Perfluorobutane Microbubble Preparation for Vial Uniformity
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Solution Overview
Problem
Existing methods for preparing ultrasound contrast agents with phospholipid-stabilized perfluorocarbon microbubbles face challenges in controlling vial-to-vial variation of microbubble concentration and size distribution, yield, and are not suitable for commercial-scale manufacture, lacking uniformity and safety profiles that meet regulatory requirements.
Innovation Solution
A method involving the preparation of perfluorobutane microbubbles stabilized by hydrogenated egg phosphatidylserine in sucrose, with controlled median size distribution (2 to 5 µm) and a holding time of 1.0 to 2.75 minutes between dispensing and freezing, followed by freeze-drying and back-filling, ensures consistent vial-to-vial yields and size distribution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional microbubble preparation methods (sonication, high shear emulsification) are used, then good yields and low cost production are achieved, but difficulty in controlling size distribution of microbubbles occurs
Solution Approach 1:
The patent applies preliminary action by performing size adjustment of microbubbles before lyophilization. The microbubbles are subjected to flotation and resuspension cycles to select and enrich the desired size fraction (2-5 μm) prior to freezing, ensuring that the size distribution is controlled in the final lyophilized product while maintaining good yield through the subsequent reconstitution process
2Ease of operation
If microbubbles are dispensed into vials and held for extended periods before freezing, then ease of operation is improved, but vial-to-vial variation in microbubble concentration and size distribution increases
Solution Approach 1:
The patent implements feedback control by monitoring and controlling the holding time parameter. The method specifies that vials should be frozen within a defined holding time window (typically 0-30 minutes) after dispensing, and this time parameter is controlled and monitored during manufacturing to ensure consistent microbubble concentration and size distribution across all vials, preventing creaming and aggregation variations
3Ease of operation
If microbubbles are allowed to cream rapidly after dispensing, then ease of operation is improved, but loss of microbubbles occurs due to impaired drying and depletion of survival rate
Solution Approach 1:
The patent applies preliminary action by performing size adjustment and selecting microbubbles of optimal size (2-5 μm) before dispensing into vials. This preliminary size selection is critical because it pre-determines the creaming behavior during storage and transport, ensuring that the microbubbles will remain stable and not be lost during the subsequent lyophilization process, thereby preventing microbubble loss while maintaining processing efficiency
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 method achieves optimal yield and concentration of microbubbles in each vial, minimizing vial-to-vial variation and ensuring compliance with regulatory standards, while maintaining microbubble stability and safety.
Implementation Method 1
lyophilization of perfluorocarbon microbubbles in the presence of a freeze-drying stabiliser
Implementation Method 2
cooling each such filled vial to a temperature of -40 °C to -70 °C
Data Source
Figure 1~2
Figure 3~4
AI summary
The present invention relates to a method of preparation of ultrasound contrast agent precursors comprising phospholipid- stabilised perfluorobutane microbubbles. The method is amenable to commercial scale manufacture, and provides more consistent vial-to-vial yields and size distribution of said microbubbles. Also provided are methods of preparing kits and ultrasound contrast agents using the method of the invention.