Purified Hydroxypropyl Beta-Cyclodextrin for Chronic CNS Administration
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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, making them unsuitable for chronic intrathecal or intracerebroventricular administration, and their complex mixtures lack precise compositional control, necessitating pharmaceutical compositions of higher purity and defined species ratios.
Innovation Solution
Development of a pharmaceutical composition comprising beta-cyclodextrin molecules with specific degrees of hydroxypropyl substitution, reduced impurities, and controlled 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 chronic 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 prevent chronic administration
Solution Approach 2:
The patent changes the compositional parameters of the hydroxypropyl beta-cyclodextrin by controlling the degree of substitution (DS) to specific ranges (DS≥2 for intravenous use, DS≥3 for intrathecal use) and reducing impurity levels, thereby transforming the composition from unsuitable for chronic administration to suitable for long-term use
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are administered, then therapeutic effects are observed, but lack of precise compositional control limits safety and efficacy optimization
Solution Approach 1:
The patent applies parameter changes by defining specific degree of substitution (DS) ranges for different administration routes (DS≥2 for intravenous, DS≥3 for intrathecal) and controlling impurity levels, thereby achieving precise compositional control that optimizes both safety and efficacy for chronic administration
Solution Approach 2:
The patent applies local quality by specifying different compositional requirements for different administration routes, with higher purity and substitution degree requirements for intrathecal administration compared to intravenous administration, thereby optimizing the composition for each specific use case
3Duration of action of stationary object
If current compositions are used for chronic intrathecal or intracerebroventricular administration, then treatment continuity is possible, but impurities cause ototoxicity and other adverse effects
Solution Approach 1:
The patent applies extraction by specifically removing propylene glycol and other ototoxic impurities from the hydroxypropyl beta-cyclodextrin composition, thereby enabling chronic intrathecal or intracerebroventricular administration without the risk of ototoxicity that would otherwise limit treatment duration
Solution Approach 2:
The patent changes the purity parameters of the composition by establishing strict limits on impurity levels (propylene glycol, unsubstituted beta-cyclodextrin, bacterial endotoxin) and controlling the degree of substitution, thereby transforming the composition from ototoxic to safe for chronic central nervous system administration
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 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 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.