Hydroxypropyl Beta-Cyclodextrin Purification for 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 with a controlled mixture of beta-cyclodextrin molecules having specific degrees of hydroxypropyl substitution, reduced impurities, and improved manufacturing methods to ensure safety and efficacy for chronic administration, including 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 effects 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 (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 retaining the therapeutic benefits
Solution Approach 2:
The patent changes the compositional parameters of the hydroxypropyl beta-cyclodextrin by controlling the degree of hydroxypropyl substitution and removing impurities, transforming the composition from an impure form unsuitable for chronic administration to a purified form with defined composition that is safe for long-term use
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are used, then therapeutic effects are observed, but precise compositional control is lacking
Solution Approach 1:
The patent applies local quality by defining specific compositional characteristics for different components of the hydroxypropyl beta-cyclodextrin mixture, controlling the degree of hydroxypropyl substitution at specific positions and maintaining defined ratios of substituted versus unsubstituted molecules, thereby achieving precise compositional control while preserving therapeutic efficacy
Solution Approach 2:
The patent changes the compositional parameters by establishing defined ranges for the degree of hydroxypropyl substitution (DS) and controlling the ratio of substituted to unsubstituted beta-cyclodextrin molecules, transforming the composition from an uncontrolled complex mixture to a precisely defined pharmaceutical composition with reproducible 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 by reducing impurities, allowing for longer and more frequent dosing without adverse effects, as confirmed by gene expression profiling and clinical trial data.
Implementation Method 1
absorption chromatography on alumina
Implementation Method 2
absorption chromatography on alumina
Implementation Method 3
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.