Mechanisms of oral absorption improvement for insoluble drugs by the combination of phospholipid complex and SNEDDS

In the present study, a water insoluble drug named silybin was encapsulated into self-nanoemulsifying drug delivery system (SNEDDS) following the preparation of silybin–phospholipid complex (SB–PC), then several methods were carried out to characterize SB–PC–SNEDDS and elucidate its mechanisms to improve the oral absorption of SB. Using a dynamic in vitro digestion model, the lipolysis of SB–PC–SNEDDS was proved to be mainly related with the property of its lipid excipients. SB–PC–SNEDDS could significantly enhance the transport of SB across Caco-2 cells, which may partly attribute to the increased cell membrane fluidity and the loss of tight junction according to the analysis results of fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and tight junction protein (ZO-1). The result of in situ perfusion showed the intestinal absorption of SB from high to low was SB–PC–SNEDDS, SB–PC, and SB. The extent of lymphatic transport of SB–PC and SB–PC–SNEDDS via the mesenteric duct was 12.2 and 22.7 folds of that of SB, respectively. In the lymph duct cannulated rats, the relative bioavailability (Fr) of SB–PC and SB–PC–SEDDS compared to SB was 1265.9% and 1802.5%, respectively. All the above results provided mechanistic support for oral absorption improvement of water insoluble drugs by the combination of PC and SNEDDS.