Design and characterization of 2% propofol lipid nanocapsules formulated by microfluidics

3 October 2024

Emilie Tireau ^a,b, Marie Bonnin ^a, Jean-Christophe Gimel ^a, Louise Stinat ^a,b, Guillaume Lefebvre ^a, Nolwenn Lautram ^a, Frederic Lagarce ^a,b, Brice Calvignac ^a, Sylvie Crauste-Manciet ^a,b
^a Université d’Angers, CHU Angers, INSERM, CNRS, MINT, SFR ICAT, 49000 Angers, France
^b CHU Angers, département Pharmacie, 4 rue Larrey, 49933 Angers cedex 9, France

Introduction
It is necessary to anticipate the feasibility of dispersed nanosystems for intravenous delivery of lipophilic drugs as hospital preparations. In this work, lipid nanocapsules (LNC) were chosen as nanocarriers to encapsulate propofol as a model lipidic drug. LNC consist of a lipid core surrounded by a shell of pegylated surfactants and are prepared by a low energy self-emulsification method by phase inversion composition (PIC) using a microfluidic device.

Materials and Methods
The oil phase (medium chain triglyceride) and surfactants (Koliphor^® HS15 and polysorbate 85) were selected based on previous work of the laboratory and concentration limits for IV administration. The nanocapsules were formed either by spontaneous emulsification with gentle stirring at 50° or by the microfluidic process using a micromixer. The best formulation was selected based on stability assessment by turbidimetric measurement (Turbiscan®) combined with granulometric analysis by laser diffraction (Mastersizer®) and dynamic light scattering (NanoZS®). Finally, the best sterilization method (heat or filtration) was selected in terms of formulation characteristics.

Results
Trials were conducted to select a formulation with the best stability over time with the lowest surfactant and co-surfactant content. Among the co-surfactants tested, the best results were obtained with polysorbate 85. The selected LNCs formulation had a mean diameter of 80 nm, a polydispersity index of 0.123 and a zeta potential of -20 mV, with no droplets larger than 5 µm. The pH and osmolarity were adjusted to allow for further IV injection. Finally, the sterile filtration method was selected without any effect on the system, unlike heat sterilization where a yellowish coloration was noted. Propofol encapsulation efficiency was found to be greater than 99%.

Conclusion
A proof-of-concept injectable grade LNC of 2% w/v propofol was successfully developed using microfluidics. This paves the way to envision customized formulations of lipophilic drugs in the hospital pharmacy environment.