Compositions of hydroxypropyl-beta-cyclodextrin and methods of purifying the same
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Solution Overview
Problem
Existing hydroxypropyl-beta-cyclodextrin (HPBCD) mixtures lack the ability to selectively solubilize or deliver guest molecules due to their uncontrolled alkylation process, resulting in a gross mixture of isomers that are not suitable for precise pharmacological or chemical applications, such as treating diseases like Niemann-Pick disease Type C, liver disease, cardiovascular disease, and familial hypercholesterolemia.
Innovation Solution
The development of a composition comprising a mixture of beta-cyclodextrin molecules with controlled hydroxypropyl substitution patterns, specifically less than 0.05% unsubstituted and less than 0.05% monosubstituted, and an average degree of substitution between 6.02-7.98, suitable for intrathecal, intravenous, or intracerebroventricular administration, allowing for precise solubilization and delivery of guest molecules.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If uncontrolled alkylation process is used to manufacture HPBCD on large scale, then manufacturing productivity is improved, but manufacturing precision deteriorates resulting in gross mixture of isomers
Solution Approach 1:
The patent applies parameter changes by precisely controlling the alkylation reaction conditions including the molar ratio of beta-cyclodextrin to propylene oxide (1:1.5 to 1:3), reaction temperature (0-50°C), and reaction time (2-48 hours). These parameter optimizations enable the production of HPBCD with controlled degree of substitution (6.02-7.98) and limited isomeric configurations, resolving the contradiction between manufacturing productivity and manufacturing precision.
2Ease of manufacture
If gross mixture of HPBCD isomers is used, then ease of manufacture is improved, but selectivity for guest molecule solubilization deteriorates
Solution Approach 1:
The patent applies local quality by creating HPBCD molecules with specific substitution patterns at particular hydroxyl positions (2-OH, 3-OH, 6-OH) of the cyclodextrin ring. By controlling which positions are substituted and with what degree of substitution, the patent achieves selective solubilization capability for specific guest molecules like cholesterol, while maintaining ease of manufacture through optimized reaction conditions.
3Quantity of substance
If exhaustive alkylation with all 21 positions occupied occurs, then quantity of hydroxypropyl groups is maximized, but solubility and therapeutic efficacy deteriorate
Solution Approach 1:
The patent applies partial action by achieving a degree of substitution of 6.02-7.98 out of the maximum 21 possible hydroxyl positions. This partial substitution optimizes the balance between the quantity of hydroxypropyl groups (which provide solubility) and the retention of hydroxyl groups (which maintain hydrogen bonding capability and therapeutic efficacy). The controlled partial alkylation prevents exhaustive substitution that would harm solubility and therapeutic performance.
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 achieves improved affinity for cholesterol, effectively treating or preventing diseases like Niemann-Pick disease Type C, liver disease, and cardiovascular disease by selectively solubilizing and delivering cholesterol, with enhanced therapeutic efficacy.
Implementation Method 1
HPBCD is a common organic molecule having various industrial applications. Such applications include pharmaceutical excipients, polymers, solubilizing agents, chelating agents, drug delivery vehicles
Data Source
AI summary
The present disclosure relates to compositions comprising mixtures of hydroxypropyl-β-cyclodextrin, wherein the compositions may be isomerically purified. The disclosure also relates to methods of isomerically purifying a mixture of hydroxypropyl-β-cyclodextrins.