Purified Hydroxypropyl Beta-Cyclodextrin 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, 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 defined mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, with controlled impurity levels, suitable for intrathecal or intracerebroventricular administration, achieved through purification methods such as absorption chromatography and solvent precipitation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxypropyl beta-cyclodextrin compositions are used to treat Niemann-Pick disease Type C, then therapeutic benefit is achieved through cholesterol extraction, but impurities like propylene glycol, unsubstituted beta-cyclodextrin, and bacterial endotoxin cause harmful effects and limit chronic administration
Solution Approach 1:
The patent applies extraction by removing impurities (propylene glycol, unsubstituted beta-cyclodextrin, and bacterial endotoxin) from the hydroxypropyl beta-cyclodextrin composition through purification processes, thereby retaining the therapeutic active ingredient while eliminating harmful components that prevent chronic administration
Solution Approach 2:
The patent changes the compositional parameters of the hydroxypropyl beta-cyclodextrin composition by controlling the degree of substitution (DS) to be between 2.0 and 7.0 and limiting impurity content (propylene glycol ≤0.5%, unsubstituted beta-cyclodextrin ≤1.0%, endotoxin ≤5 EU/mg), transforming the composition from an impure state to a purified state suitable for chronic intrathecal or intracerebroventricular administration
2Ease of manufacture
If variable composition hydroxypropyl beta-cyclodextrin compositions are used, then manufacturing is simplified, but pharmacological effects become unpredictable and reliability decreases
Solution Approach 1:
The patent establishes specific parameter ranges for the hydroxypropyl beta-cyclodextrin composition, including degree of substitution (DS) between 2.0 and 7.0, propylene glycol content ≤0.5%, unsubstituted beta-cyclodextrin ≤1.0%, and endotoxin ≤5 EU/mg, thereby standardizing the composition to ensure consistent pharmacological effects while maintaining manufacturing feasibility
Solution Approach 2:
The patent promotes homogeneity in the hydroxypropyl beta-cyclodextrin composition by controlling the degree of substitution and limiting impurity variations between batches, ensuring that each composition exhibits consistent pharmacological properties for reliable treatment of Niemann-Pick disease Type C
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 benefit for Niemann-Pick disease with reduced impurities, allowing safer and more effective chronic administration, maintaining gene expression stability and improving clinical outcomes.
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
The purified composition effectively stabilizes or improves symptoms in Niemann-Pick disease Type C patients with reduced side effects
Implementation Method 3
using 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.