Serial Filtration for Small High-Cholesterol Liposomes
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Solution Overview
Problem
Existing methods struggle to produce small, uniformly sized liposomes containing cholesterol, particularly those with diameters less than 100 nm, due to limitations in current techniques such as extrusion and sonication, which face issues like low yield, clogging, and inefficiency in producing stable formulations.
Innovation Solution
A method involving serial filtration through a filter assembly with multiple filters connected in series and an orifice between each pair, allowing for the production of small, monodisperse liposomes with diameters less than 100 nm, even with high cholesterol content, by passing a heated lipid suspension through this assembly.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If extrusion method is used to produce liposomes, then liposomes can be produced with controlled size, but the method is limited to small batches and membranes are prone to clogging resulting in low yield
Solution Approach 1:
The invention divides the single filtration step into multiple sequential filtration steps using a series of filters with decreasing pore sizes (e.g., 0.45 μm, 0.22 μm, 0.11 μm). This segmentation allows each filter to handle a specific size range, preventing clogging while progressively reducing liposome size to achieve the desired small diameter with high yield
Solution Approach 2:
The method performs preliminary filtration through larger pore size filters before using smaller pore size filters. This preliminary action removes larger aggregates and prevents clogging of the smaller pore filters, thereby maintaining high productivity throughout the filtration sequence while achieving precise size control
2Length of moving object
If probe sonication or bath sonication is used to produce small liposomes, then liposome size can be reduced, but the methods are time-consuming and result in low yield
Solution Approach 1:
The invention replaces the mechanical sonication process (probe or bath) with a filtration-based mechanical system. Instead of using ultrasonic waves to break down liposomes, the method uses controlled filtration through porous membranes to physically separate and size-select liposomes, achieving the same size reduction effect with much higher efficiency and yield
3Stability of the object's composition
If cholesterol-containing liposomes are produced to ensure serum stability, then liposome stability is improved, but producing liposomes with diameter less than 100 nm becomes difficult
Solution Approach 1:
The invention changes the physical state parameter of the lipid suspension by heating it to a temperature above the phase transition temperature of the component lipids before filtration. This parameter change increases membrane fluidity and allows cholesterol-containing liposomes to be successfully filtered through small pore size filters to achieve diameters less than 100 nm while maintaining serum stability
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 consistent production of small, monodisperse liposomes with high cholesterol content, maintaining a polydispersity index of 0.20 or less and a diameter significantly smaller than the filter pores, with improved yield and reduced clogging, enabling efficient drug delivery systems.
Implementation Method 1
passing the heated lipid suspension through a filter assembly. The filter assembly may comprise two or more filters connected in series with an orifice disposed between adjacent filters
Implementation Method 2
heating the lipid suspension to a temperature which is above the phase transition temperature of the component lipids
Data Source
AI summary
The present invention provides methods and systems for producing liposomes by filtration. The methods include passing a heated lipid suspension through a filter assembly comprising two or more filters connected in series, wherein an orifice is disposed between adjacent filters. The methods and systems can produce liposomes having an average diameter that is less than half the diameter of the filter pores. Further, the methods and systems can produce liposomes with <100 nm average diameter, even when the liposomes comprise at least 30% sterol.