ApoA-1 and HDL Stabilize Proteins Against Adsorption
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Solution Overview
Problem
Protein therapeutics are prone to aggregation, denaturation, and adsorption to surfaces during manufacturing, transport, and storage, leading to loss and fouling of medical devices, which results in premature device removal and increased costs due to catheter-related infections.
Innovation Solution
The use of ApoA-1 and/or HDL at sufficient concentrations to prevent protein adsorption to surfaces and self-association, thereby stabilizing proteins like VWF and ADAMTS13, and applying these to medical devices to prevent fouling and clogging.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If protein therapeutics are formulated with excipients to prevent aggregation and denaturation, then protein stability is improved, but device fouling and clogging may worsen due to excipient accumulation on surfaces
Solution Approach 1:
The patent introduces a specific excipient composition comprising HDL and/or ApoA-1 as an intermediary substance that mediates between the protein therapeutic and the device surface. This intermediary layer prevents direct interaction between proteins and surfaces, reducing fouling while maintaining protein stability through the unique properties of HDL/ApoA-1 which include resistance to biofilm formation and catheter-related infections
Solution Approach 2:
The patent changes the chemical and physical parameters of the excipient composition by specifying precise concentrations (HDL: 0.1-100 μg/mL, ApoA-1: 0.1-100 μg/mL) and molecular characteristics. This parameter optimization ensures the excipient provides sufficient steric and electrostatic repulsion to prevent fouling while maintaining protein stability, resolving the contradiction between stability enhancement and fouling prevention
2Loss of substance
If higher concentrations of ApoA-1 and HDL are used to prevent protein adsorption, then protein loss prevention is improved, but composition complexity and manufacturing cost worsen
Solution Approach 1:
The patent applies partial action by using relatively low concentrations of ApoA-1 (0.1-100 μg/mL) and HDL (0.1-100 μg/mL) compared to traditional excipient levels. This partial action is sufficient to prevent protein adsorption and maintain stability due to the high efficacy of these specific proteins, thereby reducing composition complexity and manufacturing burden while still achieving the goal of minimizing protein loss
Solution Approach 2:
The patent creates a composite excipient system combining HDL and ApoA-1 with specific ratios and concentrations. This composite approach leverages the synergistic effects of both proteins - HDL for steric barrier formation and ApoA-1 for electrostatic repulsion - achieving effective protein protection at lower overall concentrations than single excipients would require, thus managing composition complexity
3Ease of manufacture
If protein therapeutics are stored in contact with container surfaces, then manufacturing and storage simplicity is improved, but protein adsorption and loss worsen
Solution Approach 1:
The patent applies preliminary action by pre-formulating the protein therapeutic with ApoA-1 and HDL excipients before storage and transport. This preliminary incorporation creates a protective environment that proactively prevents protein-surface interactions during subsequent storage in standard containers, maintaining protein levels without requiring specialized adsorption-resistant container materials or complex handling procedures
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
This approach effectively reduces protein loss and device fouling, maintaining protein stability and extending the lifespan of medical devices by preventing adsorption and self-association, thus reducing morbidity and mortality associated with catheter-related infections.
Implementation Method 1
maintaining the protein in the presence of an amount of ApoA-1 and/or HDL sufficient to prevent adsorption of the protein to a surface
Implementation Method 2
maintaining the protein in the presence of an amount of ApoA-1 and/or HDL sufficient to prevent adsorption of the protein to a surface or protein self-association
Data Source
AI summary
Compositions and methods are described for preventing or reducing protein loss due to protein aggregation, denaturation, and absorption to surfaces. Also described are compositions and methods for preventing or reducing the fouling or clogging of medical devices that come into contact with blood, such as catheters. Also described are methods to treat diseases caused by activation of the microvasculature.