三叶苷-磷脂复合物/壳聚糖纳米粒的制备、口服药动学及对急性肝损伤保护作用评价OA

Objective To prepare trifolin-phospholipids complex/chitosan nanoparticles(Tri-PC/CS-NPs),and investigate its in vivo pharmacokinetic behavior and protective effect on acute liver injury.Methods Trifolin-phospholipids complex(Tri-PC)was prepared by solvent evaporation method.Single factor experiments combined Box-Behnken design-response surface methodology(BBD-RSM)were used to optimize the prescriptions of Tri-PC/CS-NPs.Transmission electron microscope(TEM)was employed to observe microscopic appearance of Tri-PC/CS-NPs,X-ray powder diffraction(XRPD)was used to analyze crystal form of Tri-PC/CS-NPs.Saturated solubility,oil/water partition coefficient and drug release behavior in simulated gastrointestinal fluids of trifolin,Tri-PC and Tri-PC/CS-NPs were compared.SD rats were administered intragastrically with trifolin,Tri-PC and Tri-PC/CS-NPs,respectively.Blood drug concentration was determined,and the main pharmacokinetic parameters were calculated.The model of acute liver injury was established,and the protective effect of trifolin,Tri-PC,Tri-PC/CS-NPs on acute liver injury were compared.Results Optimal formulations of Tri-PC/CS-NPs:the volume of water phase was 20.50 mL,the mass ratio of Tri-PC to chitosan was 4.15∶1,and the mass fraction ofPoloxamer 188 was 0.10％.Envelopment efficiency,drug loading,particle size and ζ potential were(84.80±1.21)％,(15.56±0.10)％,(197.74±5.58)nm and(32.69±1.14)mV,respectively.The appearance of Tri-PC/CS-NPs were spherical.The state of trifolin changed into amorphous form in Tri-PC and Tri-PC/CS-NPs.Tri-PC and Tri-PC/CS-NPs significantly enhanced the saturated solubility and oil/water partition coefficient of trifolin(P＜0.01).Cumulative release rate of Tri-PC and Tri-PC/CS-NPs were 56.68％and 88.45％in 18 h,respectively.The drug release process of Tri-PC/CS-NPs conformed to the Weibull model.Compared with trifolin,the relative bioavailability of Tri-PC and Tri-PC/CS-NPs was enhanced to 2.41-fold and 5.36-fold,respectively.Tri-PC and Tri-PC/CS-NPs effectively enhanced the protective effect of trifolin against acute liver injury,and the protective effect of Tri-PC/CS-NPs was superior to that of Tri-PC.Conclusion Tri-PC/CS-NPs changed the pharmacokinetic behavior of trifolin in vivo,effectively promoted the absorption of trifolin,and enhanced the protective effect of trifolin on acute liver injury.