Formation of monodisperse hierarchical lipid particles utilizing microfluidic droplets in a nonequilibrium state.

A new microfluidic process was used to generate unique micrometer-sized hierarchical lipid particles having spherical lipid-core and multilamellar-shell structures. The process includes three steps: (1) formation of monodisperse droplets in a nonequilibrium state at a microchannel confluence, using a phospholipid-containing water-soluble organic solvent as the dispersed phase and water as the continuous phase; (2) dissolution of the organic solvent of the droplet into the continuous phase and concentration of the lipid molecules; and (3) reconstitution of multilamellar lipid membranes and simultaneous formation of a lipid core. We demonstrated control of the lipid particle size by the process conditions and characterized the obtained particles by transmission electron microscopy and microbeam small-angle X-ray scattering analysis. In addition, we prepared various types of core-shell and core-core-shell particles incorporating hydrophobic/hydrophilic compounds, showing the applicability of the presented process to the production of drug-encapsulating lipid particles.