Sulfobutyl Ether Beta-Cyclodextrin Preservative Binding
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Solution Overview
Problem
Administering neurokinin receptor antagonists, such as compounds of Formula I and Ia, poses challenges with injection site tolerance due to irritability, inflammation, and other adverse reactions, and existing solutions fail to effectively balance antimicrobial preservative efficacy and injection site toleration.
Innovation Solution
A pharmaceutical composition comprising a therapeutically effective amount of an Active Pharmaceutical Ingredient, β-cyclodextrin, and a pharmaceutically acceptable preservative like meta-cresol, where the preservative's binding value to cyclodextrin is less than the API's, ensuring adequate antimicrobial effectiveness and improved injection site toleration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclodextrin is used to enhance solubility of the API, then solubility and injection site toleration are improved, but preservative binding occurs which reduces antimicrobial effectiveness
Solution Approach 1:
The patent changes the chemical structure parameters of the cyclodextrin by introducing sulfobutyl ether groups at specific positions (2,6-O-sulfobutyl ether-β-cyclodextrin). This structural modification alters the binding characteristics of the cyclodextrin cavity, reducing its affinity for preservatives while maintaining its ability to complex with the API and enhance solubility. The sulfobutyl ether substitution changes the electronic and steric properties of the cyclodextrin, preventing preservative inactivation.
Solution Approach 2:
The patent creates a composite formulation system combining modified cyclodextrin (sulfobutyl ether-β-cyclodextrin) with conventional preservatives (meta-cresol, phenol). The modified cyclodextrin acts as a solubility-enhancing excipient that does not interfere with preservative function, allowing the composite system to achieve both improved API solubility and maintained antimicrobial effectiveness. This composite approach resolves the contradiction by selecting materials with compatible properties.
2Object-affected harmful factors
If conventional preservatives are used in formulations with cyclodextrin, then antimicrobial protection is provided, but the preservatives bind to cyclodextrin and become inactive
Solution Approach 1:
The patent modifies the cyclodextrin parameter (chemical structure) rather than changing the preservative. By introducing sulfobutyl ether groups at positions 2 and 6 of the β-cyclodextrin ring, the patent alters the binding pocket characteristics, reducing preservative affinity while maintaining API complexation capability. This parameter change allows conventional preservatives to remain active in the formulation.
Solution Approach 2:
The modified cyclodextrin serves as an intermediary substance that fulfills the solubility-enhancing function without interfering with preservative activity. The sulfobutyl ether-β-cyclodextrin acts as a mediator between the hydrophobic API and the aqueous environment, providing solubility enhancement while its modified structure prevents it from acting as a mediator for preservative binding and inactivation.
3Reliability
If higher concentrations of preservative are used to ensure antimicrobial effectiveness, then microbial protection is improved, but injection site toleration deteriorates
Solution Approach 1:
The modified cyclodextrin (sulfobutyl ether-β-cyclodextrin) provides self-service by enhancing API solubility without requiring higher preservative concentrations. The improved solubility and stability provided by the modified cyclodextrin creates a formulation environment where lower preservative concentrations are sufficient to achieve the required antimicrobial effectiveness, thereby reducing injection site irritation.
Solution Approach 2:
By changing the cyclodextrin structure to sulfobutyl ether-β-cyclodextrin, the patent improves the overall formulation stability and solubility characteristics. This parameter change in the excipient allows the system to achieve better API dissolution and stability, which in turn allows using lower preservative concentrations while maintaining adequate antimicrobial protection, thus reducing injection site toleration issues.
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 composition achieves a significant log reduction in bacterial and fungal growth while maintaining acceptable injection site toleration, meeting stringent antimicrobial criteria and reducing adverse reactions.
Implementation Method 1
Cyclodextrin may enhance solubility by forming an inclusion complex with the drug molecule whereby the insoluble/hydrophobic drug is inserted into the hydrophobic cavity of the cyclodextrin
Implementation Method 2
Unfortunately, the cyclodextrin used to form the inclusion complex may also bind preservatives, inactivating many poorly water-soluble preservatives
Data Source
AI summary
The present invention is directed to pharmaceutical compositions containing a therapeutically effective amount of an Active Pharmaceutical Ingredient (“API”), a pharmaceutically acceptable cyclodextrin and a pharmaceutically acceptable preservative. The invention is also directed to pharmaceutical compositions of the compounds of Formula (I) wherein R2 is selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl and tert-butyl and a pharmaceutically acceptable cyclodextrin and preservative. Formula (I): In particular, the invention is directed to pharmaceutical compositions of the compound of Formula 1a, and a pharmaceutically acceptable cyclodextrin and a preservative.