Cyclodextrin Copolymer Composition for Low-Toxicity Cholesterol Efflux
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Solution Overview
Problem
Existing cyclodextrins, particularly beta-cyclodextrin, cause cytotoxicity and hearing loss due to excessive extraction of cholesterol from plasma membranes, necessitating a solution that can effectively remove intracellular and extracellular cholesterol without disrupting cell membranes.
Innovation Solution
A pharmaceutical composition comprising a cyclodextrin copolymer with a molar ratio of gamma-cyclodextrin to beta-cyclodextrin ranging from 30:70 to 80:20, which can be cross-linked, random, alternating, block, or graft copolymers, with molecular weights between 2.5 kDa and 500 kDa, to solubilize cholesterol and enhance cellular cholesterol efflux while minimizing cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If beta-cyclodextrin is used to extract cholesterol, then cholesterol removal efficiency is improved, but cytotoxicity and hemolytic activity increase
Solution Approach 1:
The patent applies composite materials by combining gamma-cyclodextrin and beta-cyclodextrin in a copolymer structure. Gamma-cyclodextrin provides low cytotoxicity while beta-cyclodextrin contributes high cholesterol binding affinity. The copolymer integrates these complementary properties to achieve effective cholesterol removal with reduced cellular damage, directly resolving the contradiction between productivity and harmful effects.
Solution Approach 2:
The patent applies local quality by creating a non-uniform distribution of cyclodextrin types within the copolymer structure. Different segments of the copolymer contain varying ratios of gamma and beta units, allowing local optimization where beta-cyclodextrin segments handle cholesterol binding while gamma-cyclodextrin segments protect against membrane disruption. This spatial differentiation resolves the contradiction between extraction efficiency and cellular safety.
2Quantity of substance
If cyclodextrin extracts cholesterol from plasma membrane, then intracellular cholesterol is removed, but cell membrane stability is disrupted
Solution Approach 1:
The patent applies intermediary by using gamma-cyclodextrin units as mediators within the copolymer structure. These gamma units act as protective intermediaries that prevent beta-cyclodextrin units from excessively extracting cholesterol from the plasma membrane. The gamma-cyclodextrin segments modulate the interaction between the copolymer and cell membrane, enabling cholesterol removal while maintaining membrane integrity, thus resolving the contradiction between substance removal and structural stability.
3Productivity
If hydroxypropyl-beta-cyclodextrin is used clinically, then cholesterol metabolism is improved, but hearing loss occurs due to outer hair cell loss
Solution Approach 1:
The patent applies composite materials to resolve ototoxicity by combining gamma-cyclodextrin (low cytotoxicity) with beta-cyclodextrin (high cholesterol affinity) in a copolymer. This composite structure maintains cholesterol metabolism improvement while significantly reducing outer hair cell loss and hearing loss, directly addressing the harmful effects of clinical hydroxypropyl-beta-cyclodextrin usage.
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 cyclodextrin copolymer effectively solubilizes cholesterol and promotes cellular cholesterol efflux with reduced cytotoxicity and hemolytic activity, offering improved cholesterol metabolism and disease prevention or alleviation, including conditions like Niemann-pick disease, Alzheimer's dementia, and cardiovascular diseases.
Implementation Method 1
Cyclodextrin forms inclusion complexes by the inclusion of hydrophobic molecules in the ring, and due to its property of improving water-solubility of the accommodated hydrophobic molecules
Implementation Method 2
as hydrogen groups of C3 and C5 and ether-like oxygen are positioned inward, the inside of the ring is relatively hydrophobic
Implementation Method 3
beta-cyclodextrin is known to form complex with cholesterol most effectively
Data Source
AI summary
One or more embodiments relate to a pharmaceutical composition including a cyclodextrin copolymer for prevention or treatment of diseases caused by the harmful or toxic effects of cholesterol and a use thereof. The pharmaceutical composition including a cyclodextrin copolymer composed of gamma-cyclodextrin and beta-cyclodextrin copolymer for prevention or treatment of diseases caused by the harmful or toxic effects of cholesterol according to an embodiment may minimize extraction of plasma membrane cholesterol by including the cyclodextrin copolymer, which does not cause cytotoxicity and hemolytic activity to facilitate metabolism and excretion of cholesterol in cells, and effectively suppresses secretion of IL-1β, MCP-1, and TNF-α cytokines, thereby exhibiting an excellent anti-inflammatory effect.