Purified Hydroxypropyl Beta-Cyclodextrin for Intrathecal Dosing
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Solution Overview
Problem
Current hydroxypropyl beta-cyclodextrin compositions used for treating Niemann-Pick disease contain impurities such as 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 a mixture of beta-cyclodextrin molecules with controlled hydroxypropyl substitution, reduced impurities, and specific ratios, suitable for intrathecal or intracerebroventricular administration, achieved through purification methods like 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 (propylene glycol, unsubstituted beta-cyclodextrin molecules, 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 preserving 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 specifying precise ratios of substituted versus unsubstituted molecules, thereby transforming the composition from an impure form to a purified, clinically suitable form
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 parameter changes by precisely controlling the degree of hydroxypropyl substitution (specifying ratios of mono-, di-, tri-, tetra-, penta-, and hexa-substituted molecules) and maintaining specific concentration ranges, thereby achieving both therapeutic efficacy and manufacturing precision
Solution Approach 2:
The patent applies local quality by specifying different requirements for different components of the mixture (e.g., unsubstituted beta-cyclodextrin at 0.1-10%, mono-substituted at 5-50%, etc.), allowing each component to contribute optimally to therapeutic effect while maintaining overall compositional control
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-term administration without adverse effects, and maintains gene expression related to cholesterol metabolism.
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 like absorption chromatography and solvent precipitation
Implementation Method 3
purification methods like 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.