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, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin, which are unsuitable for chronic intrathecal or intracerebroventricular administration, and have undefined species ratios contributing to varying pharmacological effects.
Innovation Solution
Development of a pharmaceutical composition with controlled ratios of beta-cyclodextrin molecules substituted with hydroxypropyl groups, reduced impurities, and defined species ratios, suitable for intrathecal or intracerebroventricular administration, achieved through purification methods such as absorption chromatography 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 benefits are achieved, but impurities like propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin cause adverse effects and limit suitability for chronic intrathecal or intracerebroventricular administration
Solution Approach 1:
The patent applies extraction by removing harmful impurities (propylene glycol, unsubstituted beta-cyclodextrin molecules, and bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby retaining the therapeutic benefits while eliminating adverse effects that limit chronic intrathecal or intracerebroventricular administration
Solution Approach 2:
The patent applies parameter changes by controlling the degree of substitution (DS) distribution and purifying the composition to achieve specific purity parameters, transforming the composition from an impure state with adverse effects to a purified state suitable for chronic intrathecal or intracerebroventricular administration while maintaining therapeutic efficacy
2Ease of manufacture
If conventional hydroxypropyl beta-cyclodextrin compositions with undefined species ratios are used, then manufacturing is simpler, but pharmacological effects vary and safety is compromised
Solution Approach 1:
The patent applies parameter changes by defining and controlling the degree of substitution (DS) distribution parameters, specifying that the composition contains hydroxypropyl beta-cyclodextrin molecules with DS values predominantly in the range of 3-7, thereby ensuring consistent pharmacological effects while maintaining a practical manufacturing approach
Solution Approach 2:
The patent applies local quality by specifying particular characteristics for different molecular species within the composition, namely controlling the DS distribution to ensure that hydroxypropyl substitution occurs at specific levels (DS 3-7), which provides consistent and predictable pharmacological effects throughout the composition
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 benefits for Niemann-Pick disease with improved safety and efficacy, allowing longer 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 and solvent precipitation
Implementation Method 2
purification methods such as absorption chromatography 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.