Freeze-Drying Surfactant-Stabilized Microbubbles
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Solution Overview
Problem
Existing methods for freeze-drying contrast agents, such as flash freezing with liquid nitrogen, do not produce echogenic bubbles, which are essential for ultrasound contrast agents, and are often costly to prepare.
Innovation Solution
A method involving preparing vials with microbubbles, partially submerging them in a chilled water bath, and then freeze-drying them in a lyophilizer, while incorporating a lyoprotectant like glucose to maintain the integrity of the microbubbles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If flash freezing with liquid nitrogen is used, then freezing speed is improved, but echogenicity of microbubbles is lost
Solution Approach 1:
The patent changes the freezing temperature parameter from extreme cold (liquid nitrogen at -196°C) to controlled sub-freezing temperatures (-20°C to -80°C), and adjusts the freezing rate to produce smaller ice crystals that preserve microbubble echogenicity while still achieving effective freezing for lyophilization
Solution Approach 2:
The patent applies preliminary freezing at controlled rates before the final lyophilization process, preparing the microbubble solution in a way that preserves echogenicity structures in advance of the drying step
2Duration of action of stationary object
If conventional freeze-drying is used, then shelf-life stability is improved, but microbubble integrity is compromised
Solution Approach 1:
The patent performs preliminary freezing at controlled rates to form a protective ice matrix around microbubbles before lyophilization, preserving their integrity in advance of the drying process
Solution Approach 2:
The patent modifies lyophilization parameters including lowering the drying temperature and adjusting pressure conditions to prevent microbubble collapse while achieving effective water removal for long-term stability
3Reliability
If lyoprotectant concentration is increased, then microbubble protection is improved, but solution viscosity increases
Solution Approach 1:
The patent optimizes the concentration of lyoprotectants (such as sugars or polymers) to provide sufficient microbubble protection during freezing and drying while maintaining solution viscosity at levels that allow proper mixing and 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
This method effectively preserves the echogenicity of microbubbles, ensuring their functionality as ultrasound contrast agents and improving their shelf-life stability by using a higher glucose concentration.
Implementation Method 1
partially submerging the vials in a chilled water bath, wherein the water bath has a sub-freezing temperature
Implementation Method 2
placing the vials on a cooled shelf of a lyophilizer
Implementation Method 3
freeze-drying the vials in the lyophilizer
Data Source
AI summary
One aspect of the invention provides a method for freeze-drying surfactant-stabilized microbubbles. The method includes: preparing vials comprising a mixture comprising microbubbles; partially submerging the vials in a chilled water bath, wherein the water bath has a sub-freezing temperature; placing the vials on a cooled shelf of a lyophilizer; freeze-drying the vials in the lyophilizer; and capping the freeze-dried vials. Another aspect of the invention provides a method for annealing surfactant-stabilized microbubbles. The method includes: preparing vials comprising a mixture comprising microbubbles; passing the vials in and out of liquid nitrogen (LN2) until the mixture is frozen; holding the vials at −20° C.; placing the vials on a cooled shelf of a lyophilizer; freeze-drying the vials in the lyophilizer; and capping the freeze-dried vials.