目的 制备脂质体包覆的辣椒素介孔二氧化硅纳米粒（liposomes-coated mesoporous silica nanoparticles loaded with capsaicin，Cap-MSN@Lips），考察Cap-MSN@Lips口服药动学行为，并评价胃黏膜刺激性。方法 溶剂挥发法制备Cap-MSN粉末。单因素考察结合Box-Behnken设计-响应面法（Box-Behnken design-response surface method，BBD-RSM）优化Cap-MSN@Lips处方，测定包封率、载药量、粒径、多分散指数（polydispersity index，PDI）和ζ电位。透射电镜（transmission electron microscopy，TEM）观察Cap-MSN和Cap-MSN@Lips微观形貌，X射线粉末衍射法（X-ray powder diffraction，XRPD）分析晶型。考察Cap-MSN和Cap-MSN@Lips在不同介质中的溶解度及体外释药。比较辣椒素、Cap-MSN和Cap-MSN@Lips口服药动学行为，计算主要药动学参数及其相对口服吸收生物利用度。对大鼠连续ig 7 d，观察胃黏膜组织形态，评价Cap-MSN和Cap-MSN@Lips胃黏膜刺激性。结果 Cap-MSN@Lips最佳处方为介孔二氧化硅纳米粒粉末与辣椒素用量比3.2∶1，磷脂与胆固醇用量比4.0∶1，总脂质与辣椒素用量比4.6∶1。Cap-MSN@Lips包封率、载药量、粒径、PDI值和ζ电位分别为（93.88±1.17）%、（10.36±0.19）%、（176.76±5.69）nm、0.106±0.011和（−27.07±0.88）mV。Cap-MSN和Cap-MSN@Lips外观为圆球形，辣椒素在Cap-MSN和Cap-MSN@Lips可能以无定形态存在，在不同介质中辣椒素溶解度均得到极显著性提高。Cap-MSN@Lips在模拟胃肠液和水中累积释放度分别达84.76%和91.43%。口服药动学显示，Cap-MSN@ Lips达峰时间（t_max）延后至（2.56±0.62）h，半衰期（t_1/2）延长至（5.79±0.94）h，达峰浓度（C_max）增加至（893.71±222.17）ng/mL，相对口服吸收生物利用度提高至6.19倍，而Cap-MSN口服吸收生物利用度仅提高至3.49倍。胃黏膜刺激性评价结果显示，Cap-MSN@Lips对大鼠胃黏膜无损伤作用。结论 制备的Cap-MSN@Lips提高了辣椒素累积释放度，有效促进了口服吸收，并避免了胃黏膜刺激，值得进一步开发。

Objective Liposomes-coated mesoporous silica nanoparticles loaded with capsaicin (Cap-MSN@Lips) was prepared, oral pharmacokinetic behavior was studied, and irritation of gastric mucosa was also evaluated. Methods Solvent evaporation method was employed to prepare Cap-MSN powder. Single factor investigation combined with Box-Behnken response surface design method (BBD-RSM) was used to investigate the optimal prescriptions of Cap-MSN@Lips. Encapsulation efficiency, drug loading, particle size, polydispersity index (PDI) and ζ potential were determined. The micromorphology of Cap-MSN and Cap-MSN@Lips was observed by transmission electron microscopy (TEM), and their crystal form was analyzed by X-ray powder diffraction (XRPD). The solubility and in vitro release of Cap-MSN and Cap-MSN@Lips in different media were also studied. Pharmacokinetic behavior of capsaicin, Cap-MSN and Cap-MSN@Lips were compared, main pharmacokinetic parameters and relative oral bioavailability were calculated. The gastric mucosa of rats was observed after 7-day administration of Cap-MSN and Cap-MSN@Lips, and then evaluating its irritation of gastric mucosa. Results The optimal formulation of Cap-MSN@Lips: mesoporous silica nanoparticles to capsaicin ratio was 3.2:1, phospholipids to cholesterol ratio was 4.0:1 and total lipids to capsaicin ratio was 4.6:1. Encapsulation efficiency, drug loading, particle size, polydispersity index (PDI) and ζ potential of Cap-MSN@Lips were (93.88 ± 1.17)%, (10.36 ± 0.19)%, (176.76 ± 5.69) nm, 0.106 ± 0.011 and (−27.07 ± 0.88) mV, respectively. Appearance of Cap-MSN and Cap-MSN@Lips were both spherical, capsaicin might existence as in an amorphous state in the Cap-MSN and Cap-MSN@Lips, and the solubility of capsaicin was significantly increased in different media. The cumulative release rate of Cap-MSN@Lips in simulate gastrointestinal fluids and water were enhanced to 84.76% and 91.43%, respectively. Oral pharmacokinetics showed that t_max of Cap-MSN@Lips postponed to (2.56 ± 0.62) h, t_1/2 was prolonged to (5.79 ± 0.94) h, C_max increased to (893.71 ± 222.17) ng/mL and relative oral bioavailability increased to 6.19-fold. The oral bioavailability of Cap-MSN was only increased to 3.49 times. Results of gastric mucosa irritation evaluation showed that Cap-MSN@Lips had no injure effects on gastric mucosa. Conclusion The prepared Cap-MSN@Lips improved the cumulative release degree of capsaicin, effectively promoted oral absorption of capsaicin in vivo and avoided the irritation on gastric mucosa, which was worth further developing.

R283.6

河南省高等学校重点科研项目计划（21B360011）；河南省中医药拔尖人才培养项目资助（2021-15）；河南省2024年科技发展计划科技攻关项目（242102310577）