Design and optimization of the surfactant mixture ratio for oleic acid-based ophthalmic nanoemulsions prepared by the HPH technology - feasibility study for clotrimazole as a model drug.

Developing ophthalmic nanoemulsions is a complex process that requires the selection of appropriate pharmaceutical excipients and optimal parameters of the technological process to achieve formulations with desirable physicochemical properties. To develop appropriate preparations, a design of experiments was conceptualized. Varying concentrations of the surfactants (2 - 6 %) and cosurfactants (0 - 6 %) were used in nanoemulsions based on oleic acid (13 %) that were prepared under constant conditions of high-pressure homogenization technology (3 cycles, 1000 Bar). After composition optimization, the optimal concentration of the surfactants (Kolliphor EL 6 % and Tween 80 5 %) and cosurfactants (propylene glycol 2 %, PEG 200 4 %, triacetin 6 %) was selected. Utilising a developed model, clotrimazole-loaded nanoemulsions with monomodal droplet size distribution were prepared, with the average droplet diameters in the range of 88.53 - 97.06 nm and PDI values 0.080 - 0.117. After physicochemical assessment, nanoemulsion NE4_KOL6_PG2 was selected for further studies, with the highest stability, optimal physicochemical properties, and shelf-life estimation parameter at a level higher than 5 months. The release rate of clotrimazole (CLT) from the nanoemulsion NE4_KOL6_PG2 (T 50% = 9.4 h) was significantly higher than in the case of the 1 % CLT oily solution in castor oil (T 50% = 32.6 h). In the in vitro study, the prepared formulation obtained the MIC100 value 0.008 % (0.08 mg/ml) against C. albicans ATCC 10231. In the model with Galleria mellonella larvae, formulation did not affect larval survival within six days. This study demonstrated the usefulness of the obtained optimization for scalable manufacturing of stable CLT-loaded nanoemulsions with the required properties for ophthalmic use.