The aim of this study was to develop a new drug nanocrystals self-stabilized Pickering emulsion (NSSPE) for improving oral bioavailability of quercetin (QT). Quercetin nanocrystal (QT–NC) was fabricated by high pressure homogenization method, and QT–NSSPE was then prepared by ultrasound method with QT–NC as solid particle stabilizer and optimized by Box-Behnken design. The optimized QT–NSSPE was characterized by fluorescence microscope (FM), scanning electron micrograph (SEM), X-ray diffraction (XRD), and differential scanning calorimetry (DSC). The stability, in vitro release, and in vivo oral bioavailability of QT–NSSPE were also investigated. Results showed that the droplets of QT–NSSPE with the size of 10.29 ± 0.44 μm exhibited a core-shell structure consisting of a core of oil and a shell of QT–NC. QT–NSSPE has shown a great stability in droplets shape, size, creaming index, zeta potential, and QT content during 30 days storage at 4, 25, and 40 °C. In vitro release studies showed that QT–NSSPE performed a better dissolution behavior (65.88% within 24 h) as compared to QT–NC (50.71%) and QT coarse powder (20.15%). After oral administration, the AUC0–t of QT–NSSPE was increased by 2.76-times and 1.38 times compared with QT coarse powder and QT–NC. It could be concluded that NSSPE is a promising oral delivery system for improving the oral bioavailability of QT.
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