目的 制备半乳糖修饰的桔皮素仿生纳米粒（galactose modified tangeretin biomimetic nanoparticles，Gal-Tan-BNps），并考察理化性质及口服药动学行为。方法 单因素考察处方工艺对Gal-Tan-BNps包封率、载药量和粒径的影响，选择PLGA与药物用量比、N-油酰-D-半乳糖胺质量分数和泊洛沙姆188质量分数作为主要影响因素，采用Box-Behnken设计-响应面法（Box-Behnken design-response surface method，BBD-RSM）优化Gal-Tan-BNps处方，并测定包封率、载药量、粒径和ζ电位。透射电子显微镜（transmission electron microscope，TEM）观察Gal-Tan-BNps形貌，X射线粉末衍射（X-ray powder diffraction，XRPD）法和差示扫描量热法（differential scanning calorimetry，DSC）分析桔皮素晶型，透析袋法考察Gal-Tan-BNps释药行为。比较Caco-2细胞对Gal-Tan-BNps和桔皮素纳米粒（tangeretin nanoparticles，Tan-Nps）的摄取能力。SD大鼠ig给予Gal-Tan-BNps和Tan-Nps，测定血药浓度，计算主要药动学参数和相对生物利用度。结果 Gal-Tan-BNps最佳处方为PLGA与药物用量比为9.33∶1，N-油酰-D-半乳糖胺质量分数为0.33%，泊洛沙姆188质量分数为0.81%。Gal-Tan-BNps的包封率、载药量、粒径和ζ电位分别为（84.76±1.22）%、（8.04±0.11）%、（190.94±6.60）nm和（-19.92±0.97）mV。Gal-Tan-BNps外貌呈圆形或椭圆形，Gal-Tan-BNps在24 h内累积释放率达77.13%，释药行为符合Weibull模型，包含快速和缓慢释药期。Caco-2细胞对Gal-Tan-BNps的摄取能力优于Tan-Nps，荧光平均吸光度值存在显著性差异（P＜0.05）。与桔皮素原料药相比，Gal-Tan-BNps达峰时间（t_max）延后至（3.06±0.75）h，半衰期（t_1/2）延长至（5.71±1.47）h，达峰浓度（C_max）增加至（1 196.44±230.89）ng/mL，相对生物利用度提高至6.43倍。Gal-Tan-BNps对桔皮素生物利用度的提高幅度高于Tan-BNps。结论 Gal-Tan-BNps包封率较高，提高了桔皮素体外释放度及口服吸收生物利用度，为后续研究奠定基础。

Objective To prepare galactose modified tangeretin biomimetic nanoparticles (Gal-Tan-BNps), and investigate its physicochemical properties and oral pharmacokinetic behavior. Methods The effects of formulations on the encapsulation efficiency, drug loading and particle size of Gal-Tan-BNps were investigated by single factor experiments. PLGA to drug dosage ratio, N-oleoyl-D-galactosamine quality fraction and poloxamer 188 quality fraction were used as main influencing factors, Box-Behnken design- response surface method (BBD-RSM) was employed to investigate the optimal prescriptions of Gal-Tan-BNps. Encapsulation rate, drug loading, particle size and ζ potential were all determined. Appearance of Gal-Tan-BNps was observed by transmission electron microscopy (TEM), crystal form of tangeretin in Gal-Tan-BNps was analyzed by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC), drug release behavior of Gal-Tan-BNps was studied by dialysis bag method. The uptake capacity of Gal-Tan-BNps and tangeretin nanoparticles (Tan-Nps) by Caco-2 cells were compared. SD rats were ig administered with Gal-Tan-BNps and Tan-Nps, their main pharmacokinetic parameters and relative bioavailability were also calculated. Results Optimal formulations of Gal-Tan-BNps were as follows: PLGA to drug ratio was 9.33:1, N-oleoyl-D-galactosamine quality fraction was 0.33%, and quality fraction of poloxamer 188 was 0.81%. Encapsulation efficiency, drug loading, particle size and ζ potential of Gal-Tan-BNps were (84.76 ± 1.22)%, (8.04 ± 0.11)%, (190.94 ± 6.60) nm and (-19.92 ± 0.97) mV, respectively. The appearance Gal-Tan-BNps were round or oval vesicles, and tangeretin existed in an amorphous form in Gal-Tan-BNps. The cumulative release rate of Gal-Tan-BNps reached 77.13% in 24 h, and its release behavior accorded with Weibull model including rapid and slow-release period. Caco-2 cells exhibited superior uptake capacity of Gal-Tan-BNps compared to Tan-Nps, and their average density value had significantly difference (P < 0.05). Compared with tangeretin, peak time (t_max) of Gal-Tan-BNps was delayed to (3.06 ± 0.75) h, half-life (t_1/2) was prolonged to (5.71 ± 1.47) h, peak contration (C_max) increased to (1 196.44 ± 230.89) ng/mL, and relative bioavailability increased to 6.43-fold. Gal-Tan-BNps enhanced the bioavailability of tangeretin to a greater extent than that of Tan-BNps. Conclusion Gal-Tan-BNps had a higher encapsulation rate, the cumulative release rate of tangeretin in vitro and oral bioavailability of tangeretin in vivo were improved greatly, which laying the foundation for subsequent research.

R283.6

山西省中医药科技创新工程项目(2023kjzy009);山西省中央引导地方科技发展资金项目(YDZJSX2024B014);山西省中医药管理局科研课题(2023ZYYC2107)