Oral Bioavailability of Fenofibrate from Melt-extruded Phospholipid-containing Solid Dispersions: a Rat Study

• Hot-melt-extruded ternary ASDs with hydrogenated phospholipids enhanced fenofibrate bioavailability. • HPL-based systems achieved complete amorphization, unlike synthetic surfactant formulations with residual crystallinity. • Approximately 2-fold lower AUC for synthetic surfactant ASDs was linked to crystallinity and micellar drug trapping. • HPLs represent a promising natural alternative to synthetic surfactants in ASD formulations. Amorphous solid dispersions (ASDs) are an established strategy to improve the bioavailability of poorly soluble drugs. In this study, we compared the in vivo pharmacokinetics of fenofibrate (FEN) in hot-melt-extruded ternary ASDs containing copovidone (VA64) and either a natural surfactant (hydrogenated phospholipid, HPL) or a synthetic surfactant (linoleoyl macrogol-6 glycerides). Oral bioavailability was evaluated in a rat model using formulations dispersed in buffer and administered by oral gavage. In the first stage, the effect of dispersion concentration was assessed, and 5 mg/mL was selected as the optimal concentration. Subsequently, pharmacokinetics were studied under fasted and fed conditions. X-ray powder diffraction confirmed complete amorphization of FEN in HPL-containing systems, whereas formulations with the synthetic surfactant exhibited residual crystallinity. Ternary ASDs with HPL showed higher bioavailability than both the marketed nanoparticulate FEN product and the surfactant-based ASD. The approximately two-fold lower AUC observed for the latter was attributed to residual crystallinity and/or strong micellar solubilization, limiting drug release. Food intake did not significantly affect pharmacokinetics. These findings indicate that HPLs are a promising, naturally derived alternative to synthetic surfactants in ASD formulations, addressing the currently limited excipient landscape.