Sulfated Heptasaccharide Isolation for Antithrombotic Consistency
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Solution Overview
Problem
Current antithrombotic drugs, such as heparin and Low Molecular Weight Heparins, have complex structures and variable sulfation levels, leading to inconsistent anticoagulant activity and side effects, while synthetic oligosaccharides like fondaparinux have limitations in duration of action and pharmacodynamic profiles.
Innovation Solution
A novel sulfated heptasaccharide is isolated using orthogonal separation methods like Gel Permeation Chromatography, Antithrombin affinity chromatography, and anion exchange chromatography from Low Molecular Weight Heparins, providing a more potent and consistent antithrombotic agent with improved pharmacodynamic profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If heparin and LMWHs are used as antithrombotic drugs, then anticoagulant activity is achieved, but structural complexity and variable sulfation levels lead to inconsistent activity and side effects
Solution Approach 1:
The patent applies segmentation by isolating a specific heptasaccharide unit (comprising 7 monosaccharide residues) from the complex heparin/LMWH mixture. This specific structure contains the essential antithrombin-binding pentasaccharide sequence plus two additional residues, providing consistent anticoagulant activity without the structural variability of whole heparin molecules.
Solution Approach 2:
The patent extracts the active antithrombotic component (specific heptasaccharide) from the complex heparin/LMWH mixture through chromatographic separation methods. This extraction isolates the therapeutically active unit while removing other components that contribute to structural complexity and inconsistent activity.
2Duration of action of moving object
If synthetic oligosaccharides like fondaparinux are used, then selective factor Xa inhibition is achieved, but duration of action and pharmacodynamic profiles are limited
Solution Approach 1:
The patent changes the structural parameters of synthetic oligosaccharides by using a heptasaccharide (7 residues) instead of the common pentasaccharide (5 residues) or longer sequences. This parameter change (increasing chain length from 5 to 7 monosaccharide units) extends duration of action while maintaining selectivity for factor Xa inhibition, improving the pharmacodynamic profile.
Solution Approach 2:
The patent creates a composite structure combining the essential pentasaccharide antithrombin-binding sequence with two additional monosaccharide residues. This composite heptasaccharide structure provides both the selective factor Xa inhibition of synthetic oligosaccharides and extended duration of action, achieving versatile pharmacodynamic properties.
3Reliability
If longer oligosaccharides are synthesized to improve antithrombin activity, then potency increases, but synthesis complexity and cost increase
Solution Approach 1:
The patent uses chromatographic separation methods (anion exchange, gel permeation, affinity chromatography) as intermediary techniques to isolate the active heptasaccharide from LMWH mixtures. This intermediary approach provides a practical manufacturing route that avoids the complexity of de novo chemical synthesis while ensuring high purity and consistent potency.
Solution Approach 2:
The patent identifies and isolates a naturally occurring heptasaccharide structure from LMWHs that already possesses the desired high antithrombin activity. Rather than synthesizing longer oligosaccharides from scratch, the method copies/isolates the naturally optimized structure, reducing manufacturing complexity while maintaining high potency.
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 sulfated heptasaccharide demonstrates high antithrombotic activity, with 1.65-fold relative anti-FXa activity compared to fondaparinux, making it suitable for treating and preventing thromboses and arterial thrombotic events with potentially reduced side effects.
Implementation Method 1
Gel Permeation Chromatography can be performed on columns filled with ACA202 (Prolabo) circulated with NaClO4
Implementation Method 2
AT affinity chromatography can be performed on columns filled with AT-Sepharose. The stationary phase is prepared by coupling human AT (1 g; Biomed) to CNBr-activated Sepharose 4B (Sigma)
Implementation Method 3
Anion exchange chromatography can be achieved using AS11 (Dionex) semi-preparative HPLC columns
Implementation Method 4
Selected fractions are recovered by precipitation, for example by methanolic precipitation
Data Source
AI summary
The instant invention relates to the heptasaccharide of formula (I) : in its acid form or in the form of any one of its pharmaceutically acceptable salts, and to its process of preparation. The oligosaccharide of formula (I) is useful as an antithrombotic agent.