Glucose-Responsive Insulin Conjugates for Controlled Release
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Solution Overview
Problem
Existing drug delivery systems, particularly for diabetes treatment, fail to release insulin in proportion to varying blood glucose concentrations, leading to uncontrolled and slow release of insulin, which is undesirable and ineffective in managing the disease.
Innovation Solution
Development of conjugates with low molecular weight polymeric frameworks that include multiple affinity ligands, capable of forming insoluble cross-linked materials with multivalent cross-linking agents, allowing controlled release of insulin in response to glucose concentrations.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If high molecular weight natural carbohydrates (dextran, glycogen) are used as the basis for conjugates, then the conjugates can form insoluble cross-linked materials with multivalent cross-linking agents, but the conjugates suffer from enzymatic degradation and have poor pharmacokinetic properties
Solution Approach 1:
The patent changes the molecular weight parameter from high (natural carbohydrates) to low (synthetic polymers with controlled MW), which fundamentally alters the conjugate's resistance to enzymatic degradation while maintaining the ability to form cross-linked materials through controlled synthesis
Solution Approach 2:
The patent creates composite conjugates by combining synthetic polymeric frameworks with affinity ligands (such as saccharides), resulting in materials that exhibit both the desired stability against enzymatic degradation and the capability to form insoluble cross-linked structures with multivalent cross-linking agents
2Productivity
If insulin is released in uncontrolled slow release manner, then the delivery system is simple to manufacture, but the release is not proportional to varying blood glucose concentrations leading to ineffective diabetes management
Solution Approach 1:
The patent implements feedback control by designing conjugates that respond to glucose concentration levels in the body. The affinity ligands on the conjugates bind to multivalent cross-linking agents in a glucose-dependent manner, creating a feedback loop where insulin release is automatically adjusted according to blood glucose concentrations
Solution Approach 2:
The patent transforms the static, uncontrolled release system into a dynamic system where the conjugates can adjust their insulin release rate in real-time based on glucose levels. The cross-linked materials dynamically assemble and disassemble in response to glucose concentration changes, enabling adaptive insulin delivery
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 conjugates enable controlled and proportional release of insulin in response to glucose levels, maintaining bioactivity while avoiding enzymatic degradation, thus improving pharmacokinetic and pharmacodynamic properties.
Implementation Method 1
combining the conjugates with multivalent cross-linking agents that non-covalently bind the affinity ligands of the conjugates and thereby cross-link the conjugates to form the cross-linked material
Implementation Method 2
The non-covalent bonds between the multivalent cross-linking agents and the affinity ligands are competitively dissociated in the presence of excess amounts of the target molecule
Data Source
AI summary
The present disclosure provides inter alia conjugates of formula (I): wherein n, R1, R2, Rx, Z, X, Y and Z are as defined herein. A conjugate of formula (I) can also be converted to a conjugate of formulae (II) or (III) as described herein. Without limitation, the conjugates can be used to make controlled release materials and chemical sensors.