Hydroxypropyl Beta-Cyclodextrin Purification for Chronic Intrathecal Use
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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 a need for higher purity and defined compositions.
Innovation Solution
Development of a pharmaceutical composition comprising beta-cyclodextrin molecules with controlled hydroxypropyl substitution, reduced impurities, and specific ratios, suitable for intrathecal or intracerebroventricular administration, achieved through purification methods such as absorption chromatography and solvent precipitation, ensuring low levels of propylene glycol, endotoxin, and precise compositional control.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used to treat Niemann-Pick disease, then therapeutic benefits are achieved, but impurities like 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 harmful impurities from the hydroxypropyl beta-cyclodextrin composition through purification processes. Specifically, unsubstituted beta-cyclodextrin molecules are removed to prevent precipitation and reduce toxicity, propylene glycol is eliminated to reduce ototoxicity, and bacterial endotoxin is removed to reduce inflammatory responses, thereby making the composition suitable for chronic intrathecal or intracerebroventricular administration
Solution Approach 2:
The patent applies parameter changes by precisely controlling the degree of substitution (DS) of hydroxypropyl groups on beta-cyclodextrin molecules. The composition is designed to contain specifically DS-3, DS-4, DS-5, and DS-6 substituted molecules while eliminating unsubstituted and low-substitution molecules, thereby changing the compositional parameters to achieve both therapeutic efficacy and safety for chronic administration
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are used, then therapeutic effects are achieved, but precise compositional control is lacking
Solution Approach 1:
The patent applies local quality by creating a composition with non-uniform but precisely controlled distribution of hydroxypropyl substitution degrees. Rather than a random complex mixture, the composition specifically contains molecules with DS-3, DS-4, DS-5, and DS-6 substitutions in defined proportions, providing localized compositional control that ensures both therapeutic efficacy and safety
Solution Approach 2:
The patent applies parameter changes by defining specific ranges for the degree of substitution (DS) of hydroxypropyl groups. The composition is manufactured to contain only molecules with DS values of 3, 4, 5, or 6, excluding molecules with DS-0 through DS-2 and DS-7 or higher, thereby achieving precise compositional control while maintaining therapeutic effects
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 effectively modulates disease progression and improves safety, allowing for longer-term administration with therapeutic benefits while maintaining gene expression stability in cholesterol metabolism.
Implementation Method 1
treating the composition with alumina adsorption
Implementation Method 2
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.