Purified Hydroxypropyl Beta-Cyclodextrin 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, 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 with controlled ratios 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 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 bacterial endotoxins are eliminated to ensure safety for chronic intrathecal or intracerebroventricular administration, while retaining the therapeutic hydroxypropyl substituted molecules.
Solution Approach 2:
The patent changes the compositional parameters of the cyclodextrin mixture by controlling the degree of hydroxypropyl substitution and removing specific molecular forms. This involves adjusting the substitution pattern to ensure molecules are substituted at one or more hydroxyl positions while eliminating unsubstituted forms, thereby changing the physical and chemical properties to achieve solubility and safety for chronic administration.
2Reliability
If complex mixtures of beta-cyclodextrin molecules are used, then therapeutic efficacy is achieved, but compositional control is imprecise
Solution Approach 1:
The patent applies local quality by specifying precise substitution patterns at different hydroxyl positions of the beta-cyclodextrin molecules. Instead of treating all molecules uniformly, the invention defines specific substitution locations (at one or more hydroxyl positions) to achieve both therapeutic efficacy and compositional precision, allowing controlled heterogeneity rather than complete uniformity.
Solution Approach 2:
The patent changes the compositional parameters by defining specific criteria for acceptable molecules (substituted at one or more hydroxyl positions) while excluding others (unsubstituted molecules). This parameter-based definition enables precise manufacturing control through analytical methods that can distinguish and quantify substitution patterns, achieving both therapeutic reliability and manufacturing precision.
3Ease of manufacture
If unsubstituted beta-cyclodextrin molecules are present in the composition, then the mixture is easier to manufacture, but they form precipitates and have acute toxicity
Solution Approach 1:
The patent applies extraction by specifically removing unsubstituted beta-cyclodextrin molecules from the composition through purification processes. This eliminates the harmful effects of precipitation and acute toxicity associated with unsubstituted molecules while retaining the therapeutic substituted forms, achieving safety for chronic administration without significantly complicating manufacturing.
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, demonstrating therapeutic benefits in Niemann-Pick disease by modulating relevant biomarkers and slowing disease progression without accelerating adverse effects like hearing loss.
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
absorption chromatography and solvent precipitation
Implementation Method 3
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.