Hydroxypropyl Beta-Cyclodextrin Purification for Chronic Intrathecal Use
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Solution Overview
Problem
Current pharmaceutical compositions of hydroxypropyl beta-cyclodextrins used for treating Niemann-Pick disease Type C contain impurities such as propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin, making them unsuitable for chronic intrathecal or intracerebroventricular administration, and have variable compositions of hydroxypropyl substitution levels which affect their pharmacological effects.
Innovation Solution
Development of a pharmaceutical composition comprising a mixture of beta-cyclodextrin molecules substituted with hydroxypropyl groups, with less than 1% unsubstituted beta-cyclodextrin and specific ratios of beta-cyclodextrin molecules with different degrees of hydroxypropyl substitution, achieved through methods such as absorption chromatography on alumina, to reduce impurities and standardize the composition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used to treat Niemann-Pick disease Type C, then therapeutic effectiveness is achieved, but impurities such as propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin make them unsuitable for chronic intrathecal or intracerebroventricular administration
Solution Approach 1:
The patent applies extraction by removing impurities (propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby making the composition suitable for chronic intrathecal or intracerebroventricular administration while maintaining therapeutic effectiveness
Solution Approach 2:
The patent applies parameter changes by standardizing the composition to contain specific ratios of beta-cyclodextrin molecules with different degrees of hydroxypropyl substitution (DS 2-6), controlling the average degree of substitution and molar substitution parameters to optimize both safety and therapeutic effectiveness for chronic administration
2Reliability
If hydroxypropyl beta-cyclodextrin compositions with variable compositions of hydroxypropyl substitution levels are used, then pharmacological effects are achieved, but the variable compositions affect the consistency and predictability of therapeutic outcomes
Solution Approach 1:
The patent applies parameter changes by defining and controlling specific composition parameters including the average degree of substitution (DS 2-6) and molar substitution, thereby standardizing the hydroxypropyl beta-cyclodextrin composition to ensure consistent and predictable therapeutic outcomes while maintaining the necessary pharmacological effects
Solution Approach 2:
The patent applies homogeneity by standardizing the composition to contain controlled ratios of beta-cyclodextrin molecules with different degrees of hydroxypropyl substitution, creating a uniform and consistent product that delivers reliable therapeutic outcomes across different batches and administrations
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 resulting composition is suitable for chronic intrathecal or intracerebroventricular administration, with reduced levels of impurities and a standardized composition that maintains therapeutic effectiveness and improves safety.
Implementation Method 1
absorption chromatography on alumina
Data Source
AI summary
This disclosure provides mixtures of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, the mixture optionally including unsubstituted beta-cyclodextrin molecules, for use as a pharmaceutically active ingredient; methods of making such mixtures; methods of qualifying such mixtures for use in a pharmaceutical composition suitable for intrathecal or intracerebroventricular administration; pharmaceutical compositions suitable for intrathecal or intracerebroventricular administration comprising such mixtures; and methods of using the pharmaceutical compositions for treatment of Niemann-Pick disease Type C.