Hospital production of propofol injectable nanoemulsion: proof-of-concept

A. Cèbe1, B. Dessane1,2, A. Venet1, JM Bernadou1, F Xuereb1, 3 , S . Crauste-Manciet1, 2
1 Pharmaceutical Technology Department, Bordeaux University Hospital, France
2 ARNA Laboratory ChemBioPharm U1212 INSERM - UMR 5320 CNRS, Bordeaux University, France
3 Pharmacokinetics and PK/PD Group, INSERM 1034, University of Bordeaux, France


Objective
In the context of essential drug shortages during the Covid-19 pandemic, we were involved in the network driven by ANSM1 for studying feasibility of hospital pharmacy production of 2% propofol injectable nanoemulsion. Objective was to find the best process to provide a physically stable sterile nanoemulsion able to reproduce the commercialized drug.

Materials and methods
Two processes for propofol formulation incorporation in nanoemulsion were assessed. The first simplest method was to add propofol oil solution directly in commercialized nanoemulsion i.e Intralipid® 20% using high speed mixer (Ultra-Turrax®, IKA) and additionally high pressure homogeneizer (HPH). The other method assessed was de novo formulation from separate raw materials (i.e. oil, water, surfactant) based on the commercial Diprivan® formulation using phase inversion emulsification process and droplet size reduction with high pressure homogeneizer (Microfluidizer®) followed by heat sterilization at 121°C 15 minutes. Optimization of the process was based on the size reduction and the pH initial adjustment before heat sterilization. Physical stability was assessed by visual observation, granulometric analysis with droplets mean diameter (MD), polydispersity index (PDI) and zeta potential using (Zetasizer® Nano ZS, Malvern), droplets larger than 1µm and 5µm were assessed by laser diffraction (Mastersizer® 3000, Malvern) and assessment of osmolality and pH.

Results – Discussion
Direct addition and mixing to Intralipid® 20% even combining high speed mixer and high pressure homogeneizer was not satisfactory giving droplets size above 5µm and phase separation both incompatible with IV administration. Conversely, de novo formulation characteristics were fully satisfactory with a monodisperse droplets repartition (PDI<0.2), 160 nm mean diameter, no droplet above 1µm, and negative zeta potential of -40mV. Process was optimized for a total number of 7 cycles through the HPH and initial pH adjustment above 9 was needed prior heat sterilization to obtain a final pH in the range 6-7.5. All-in-all, physical characteristics were comparable to the commercialized propofol nanoemulsions. Physical stability of the propofol nanoemulsion was confirmed at least for 1 month.

Conclusion
The proof of concept showed that only de novo propofol formulation can be considered, and its transposition in hospital pharmacy requires specific high pressure homogenizer, GMP approved, allowing production in controlled environements.

1 ANSM : French National Agency for Medicines and Health Products Safety

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