Modified Glycosaminoglycans for Reduced Bleeding Risk
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Solution Overview
Problem
Current heparins and low molecular weight heparins (LMWHs) have high anticoagulant activity, leading to bleeding risks and other adverse effects, limiting their use in treating conditions like deep vein thrombosis and pregnancy, and existing methods for reducing anticoagulant activity are inefficient and wasteful.
Innovation Solution
Chemically modified glycosaminoglycans with controlled molecular weights (4.6-6.9 kDa) and reduced anticoagulant activity, produced through selective oxidation and depolymerization of heparin, minimizing non-specific depolymerization to achieve high bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heparin and LMWH are used for anticoagulant therapy, then anticoagulant activity is improved, but bleeding risk and adverse effects increase
Solution Approach 1:
The patent removes the anticoagulant-active pentasaccharide sequences from heparin chains through selective chemical cleavage, extracting only the harmful anticoagulant function while retaining the beneficial anti-inflammatory and immunomodulatory properties of the heparin backbone structure
Solution Approach 2:
The patent modifies the chemical structure of heparin by changing the oxidation state of specific carbon atoms (C5 and C6) in the uronic acid residues, which triggers selective cleavage of glycosidic bonds to remove pentasaccharide sequences, thereby transforming the molecule from high anticoagulant activity to low anticoagulant activity while preserving other biological functions
2Reliability
If unfractionated heparin is used for therapy, then anticoagulant effect is achieved, but monitoring complexity and hospitalization requirements increase
Solution Approach 1:
The patent segments the polydisperse heparin chains into more uniform low molecular weight fragments by removing pentasaccharide sequences, creating a more predictable molecular weight distribution that eliminates the need for complex APTT monitoring while maintaining therapeutic efficacy
Solution Approach 2:
The patent changes the molecular weight parameter of heparin from high (unfractionated) to low (after pentasaccharide removal), which fundamentally alters the pharmacokinetic profile to enable subcutaneous administration with predictable absorption and prolonged half-life, eliminating the need for frequent monitoring
3Ease of operation
If LMWH is used for treatment, then ease of administration is improved, but anticoagulant activity and bleeding risk remain high
Solution Approach 1:
The patent extracts the anticoagulant-active pentasaccharide sequences from LMWH chains, eliminating the bleeding risk associated with anticoagulant activity while preserving the favorable pharmacokinetic properties and ease of subcutaneous administration of LMWH
Solution Approach 2:
The patent changes the anticoagulant activity parameter from high (in LMWH) to low (after pentasaccharide removal), while maintaining the molecular weight range and structural features that enable easy subcutaneous administration and predictable pharmacokinetics
4Object-affected harmful factors
If existing methods are used to reduce anticoagulant activity, then anticoagulant effect is reduced, but production efficiency and molecular weight control decrease
Solution Approach 1:
The patent changes the chemical parameter of specific carbon atoms (oxidation of C5 and C6) in uronic acid residues, which creates a selective vulnerability in the glycosidic bonds leading to pentasaccharide sequences, enabling efficient and specific cleavage under mild conditions without requiring time-consuming dialysis or affecting overall molecular weight distribution
Solution Approach 2:
The patent uses periodate oxidation as a chemical intermediary that selectively targets and cleaves only the pentasaccharide sequences containing oxidized uronic acid residues, leaving the rest of the heparin structure intact and enabling precise control over the depolymerization process
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 modified glycosaminoglycans have low anticoagulant activity, ensuring reduced bleeding risks and increased bioavailability, allowing for effective treatment of conditions like deep vein thrombosis and pregnancy without the adverse effects of traditional heparins, while minimizing waste and production costs.
Implementation Method 1
selectively oxidizing unfractionated heparin or heparan sulfate present in an aqueous solution by subjecting it to an oxidizing agent capable of oxidizing non-sulfated uronic acids
Implementation Method 2
depolymerizing the oxidized polysaccharides by treatment with an alkaline solution
Implementation Method 3
reducing terminal aldehyde groups formed during the oxidation process
Data Source
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AI summary
The present invention relates to a chemically modified glycosaminoglycanwith an antifactor II activity of less than 10 IU/mg, an antifactor Xa activity of less than 10 IU/mg and an average molecular weight (Mw, weight average)fromabout 4.6 to6.9 kDa. Also disclosed is a method of preparing the modified glycosaminoglycanand its medical uses.