Modified Bovine Heparin for Complement Inhibition With Lower Bleeding Risk
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Solution Overview
Problem
Current treatments for sickle cell disease, particularly vaso-occlusive crisis, lack specific acute therapies, and existing heparin compounds have significant anticoagulant activity that poses risks for adverse bleeding.
Innovation Solution
A chemically modified bovine intestinal heparin with converted free carboxylic acid moieties to N-acylurea amide, maintaining complement inhibition while reducing anticoagulant activity, allowing for effective treatment of sickle cell disease and other conditions with reduced bleeding risks.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional heparin is used to treat sickle cell disease, then complement inhibition activity is maintained, but anticoagulant activity causes adverse bleeding
Solution Approach 1:
The patent chemically modifies heparin by converting free carboxylic acid moieties to N-acylurea amide, fundamentally changing the chemical parameters of the molecule. This modification selectively reduces anticoagulant activity (anti-factor IIa activity) while preserving complement inhibition activity, thereby resolving the contradiction between maintaining complement inhibition and reducing bleeding risks
Solution Approach 2:
The patent extracts and removes the harmful anticoagulant activity from heparin through chemical modification, while retaining the beneficial complement inhibition activity. The N-acylurea amide modification selectively eliminates the harmful factor (excessive anticoagulation) without compromising the useful function (complement inhibition for treating sickle cell disease)
2Object-affected harmful factors
If chemically modified heparin with reduced anticoagulant activity is used, then bleeding risks are reduced, but anti-factor IIa activity may be compromised
Solution Approach 1:
The chemical modification parameter (converting carboxylic acid to N-acylurea amide) is precisely controlled to achieve a specific outcome: reducing anti-factor IIa activity to a desired level while maintaining complement inhibition. The modification creates a new functional state that balances both activities
3Reliability
If P-selectin inhibition activity is enhanced for treating sickle cell disease, then vaso-occlusive crisis is reduced, but anticoagulant activity may increase bleeding
Solution Approach 1:
The chemical modification of heparin alters its interaction parameters with biological targets. The N-acylurea amide modification enhances P-selectin inhibition activity (beneficial for sickle cell disease) while simultaneously reducing anticoagulant activity (reducing bleeding risk), resolving the contradiction between these two effects
Data Source
AI summary
Provided is a bovine intestinal heparin chemically modified with a 1-(3-dimethylaminopropyl)-3-ethylurea (EDU)-amide having anti-factor IIA activity is about 20 to about 30 IU/mg, wherein the modified bovine intestinal heparin exhibits between 20% and 50% of the anti-factor IIa activity of the nonchemically modified bovine intestinal heparin, as well as pharmaceutical compositions, compositions comprising chemically modified bovine intestinal heparin, and methods for making and using the same