Parametric and in-situ study of lipid nanocapsule formulation by microfluidics
Étude paramétrique et in-situ de la formulation de nanocapsules lipidiques par microfluidique.
Résumé
Introduction: Continuous production of drug delivery systems (DDS) assisted by microfluidics has drawn a growing interest because of the high reproducibility, low batch-to-batch variation of formulations, narrow and controlled particle size distribution and scale-up facilities induced by this process. Besides, microfluidics offers opportunities for high throughput screening of process parameters and the implementation of Process Analytical Technologies (PAT) as close to the product as possible. In this context, we propose to spotlight the GALECHIP concept through the development of an instrumented microfluidic pilot considered as a Galenic Lab-on-Chip to formulate nanomedicines, such as lipid nanocapsules (LNC), under controlled process conditions which are essential to obtain DDS with controlled properties. Therefore, we propose (i) a parametric study of LNC formulation by microfluidics with 3D printed PEEK chips in order to rationally develop the formulation process of LNC and (ii) the in-operando Small Angle X-ray Scattering (SAXS) investigations with Silicon/Glass (Si/Glass) chips in order to understand the physicochemical mechanisms involved in the formation of LNC. Methods: LNC were produced by a phase inversion composition (PIC) process with own-developed microfluidic pilot and chips. LNC were characterized in terms of structure, size and polydispersity index (PDI). In operando SAXS characterizations of LNC were performed at the SOLEIL Synchrotron to study the PIC phenomenology. Results: A formulation chart with 28 compositions (different ratios of oil, surfactant and co-surfactant) allowing the formulation of LNC from 25 to 100 nm has been selected. A mixing plan has been conducted with the PEEK chip to assess the impact of flowrate (x5) and lipid fraction (x3) in a scale up perspective. Results show that above 60 nm a small size decrease is observed with the high flowrate. However, the high lipid fractions lead to similar results than initial formulation, but "unachieved" formulation obtained for a few compositions proves that a special attention must be given to the mixing zone design when increasing the lipid content. An in-operando study of the PIC process has been conducted for two formulations (25 and 50 nm) by SAXS measurements performed in different regions of interest of the Si/Glass chip (mixing point and after intermediates and last elbows). Results show the structure evolution of formed nano-objects, from reverse micelles to LNC. Conclusion: GALECHIP is a microfluidic tool contributing to (i) the pharmaceutical development and (ii) the implementation of PAT for process understanding. The whole project is done with the ultimate goal of "better understanding" and "better producing" in order to "better administer" future nano-DDS candidates.