Development of entrectinib-loaded supersaturated self-nanoemulsifying drug delivery system using oil suspension treated by high-pressure homogenization

초록

This study aimed to develop a supersaturated self-nanoemulsifying drug delivery system (super-SNEDDS) using high-pressure homogenization (HPH) to enhance the solubility, dissolution, and bioavailability of poorly water-soluble entrectinib (ENT). Campul MCM C8 and Capryol 90 (11.8% and 7.4%) were selected as the oil phase, and Kolliphor HS15 and TPGS (8.7% and 5.9%) were used as surfactants owing to their high solubility for ENT. An oil suspension loaded with 25% (w/w) ENT was subjected to HPH and used to formulate (FL1-FL12) with ENT-saturated surfactants. FL2 (Capmul MCM C8/Kolliphor HS15 = 20/80, w/w) showed a high solubilized loading% of ENT (10.49%) with a small dispersion particle size (<20 nm). FLP2, prepared by adding 3% (w/w) polyvinylpyrrolidone K17 to FL2, suppressed ENT precipitation when dispersed in pH 6.8 buffer solution, and was selected as the optimized formulation. In the dissolution test, FL2 and FLP2 exhibited a dissolution rate of >95% within 30 min in pH 6.8 buffer solution, whereas the dissolution rate of raw ENT was below the quantification limit. Under pH shift (pH 1.2 -> 6.8) conditions, FLP2 recovered to over 95% within 5 min after the pH shift, whereas FL2 maintained approximately 90% and raw ENT decreased to below 5%. In addition, FLP2 exhibited enhanced oral bioavailability in rats (1.83-fold in C-max and 1.49-fold in AUC(infinity)) compared with the raw ENT suspension group. In conclusion, FLP2 is a novel super-SNEDDS for enhancing the solubility, dissolution, and bioavailability of ENT.

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