Using Self-Nanoemulsifying System to Improve Oral Bioavailability of a Pediatric Antiepileptic Agent Stiripentol: Formulation and Pharmacokinetics Studies

This study aimed to develop a self-nanoemulsifying drug delivery system (SNEDDS) for poorly water-soluble drug stiripentol (STP) with enhanced oral bioavailability. Optimal excipients were selected by constructing pseudo-ternary phase diagrams using determined solubilities of STP, and then the proper composition of SNEDDS was investigated by employing a central composite design method. The optimized SNEDDS was composed of oil (ethyl oleate 39.61%), surfactant (Cremophor® RH 40 43.18%), co-surfactant (1,2-propanediol 17.21%), and STP of 50 mg/mL. The hydrodynamic size, zeta potential, and polydispersity index (PDI) were found to be 45.52 ± 1.99 nm, − 21.67 ± 0.24 mV, and 0.076 ± 0.011, respectively. The optimized STP-SNEDDS showed good stability in accelerated and dilution stability studies. It was also helpful to suppress STP degradation in acidic solution. Compared with STP suspension, STP-SNEDDS presented much faster dissolution rate. STP-SNEDDS successfully resulted in superior levels of C max and AUC 0 → 6 h (4048.38 ± 704.54 μg/L and 7754.58 ± 1489.37 h μg/L, respectively) to STP suspension (1894.09 ± 1077.64 μg/L and 3556.93 ± 2470.01 h μg/L, respectively). The relative oral bioavailability of STP was 218.01%. The brain biodistribution studies showed that STP-SNEDDS presented significantly higher STP concentrations in the brain at 0.5 h and 1 h than that of STP suspension after administration. These findings indicated that a SNEDDS-based oral formulation of STP would be helpful for increasing its therapeutic potential.