Hydroxypropyl Beta-Cyclodextrin Purification for Chronic CNS Dosing
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Solution Overview
Problem
Current hydroxypropyl beta-cyclodextrin compositions used for treating Niemann-Pick disease contain impurities like propylene glycol, beta-cyclodextrin molecules with no hydroxypropyl substitutions, and bacterial endotoxin, making them unsuitable for chronic intrathecal or intracerebroventricular administration, and their complex mixtures lack precise compositional control, necessitating the development of higher purity and defined pharmaceutical compositions.
Innovation Solution
Development of a pharmaceutical composition comprising beta-cyclodextrin molecules with controlled hydroxypropyl substitution levels, reduced impurities, and specific ratios, suitable for intrathecal or intracerebroventricular administration, achieved through purification methods such as absorption chromatography on alumina and solvent precipitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used for treating Niemann-Pick disease, then therapeutic benefit is achieved, but impurities like propylene glycol, unsubstituted beta-cyclodextrin, and bacterial endotoxin cause adverse effects and limit chronic administration
Solution Approach 1:
The patent applies extraction by removing harmful impurities (propylene glycol, unsubstituted beta-cyclodextrin, and bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby retaining the therapeutic benefits while eliminating adverse effects that prevent chronic administration
Solution Approach 2:
The patent changes the compositional parameters of the hydroxypropyl beta-cyclodextrin composition by controlling the degree of substitution and removing impurities, transforming the composition from a crude form with harmful contaminants to a purified pharmaceutical grade product suitable for chronic intrathecal or intracerebroventricular administration
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are used, then therapeutic activity is achieved, but lack of precise compositional control reduces manufacturing precision and safety
Solution Approach 1:
The patent applies parameter changes by precisely controlling the degree of substitution (DS) of hydroxypropyl groups on beta-cyclodextrin molecules and establishing specific compositional ratios, thereby achieving both therapeutic activity and manufacturing precision through defined pharmaceutical compositions rather than complex mixtures
Solution Approach 2:
The patent applies local quality by specifying particular compositional characteristics (degree of substitution ranges, purity levels, and ratio specifications) for different aspects of the hydroxypropyl beta-cyclodextrin composition, allowing precise control over therapeutic activity while ensuring safety and consistency in manufacturing
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 purified composition provides therapeutic benefit in Niemann-Pick disease with improved safety and efficacy, allowing longer administration periods and more frequent dosing without adverse effects like hearing loss, while maintaining gene expression related to cholesterol metabolism.
Implementation Method 1
purification methods such as absorption chromatography on alumina
Implementation Method 2
purification methods such as absorption chromatography on alumina and solvent precipitation
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.