目的 以甜菊糖苷为载体制备二氢杨梅素纳米胶束（dihydromyricetin stevioside nanomicelles，Dmy-Ste-NMs），考察其体外释药行为及体内口服药动学行为。方法 在单因素考察的前提下，选择药物质量浓度、甜菊糖苷质量浓度和搅拌时间为主要影响因素，Dmy-Ste-NMs包封率和载药量为考察指标，采用Box-Behnken设计-效应面法（Box-Behnken design-response surface method，BBD-RSM）优化Dmy-Ste-NMs处方工艺，直接冻干法制备Dmy-Ste-NMs粉末。透射电子显微镜（transmission electron microscope，TEM）观察Dmy-Ste-NMs微观形态，X射线粉末衍射（X-ray powder diffraction，XRPD）法分析晶型，透析法考察体外释药行为。SD大鼠分别ig给予Dmy和Dmy-Ste-NMs粉末，测定血药浓度，比较药动学行为，计算Dmy-Ste-NMs相对生物利用度。结果Dmy-Ste-NMs最佳处方为药物质量浓度11.24 mg/mL，甜菊糖苷质量浓度79.75 mg/mL，搅拌时间1.36 h。包封率、载药量、粒径及ζ电位分别为（90.56±1.17）%、（10.92±0.16）%、（7.17±0.65）nm和（−17.53±1.56）mV。TEM结果显示Dmy-Ste-NMs外貌为类球形，XRPD结果显示Dmy在Dmy-Ste-NMs粉末中转变为无定形态，体外释药具有缓释特征。药动学结果显示，Dmy-Ste-NMs的达峰时间（t_max）提前至（0.71±0.17）h，而半衰期（t_1/2）延长至（4.33±0.59）h，达峰浓度（C_max）和相对生物利用度分别增加至3.83倍和4.60倍。结论 采用甜菊糖苷制备的Dmy-Ste-NMs具有粒径小、载药量高、缓释特征明显等特点，显著促进了Dmy体内吸收。

Objective To prepare dihydromyricetin nanomicelles using stevioside as carriers (Dmy-Ste-NMs), release behavior in vitro and oral pharmacokinetic behavior in vivo were also studied. Methods On the base of single factor investigation, drug concentration, stevioside concentration and stirring time were selected as main influencing factors, entrapment efficiency and drug loading were used as evaluation indexes, Box-Behnken design-response surface method (BBD-RSM) were employed to optimize prescriptions of Dmy-Ste-NMs. Powder of Dmy-Ste-NMs was prepared by direct lyophilization method. Transmission electron microscope (TEM) was employed to observe microscopic appearance of Dmy-Ste-NMs. The crystal form of the powder of Dmy-Ste-NMs was analyzed by X-ray powder diffraction (XRPD), and the in vitro release behavior of Dmy-Ste-NMs was investigated using dialysis method. SD rats were administered intragastrically with dihydromyricetin and Dmy-Ste-NMs suspension, respectively. Blood drug concentration was determined, pharmacokinetics was compared and relative oral bioavailability was also calculated. Results The optimal formulations of Dmy-Ste-NMs: dihydromyricetin concentration was 11.24 mg/mL, stevioside concentration was 79.75 mg/mL, and stirring time was 1.36 h. Envelopment efficiency, drug loading, particle size and ζ potential were (90.56 ±1.17)%, (10.92 ±0.16)%, (7.17 ±0.65) nm and (−17.53 ±1.56) mV, respectively. TEM revealed that Dmy-Ste-NMs were spherical in appearance. XRPD results showed that dihydromyricetin transformed into an amorphous state in Dmy-Ste-NMs powder. Drug release in vitro had obvious sustained-release characteristics. Pharmacokinetics showed that t_max of Dmy-Ste-NMs was shorten to (0.71 ±0.17) h, t_1/2 was increased to (4.33 ±0.59) h, C_max and oral relative bioavailability were increased to 3.83-fold and 4.60-fold. Conclusion Dmy-Ste-NMs prepared with stevioside had the characteristics of small particle size, high drug loading and obvious sustained-release characteristics, which significantly promoted the absorption of dihydromyricetin in vivo.

R283.6

河南省高等学校重点科研项目计划（23B310010）;河南省医学教育研究指导性项目（WJLX2023148）