目的 制备牡荆素脂质体（vitexin liposomes，Vit-Lips）、壳聚糖修饰的Vit-Lips（chitosan modified Vit-Lips，CS-Vit-Lips）及脱氧胆酸和壳聚糖双修饰的Vit-Lips（deoxycholic acid and chitosan co-modified Vit-Lips，DA/CS-Vit-Lips），比较3种脂质体口服药动学行为。方法 合成脱氧胆酸-壳聚糖结合物（deoxycholic acid-chitosan complex，DA/CS）。薄膜超声法制备Vit-Lips，采用包封率、载药量和粒径为考察指标，单因素实验结合Box-Behnken设计-响应面法（Box-Behnken design-response surface methodology，BBD-RSM）优化Vit-Lips处方，引入壳聚糖和DA/CS分别制备CS-Vit-Lips和DA/CS-Vit-Lips。透射电子显微镜（transmission electron microscopy，TEM）观察3种脂质体的微观结构，比较其在模拟胃肠液中的粒径稳定性。考察牡荆素原料药及其3种脂质体在模拟胃肠液中释药情况，研究释药机制。考察不同肠段对牡荆素及其3种脂质体的吸收情况，计算肠吸收参数。按照20 mg/kg剂量（以牡荆素计）分别ig牡荆素原料药及其3种脂质体，采集血样，计算主要药动学参数及相对生物利用度。结果 Vit-Lips最佳处方工艺：磷脂与胆固醇用量比为7.95∶1，脂药用量比为9.63∶1，水化时间为30.00 min。采用0.8%的壳聚糖溶液和DA/CS溶液分别制备CS-Vit-Lips和DA/CS-Vit-Lips。Vit-Lips、CS-Vit-Lips、DA/CS-Vit-Lips的包封率分别为（82.31±0.96）%、（84.93±1.17）%、（85.15±1.38）%，载药量分别为（7.33±0.09）%、（6.24±0.08）%、（6.30±0.11）%，平均粒径分别为（197.70±5.07）、（233.06±7.19）、（237.93±6.96）nm，ζ电位分别为（−28.81±0.86）、（27.75±1.10）、（26.14±1.13）mV。3种脂质体外观为类圆形的囊泡状。CS-Vit-Lips和DA/CS-Vit-Lips在模拟胃肠液中粒径稳定性高于Vit-Lips。Vit-Lips、CS-Vit-Lips和DA/CS-Vit-Lips分别将牡荆素的累积释放率提高至91.02%、86.74%和83.15%，3者的释药过程均符合Weibull模型。3种脂质体有效改善了牡荆素吸收速率常数（K_a）和表观吸收系数（P_app）。以牡荆素原料药为参考，Vit-Lips、CS-Vit-Lips和DA/CS-Vit-Lips相对口服吸收生物利用度分别增加至1.10倍、3.08倍和4.70倍，其中，CS-Vit-Lips和DA/CS-Vit-Lips的半衰期（t_1/2）极显著性延长（P＜0.01），达峰浓度（C_max）极显著性提高（P＜0.01）。结论 CS-Vit-Lips和DA/CS-Vit-Lips有效促进了牡荆素口服吸收，DA/CS-Vit-Lips优势更明显，为进一步研究奠定实验基础。

Objective Vitexin liposomes (Vit-Lips), chitosan modified Vit-Lips (CS-Vit-Lips) and deoxycholic acid and chitosan co-modified Vit-Lips (DA/CS-Vit-Lips) were prepared, and their oral pharmacokinetic behavior were compared. Methods Deoxycholic acid-chitosan complex (DA/CS) was synthesized. Film-ultrasonic method was used to prepare Vit-Lips. Encapsulation rate, drug loading and particle size were used as evaluation indexes, single factor investigation combined with Box-Behnken design-response surface methodology (BBD-RSM) were used to investigate the optimal prescriptions of Vit-Lips. CS-Vit-Lips and DA/CS-Vit-Lips were prepared by introducing chitosan and DA/CS, respectively. Transmission electron microscopy (TEM) was used to observe the microstructure of the three kinds of liposomes, and their particle stability in gastrointestinal fluids were compared. Using vitexin as reference, the drug release of Vit-Lips, CS-Vit-Lips and DA/CS-Vit-Lips in simulate gastrointestinal fluid were compared, and their drug release mechanism were also studied. The absorption of the vitexin and its three kinds of liposomes in different intestinal segments was investigated, and the intestinal absorption parameters were calculated. Blood samples were collected after gastric administration of vitexin and its three kinds of liposomes at a dose of 20 mg/kg (vitexin), respectively. Main pharmacokinetic parameters and relative oral bioavailability were also calculated. Results The optimal formulation of Vit-Lips: phospholipids to cholesterol dose ratio was 7.95:1, lipids to drug dose ratio was 9.63:1 and hydration time was 30.00 min. CS-Vit-Lips and DA/CS-Vit-Lips were prepared using chitosan and DA/CS solution with mass fraction of 0.8%, respectively. Entrapment efficiency of Vit-Lips, CS-Vit-Lips and DA/CS-Vit-Lips were (82.31 ± 0.96)%, (84.93 ± 1.17)%, (85.15 ± 1.38)%, drug loading were (7.33 ± 0.09)%, (6.24 ± 0.08)%, (6.30 ± 0.11)%, particles size were (197.70 ± 5.07), (233.06 ± 7.19), (237.93±6.96) nm, and ζ potential were (−28.81 ± 0.86), (27.75 ± 1.10), (26.14 ± 1.13) mV, respectively. The appearance of three kinds of liposomes was spherical vesicular, particle stability of CS-Vit-Lips and DA/CS-Vit-Lips was higher than that of Vit-Lips in simulated gastrointestinal fluid. Vit-Lips, CS-Vit-Lips and DA/CS-Vit-Lips enhanced cumulative release rate to 91.02%, 86.74% and 83.15%, respectively. The drug release process of the three kinds of liposomes conformed to Weibull model. The three kinds of liposomes effectively improved the absorption rate constant (K_a) and apparent absorption coefficient (P_app) of vitexin. Compared to vitexin, Vit-Lips, CS-Vit-Lips and DA/CS-Vit-Lips increased relative oral bioavailability to 1.10-fold, 3.08-fold and 4.70-fold, respectively. The half-life time (t_1/2) of CS-Vit-Lips and DA/CS-Vit-Lips had significantly prolonged (P < 0.01) and the peak concentration (C_max) was significantly increased (P < 0.01). Conclusion CS-Vit-Lips and DA/CS-Vit-Lips effectively promoted the oral absorption of vitexin, and the advantage of DA/CS-Vit-Lips were more obvious, laying an experimental foundation for further research.

R283.6

国家自然科学基金项目（31371386）；国家自然科学基金项目（30871239）