used for protide formulation, then ease of manufacture is improved, but administration safety deteriorates due to pH range limitations
Solution Approach 1:
The patent changes the pH buffer capacity and range parameters of the formulation by using polar aprotic solvents that can maintain stability across a broader pH range (pH 3-9) compared to conventional aqueous systems. This parameter change eliminates pH-related harmful effects while maintaining ease of manufacture through simple formulation procedures
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 a stable and effective delivery of protides, maintaining solubility and preventing precipitation and degradation, enabling therapeutic doses for various cancers via intravenous administration.
Implementation Method 1
The use of polar aprotic solvents like dimethylacetamide (DMA) and N-methylpyrrolidone (NMP) in pharmaceutical formulations to enhance solubility and stability of protides
Data Source
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).