Liposome Formation Using a Coaxial Turbulent Jet in Co-Flow
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Liposomes are robust drug delivery systems that have been developed into FDA-approved drug products for several pharmaceutical indications. Direct control in producing liposomes of a particular particle size and particle size distribution is extremely important since liposome size may impact cellular uptake and biodistribution.
A device consisting of an injection-port was fabricated to form a coaxial turbulent jet in co-flow that produces liposomes via the ethanol injection method. By altering the injection-port dimensions and flow rates, a fluid flow profile (i.e., flow velocity ratio vs. Reynolds number) was plotted and associated with the polydispersity index of liposomes.
Certain flow conditions produced unilamellar, monodispersed liposomes and the mean particle size was controllable from 25 up to >465 nm. The mean liposome size is highly dependent on the Reynolds number of the mixed ethanol/aqueous phase and independent of the flow velocity ratio.
The significance of this work is that the Reynolds number is predictive of the liposome particle size, independent of the injection-port dimensions. In addition, a new model describing liposome formation is outlined. The significance of the model is that it relates fluid dynamic properties and lipid-molecule physical properties to the final liposome size.
KEY WORDScoaxial turbulent jet continuous manufacturing ethanol injection liposome processing monodispersed liposomes unilamellar
31 phosphorous nuclear magnetic resonance
Cryogenic transmission electron microscopy
Dynamic light scattering
Design of experiment
1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt)
Flow velocity ratio
International conference on harmonisation
Negative stain transmission electron microscopy
Process analytical technology
Combined output flow rate
ACKNOWLEDGMENTS AND DISCLOSURES
This work was supported by the U.S. FDA (Grant#: HHSF223201310117C). We thank Dr. M. Cantino and Dr. X. Sun from the Biosciences Electron Microscope Laboratory of the Physiology and Neurobiology Department at the University of Connecticut for their work on the negative stain TEM micrographs. The authors would like to acknowledge Dr. Jiwen Zheng and Dr. Yong Wu at the FDA White Oak Nanotechnology Core Facility for instrument use, scientific and technical assistance. A. Costa was an AFPE fellow during the time period of this research.
Conflict of Interest
The authors declare no competing financial interest.
The views expressed are those of authors and do not necessarily represent the official position of the Agency (FDA).
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