Hydroxypropyl Beta-Cyclodextrin Composition With Controlled Substitution
Find Innovative SolutionsGenerate Solutions
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 having specific degrees of hydroxypropyl substitution, reduced impurities, and improved purity, suitable for intrathecal or intracerebroventricular administration, achieved through methods such as absorption chromatography 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 benefit is achieved, but impurities (propylene glycol, beta-cyclodextrin molecules with no hydroxypropyl substitutions, 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. Specifically, unsubstituted beta-cyclodextrin molecules are separated from the hydroxypropyl beta-cyclodextrin molecules through controlled composition methods, eliminating the harmful component while retaining the therapeutic agent.
Solution Approach 2:
The patent applies parameter changes by precisely controlling the compositional parameters of the cyclodextrin mixture. The composition is defined to contain hydroxypropyl beta-cyclodextrin molecules with specific degrees of substitution (DS 2-6) while limiting unsubstituted molecules to less than 5%, thereby changing the purity parameter to make the composition suitable for chronic intrathecal or intracerebroventricular administration.
2Reliability
If complex mixtures of hydroxypropyl beta-cyclodextrin are used, then therapeutic effect is achieved, but precise compositional control is lacking
Solution Approach 1:
The patent applies parameter changes by defining specific compositional parameters for the hydroxypropyl beta-cyclodextrin mixture. The composition is characterized by the degree of substitution (DS 2-6) and the ratio of substituted to unsubstituted molecules (at least 95:5), providing precise compositional control while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent applies local quality by specifying different properties for different components of the mixture. Hydroxypropyl beta-cyclodextrin molecules with DS 2-6 are retained as the active therapeutic component, while unsubstituted beta-cyclodextrin molecules are limited to less than 5%, creating a composition with differentiated local qualities that ensure both efficacy and precision.
3Object-affected harmful factors
If standard hydroxypropyl beta-cyclodextrin compositions are administered, then cholesterol storage is alleviated, but side effects occur due to impurities
Solution Approach 1:
The patent applies the principle of converting harm into benefit by transforming the complex mixture, which originally contained harmful impurities, into a purified composition. The unwanted unsubstituted beta-cyclodextrin molecules (harmful factor) are removed, converting the composition into a safe therapeutic agent suitable for chronic intrathecal or intracerebroventricular administration while retaining the cholesterol-alleviating benefit.
Solution Approach 2:
The patent applies extraction by removing the harmful impurities (unsubstituted beta-cyclodextrin molecules, propylene glycol, and bacterial endotoxin) from the composition, thereby eliminating side effects while preserving the therapeutic benefit of alleviating excess cholesterol storage in Niemann-Pick disease.
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 composition provides therapeutic benefit in Niemann-Pick disease with reduced side effects and improved safety, allowing longer and more frequent dosing without altering 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
achieved through methods such as absorption chromatography and solvent precipitation
Implementation Method 3
achieved through 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.