纳米晶自稳定Pickering乳液促进葛根素口服吸收的机制研究

Study on oral absorption mechanisms of puerarin in nanocrystals self-stabilized pickering emulsion

纳米晶自稳定Pickering乳液(NSSPE)是一种仅以难溶性成分自身纳米晶为稳定剂的新型乳液。以川芎油为主要油相的NSSPE可显著促进葛根素(Pu)的口服吸收。该研究旨对其口服促吸收机制进行探讨。通过体外溶出试验揭示NSSPE对Pu溶出的影响;通过Caco-2细胞摄取和双向转运试验,探讨NSSPE对Pu肠道细胞吸收和转运的影响及机制。结果显示,NSSPE的释药速率与纳米晶相似,累积溶出率都显著高于原料药,且不受释药介质pH的影响。NSSPE中Pu的摄取具有浓度依赖性,且显著高于溶液和表面活性剂乳。与脂筏/小窝蛋白介导有关的抑制剂染料木素、吲哚美辛能显著降低NSSPE中Pu的摄取率。与溶液相比,NSSPE和表面活性剂乳液均显著提高了Pu AP→BL方向的转运速率Ka和表观渗透系数Papp,但BL→AP方向的转运无显著性差异。可见,该NSSPE中Pu的Caco-2细胞吸收同时存在被动转运和主动转运,以及脂筏/小窝蛋白介导的胞饮;其促进Pu口服吸收的机制与NSSPE中Pu以纳米晶形式存在,可促进溶出,以及用作油相的川芎油可促进药物跨膜转运、抑制外排有关。正是NSSPE的这种独特结构和组成促进了Pu的口服吸收。

Nanocrystals self-stabilized Pickering emulsion(NSSPE) is a new kind of emulsion where only nanocrystals of poorly soluble drugs are used as stabilizers. Our previous study showed that NSSPE with Ligusticum chuanxiong oil as the main oil phase can significantly promote oral absorption of puerarin. The present study aimed to explore its absorption mechanism in oral administration. The in vitro dissolution test was carried out to study the effect of NSSPE on release of puerarin. The effects and mechanism of NSSPE on uptake and transport of puerarin across Caco-2 cell were investigated. The results showed that the drug release rate of NSSPE was similar to that of nanocrystals, with their cumulative dissolution of puerarin not affected by pH of releasing mediums, both significantly higher than that of crude material. The uptake of puerarin in NSSPE was concentration-dependent and significantly higher than that of solution or surfactant stabilized emulsion. Genistein and indomethacin, inhibitors of lipid rafts/caveolin, could significantly reduce the uptake of puerarin in NSSPE. Compared with solution, NSSPE and surfactants stabilized emulsion obviously increased transport rate Ka and apparent permeability coefficient Papp of puerarin in AP → BL direction, but there was no significant difference in BL → AP direction. It could be inferred that there were both passive and active transport mechanisms, as well as lipid raft/caveolin mediated endocytosis for absorption of NSSPE. The promoted oral absorption of puerarin in NSSPE was mainly related to the existing nanocrystal form which could promote dissolution, puerarin as well as Ligusticum chuanxiong oil which could promote drug transmembrane transport and inhibit drug efflux. It is the unique structure and composition of the compound NSSPE that promoted the oral absorption of puerarin.