目的 制備二氫楊梅素混合膠束（DMY-MMs），考察口服藥動學(xué)行為，并計(jì)算口服吸收相對生物利用度。方法 通過單因素試驗(yàn)確定主要影響因素的篩選區(qū)間，Box-Behnken設(shè)計(jì)-響應(yīng)面法優(yōu)化 DMY-MMs處方。透射電鏡觀察 DMY-MMs微觀形態(tài)，X-射線粉末衍射法分析晶型，透析法考察 DMY-MMs 體外釋藥行為。SD 大鼠分別 ig 給予二氫楊梅素和 DMYMMs，比較藥動學(xué)行為和吸收相對生物利用度。結(jié)果 DMY-MMs最佳處方為：載-藥用量比為7.6∶1，Soluplus與TPGS用量比為6.4∶1，水化時間為2 h。包封率、載藥量、粒徑及Zeta電位分別為（90.21±1.60）%、（10.43±0.21）%、（68.14±7.23）nm 和（1.07±0.26）mV。DMY-MMs外貌為類球形，并以無定型態(tài)存在于 DMY-MMs凍干粉中。DMY-MMs體外釋藥行為符合Weibull模型，釋藥方程為lnln［1（/ 1－M_t/M_∞）］＝0.639 7lnt－1.781 1（r＝0.978 4）。藥動學(xué)結(jié)果顯示，DMY-MMs半衰期（t_1/2）延長至（4.11±1.07）h，C_max增加至4.41倍，相對生物利用度提高至5.18倍。結(jié)論 DMY-MMs改變了二氫楊梅素體內(nèi)藥動學(xué)行為，顯著促進(jìn)了口服吸收。

Objective To prepare dihydromyricetin mixed micelles (DMY-MMs), and evaluate oral pharmacokinetic behavior and calculate its relative oral bioavailability. Methods Single factor tests were used to determine the screening interval of the main influencing factors, and Box-Behnken design-response surface methodology was employed to optimize prescriptions of DMY-MMs. Transmission electron microscope (TEM) was employed to observe its microscopic appearance. Crystal form of lyophilized powder was analyzed by X-ray powder diffraction (XRPD). Release behavior of DMY-MMs in vitro was investigated by dialysis method. SD rats in each group were administered intragastrically with dihydromyricetin and DMY-MMs, respectively. Pharmacokinetics and relative bioavailability were also compared. Results Optimal formulation of DMY-MMs: carrier to drug ratio was 7.6∶1, Soluplus to TPGS ratio was 6.4∶1, and hydration time was 2 h. Envelopment efficiency, drug loading, particle size and Zeta potential were (90.21 ± 1.60)%, (10.43 ± 0.21)%, (68.14 ± 7.23) nm and (1.07 ± 0.26) mV, respectively. Appearance of DMY-MMs was spherical, dihydromyricetin changed into an amorphous form in DMY-MMs lyophilized powder. Release behavior in vivo of DMY-MMs was in accordance with Higuchi model, and drug release equation was lnln[1/(1－M_t/M_∞)] = 0.639 7lnt－1.781 1 (r = 0.978 4). Pharmacokinetics of DMY-MMs showed that t _1/2 was prolonged to (4.11 ± 1.07) h, C_max was enhanced to 4.41-fold and oral relative bioavailability was increased to 5.18-fold. Conclusion DMY-MMs changed pharmacokinetic behavior of dihydromyricetin in vivo and significantly promoted its oral absorption.

R945

河南省2023年度科技攻關(guān)項(xiàng)目（232102310104）；2024年鄭州市高等教育教學(xué)改革研究與實(shí)踐項(xiàng)目（2024KCSZ013）