β-Substituted β-Amino Acid Inclusion Complexes for IV Stability
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Solution Overview
Problem
Existing β-substituted β-amino acid derivatives used as chemotherapeutic agents are unstable in aqueous buffered solutions suitable for intravenous administration, limiting their clinical application.
Innovation Solution
A guest-host inclusion complex comprising (S)-3-amino-4-(5-(bis-chloroethyl)amino)-2-methylphenyl) butanoic acid and sulfobutyl ether-β-cyclodextrin is developed, which is lyophilized and reconstituted in a sodium chloride solution to form a stable aqueous formulation for intravenous administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If β-substituted β-amino acid derivatives are used as chemotherapeutic agents, then therapeutic efficacy is improved, but stability in aqueous buffered solutions deteriorates
Solution Approach 1:
A cyclodextrin derivative serves as an intermediary carrier molecule that forms an inclusion complex with the β-substituted β-amino acid derivative. The cyclodextrin's hydrophobic cavity encapsulates the chemotherapeutic agent, protecting it from aqueous degradation while maintaining its therapeutic activity. This mediator enables stable intravenous administration of the otherwise unstable compound.
Solution Approach 2:
The invention creates a composite pharmaceutical system combining the β-substituted β-amino acid derivative with a cyclodextrin derivative in a specific mass ratio (1:2 to 1:5). This composite formulation leverages the complementary properties of both components: the therapeutic efficacy of the chemotherapeutic agent and the stability-enhancing properties of the cyclodextrin carrier, resulting in a stable aqueous formulation suitable for intravenous administration.
2Adaptability or versatility
If β-substituted β-amino acid derivatives are formulated for intravenous administration, then clinical applicability is improved, but stability in aqueous solutions deteriorates
Solution Approach 1:
The cyclodextrin derivative acts as a mediator that enables the unstable chemotherapeutic agent to be formulated in aqueous buffered solutions required for intravenous administration. Without this intermediary carrier, the compound cannot be stably administered intravenously despite its therapeutic value.
Solution Approach 2:
The invention optimizes the mass ratio parameters of the chemotherapeutic agent to cyclodextrin derivative (1:2 to 1:5) to achieve the desired balance between stability and clinical applicability. This parameter optimization ensures the formulation remains stable in aqueous solutions while maintaining sufficient drug concentration for effective intravenous therapy.
3Stability of the object's composition
If a stable aqueous formulation is developed, then solubility and stability are improved, but drug degradation is prevented
Solution Approach 1:
The cyclodextrin derivative serves as a protective intermediary that physically shields the chemotherapeutic agent from degradation pathways in aqueous solution. By encapsulating the drug within its hydrophobic cavity, the cyclodextrin prevents hydrolysis and other water-mediated degradation reactions, thereby maintaining drug integrity throughout storage and administration.
Solution Approach 2:
The composite formulation of chemotherapeutic agent and cyclodextrin derivative creates a stable aqueous system where the cyclodextrin component actively prevents drug degradation. This composite approach transforms the unstable individual drug molecule into a stable complex that resists degradation while maintaining solubility and therapeutic efficacy.
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 complex provides a stable and effective chemotherapeutic agent for treating brain and metastatic cancers, maintaining therapeutic efficacy while ensuring stability and solubility for intravenous use.
Implementation Method 1
a guest-host inclusion complex comprises: (S)-3-amino-4-(5-(bis-chloroethyl)amino)-2-methylphenyl) butanoic acid (1c), or a pharmaceutically acceptable zwitterion, internal salt, or salt thereof, and a cyclodextrin derivative
Data Source
AI summary
Pharmaceutical compositions comprising a chemotherapeutic agent based on a β-substituted β-amino acid derivative are disclosed. The pharmaceutical compositions include a β-substituted β-amino acid derivative and a cyclodextrin derivative. The pharmaceutical compositions are useful for treating cancer.