Histidine-Stabilized Gas-Filled Microvesicles for Targeted Imaging
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Solution Overview
Problem
The preparation of gas-filled microvesicles for targeted imaging is hindered by aggregation issues when reconstituted with saline vehicles, and conventional pH-adjusting agents often require high concentrations, leading to undesirable pH levels incompatible with intravenous injection.
Innovation Solution
The use of histidine as a pH-adjusting agent in the reconstitution of gas-filled microvesicles, particularly with carbohydrate solutions, allows for stable microvesicle formation across a range of pH values without adverse effects, maintaining microvesicle efficacy and safety.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Temperature
If conventional pH-adjusting agents are used to adjust pH levels during reconstitution, then pH adjustment is achieved, but high concentrations are required leading to undesirable pH levels incompatible with intravenous injection
Solution Approach 1:
The patent changes the chemical parameter of the pH-adjusting agent from conventional agents (like HCl or NaOH) to histidine, which has a pKa value that allows effective pH adjustment at much lower concentrations. This parameter change enables achieving the desired pH range (7.2-7.4) without requiring high concentrations that would make the solution incompatible with intravenous injection.
2Ease of manufacture
If gas-filled microvesicles are reconstituted with saline vehicles, then suspension is formed, but aggregation issues occur compromising microvesicle stability
Solution Approach 1:
The patent introduces histidine as an intermediary substance that mediates between the saline vehicle and the gas-filled microvesicles. Histidine acts as a stabilizing agent that prevents direct adverse interactions between the saline components and the microvesicle surface, thereby preventing aggregation while maintaining ease of reconstitution.
3Manufacturing precision
If high concentrations of pH-adjusting agents are used to achieve desired pH levels, then pH adjustment is effective, but the final pH becomes incompatible with intravenous injection
Solution Approach 1:
The patent changes the chemical properties of the pH-adjusting agent to histidine, which has buffering capacity at physiological pH ranges. This allows precise pH control (maintaining pH between 7.2-7.4) without requiring high concentrations that would create harmful effects or make the solution incompatible with intravenous injection.
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
Histidine enables the production of stable and effective gas-filled microvesicles by adjusting pH levels within a physiological range, preventing aggregation and ensuring the quality of the final suspension for intravenous use.
Implementation Method 1
The use of histidine as a pH-adjusting agent in the reconstitution of gas-filled microvesicles, particularly with carbohydrate solutions, allows for stable microvesicle formation across a range of pH values without adverse effects
Implementation Method 2
the bubbles of gas are bounded at the gas/liquid interface by a very thin envelope (film) involving a stabilizing amphiphilic material (typically a phospholipid) disposed at the gas to liquid interface
Data Source
AI summary
Suspension of gas-filled microvesicles comprising a targeting ligand for binding to KDR or VEGF/KDR complex.The suspension is obtained by reconstituting a freeze-dried residue with a carbohydrate-containing solution in the presence of a physiologically acceptable gas and is stabilized by the presence of histidine.