Gemcitabine Prodrug Formulation via Polar Aprotic Solvent
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Solution Overview
Problem
Gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate, a monophosphate derivative, is extremely lipophilic and poorly water-soluble, making it challenging for effective delivery due to resistance mechanisms and instability in aqueous solutions, which limits its therapeutic efficacy in cancer treatment.
Innovation Solution
A pharmaceutical formulation comprising gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate with a polar aprotic solvent like dimethyl acetamide (DMA) and optional pharmaceutically acceptable excipients, which enhances solubility and stability, allowing for effective intravenous administration and overcoming resistance mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate is used to overcome resistance mechanisms, then therapeutic efficacy is improved, but solubility deteriorates
Solution Approach 1:
The patent uses polar aprotic solvents (dimethyl acetamide, dimethyl sulfoxide, or N-methyl-2-pyrrolidone) as intermediary substances to dissolve the lipophilic gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate compound. These solvents act as mediators between the poorly water-soluble drug and the aqueous physiological environment, enabling effective delivery while maintaining the compound's therapeutic properties against resistant cancer cells.
2Productivity
If gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate is administered intravenously, then delivery effectiveness is improved, but stability deteriorates
Solution Approach 1:
The patent changes the physical-chemical parameters of the formulation by using polar aprotic solvents with specific properties (high dielectric constant, aprotic nature) to create a stable solution environment. This parameter change allows the compound to remain stable in the formulation while enabling effective intravenous delivery, resolving the contradiction between delivery effectiveness and stability.
3Ease of manufacture
If conventional solvents are used, then ease of manufacture is improved, but solubility deteriorates
Solution Approach 1:
The patent selects polar aprotic solvents that offer an optimal balance between manufacturability and solubility. These solvents can be easily incorporated into pharmaceutical formulations using conventional manufacturing techniques while providing superior solubility for the lipophilic compound compared to traditional aqueous or alcoholic solvents.
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 formulation provides a therapeutically effective and stable solution for gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate, enabling its delivery through peripheral veins with reduced patient discomfort and maintaining stability for up to 48 hours, thus overcoming the limitations of poor solubility and resistance.
Implementation Method 1
gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate; a polar aprotic solvent
Data Source
AI summary
This invention relates to pharmaceutical formulations of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate, a monophosphate derivative of the well-known oncology drug gemcitabine. In particular, the invention relates to formulations which comprise a polar aprotic solvent, preferably dimethyl acetamide (DMA). Formulations comprising these solvent provide therapeutically effective treatments of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. The invention also relates to methods of using said formulations and kits comprising said formulations.