Hydroxypropyl Beta-Cyclodextrin Purification for Intrathecal 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, making them unsuitable for chronic intrathecal or intracerebroventricular administration, and their complex mixtures lack precise compositional control, necessitating higher purity and defined formulations for safe and effective treatment.
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 for treating 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 formulated with beta-cyclodextrin molecules that have a DS of 1-6, preferably DS 2-4, which optimizes solubility, stability, and therapeutic efficacy while minimizing harmful effects. This precise parameter control distinguishes the purified composition from conventional formulations
2Manufacturing precision
If conventional hydroxypropyl beta-cyclodextrin compositions are used, then treatment is provided, but complex mixtures lack precise compositional control
Solution Approach 1:
The patent applies segmentation by separating the complex mixture of beta-cyclodextrin molecules into distinct components based on their degree of substitution (DS). The purification process isolates beta-cyclodextrin molecules with DS 1-6 from other components, creating a segmented, well-defined composition. This segmentation enables precise compositional control and eliminates the heterogeneity of conventional complex mixtures
Solution Approach 2:
The patent applies homogeneity by creating a composition with uniform beta-cyclodextrin molecules that have consistent degrees of substitution (DS 1-6). The purification process ensures that the composition contains predominantly homogeneous molecules with similar properties, eliminating the heterogeneity found in conventional complex mixtures and enabling precise dosing and predictable therapeutic outcomes
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 in Niemann-Pick disease by modulating key biomarkers and slowing disease progression while reducing adverse effects, enabling safer and more effective chronic administration.
Implementation Method 1
2-Hydroxypropyl-beta-cyclodextrins have been shown to alleviate excess cholesterol storage in NPC cells, consistent with a previous report of related cyclodextrins extracting cholesterol from the plasma membrane of cells
Implementation Method 2
purification methods such as absorption chromatography and solvent precipitation
Implementation Method 3
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.