Hydroxypropyl Beta-Cyclodextrin Purification 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 defined mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, reducing impurities and maintaining therapeutic efficacy through methods such as absorption chromatography and solvent precipitation, ensuring specific ratios of DS-3, DS-4, DS-5, and DS-6 molecules, and minimizing DS-0, DS-1, DS-9, and DS-10.
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, 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, propylene glycol, beta-cyclodextrin molecules with no hydroxypropyl substitutions (DS-0), and bacterial endotoxins are extracted and eliminated from the composition to make it suitable for chronic intrathecal or intracerebroventricular administration in Niemann-Pick disease treatment.
Solution Approach 2:
The patent applies parameter changes by precisely controlling the degree of substitution (DS) distribution of hydroxypropyl beta-cyclodextrin molecules. The composition specifies exact ranges for DS-0 through DS-10 molecules, transforming the product from a crude mixture to a purified composition with defined parameters suitable for chronic administration.
2Manufacturing precision
If complex mixtures of beta-cyclodextrin molecules are used, then manufacturing is simpler, but compositional control and precision are lacking
Solution Approach 1:
The patent applies parameter changes by precisely defining and controlling the degree of substitution (DS) distribution. The composition specifies exact percentage ranges for each DS variant (DS-0 through DS-10), transforming the product from a crude mixture to a purified composition with defined parameters. This level of compositional control achieves high manufacturing precision while maintaining practical manufacturability.
3Duration of action of moving object
If hydroxypropyl beta-cyclodextrin compositions are administered chronically, then therapeutic benefit is achieved, but ototoxicity and safety concerns arise
Solution Approach 1:
The patent applies extraction by removing ototoxic propylene glycol and other harmful impurities from the composition. This extraction enables chronic administration capability by eliminating the substances that cause ototoxicity and safety concerns, allowing long-term intrathecal or intracerebroventricular treatment of Niemann-Pick disease.
Solution Approach 2:
The patent applies parameter changes by precisely controlling the degree of substitution distribution and purifying the composition to remove harmful impurities. These parameter changes transform the composition into a safe form for chronic administration, enabling long-term therapeutic benefit without ototoxicity or safety concerns.
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, modulating relevant biomarkers and clinical symptoms of Niemann-Pick disease, with reduced ototoxicity and improved safety profiles.
Implementation Method 1
The mixture is contacted with a chromatography medium having an affinity for beta-cyclodextrin molecules substituted with fewer than three hydroxypropyl groups, thereby retaining beta-cyclodextrin molecules substituted with three, four, five, or six hydroxypropyl groups and allowing passage of beta-cyclodextrin molecules substituted with zero, one, nine, or ten hydroxypropyl groups.
Implementation Method 2
Development of a pharmaceutical composition with a defined mixture of beta-cyclodextrin molecules substituted at one or more hydroxyl positions by hydroxypropyl groups, reducing impurities and maintaining therapeutic efficacy 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.