Continuous flow scalable production of injectable size-monodisperse nanoliposomes in easy-fabrication milli-fluidic reactors

Abstract

The production of reproducible batches of liposomes suitable for parenteral administration is a time-consuming, multi-step process requiring extensive workable area. Microfluidic Hydrodynamic Focusing (MHF) chips allow one-pot synthesis of injectable size liposomes, although the use of low height-to-width aspect ratio (AR) microreactors limits the production rates.Herein, aiming at scaling up liposome production, while avoiding lithographic methods and clean room facilities, easy-fabrication glass MHF large channel (MHF-LC) chips of AR = 1, 3 with T-shaped and coaxial injection geometries are demonstrated. Narrowly distributed unilamellar nanoliposomes (unprecedented minimum average diameters 85 nm and polydispersity index of 0.13) with the formulation of a known pharmaceutical product (i.e., DOXIL®(CAELYX®)) are synthesized at production rates 15–20 times larger than T-MHF chips. The dependence of liposome size on the Reynolds numbers (in the range of 5–50) in the coaxial configuration is discussed as due to viscosity-induced mixing dynamics at the water–ethanol interface.