Purified Hydroxypropyl Beta-Cyclodextrin for Chronic CNS Delivery
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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.
Innovation Solution
Development of a pharmaceutical composition with a controlled mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, reducing impurities and maintaining therapeutic efficacy by using a process involving absorption chromatography on alumina and solvent precipitation to achieve specific substitution levels and purity standards.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used for treating Niemann-Pick disease, then therapeutic efficacy is achieved, but impurities (propylene glycol, unsubstituted beta-cyclodextrin, bacterial endotoxin) cause adverse effects and make chronic administration unsafe
Solution Approach 1:
The patent applies extraction by removing impurities (propylene glycol, unsubstituted beta-cyclodextrin, bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby eliminating harmful factors while preserving the therapeutic active ingredient
Solution Approach 2:
The patent changes the compositional parameters of the composition by controlling the degree of substitution (DS) to be greater than 2.3, and by reducing impurity levels through purification, thereby transforming the composition from unsafe to safe for chronic administration while maintaining therapeutic efficacy
2Reliability
If complex mixtures of beta-cyclodextrin molecules are used, then therapeutic effects are observed, but compositional control and manufacturing precision are lacking
Solution Approach 1:
The patent applies parameter changes by defining specific compositional parameters (degree of substitution DS > 2.3, controlled ratios of substituted molecules) to achieve precise manufacturing control while maintaining the therapeutic effects observed with complex mixtures
Solution Approach 2:
The patent applies local quality by specifying different requirements for different components: high substitution levels for beta-cyclodextrin molecules (DS > 2.3), controlled presence of unsubstituted molecules (<5%), and strict impurity limits, thereby achieving precise compositional control across the mixture
3Duration of action of stationary object
If current compositions are administered chronically, then treatment continuity is achieved, but safety and purity standards are not met
Solution Approach 1:
The patent removes harmful impurities through purification processes, enabling the composition to meet safety and purity standards required for chronic administration while maintaining treatment continuity
Solution Approach 2:
The patent changes purity parameters by reducing impurity levels and controlling compositional parameters (DS > 2.3, unsubstituted beta-cyclodextrin <5%), thereby transforming the composition to meet reliability standards for chronic use
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 allows for safer and more effective chronic administration, reducing adverse effects and maintaining therapeutic benefits for Niemann-Pick disease treatment, as confirmed by gene expression profiling and clinical trial data.
Implementation Method 1
absorption chromatography on alumina
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.