目的 结合分子模拟和增溶实验筛选黄芩苷/多糖复合物的最适载体，制备黄芩苷/透明质酸复合物（baicalin/ hyaluronic acid complex，Bai/HA Co），以提高黄芩苷的水溶性、溶出度及生物利用度，并探讨其增溶机制。方法 通过分子对接和分子模拟计算黄芩苷与不同多糖（葡聚糖、菊糖、普鲁兰多糖、黄原胶、透明质酸）的结合自由能，并考察不同多糖对黄芩苷的增溶作用，筛选出增溶效果最好的多糖。采用加热搅拌结合冷冻干燥法制备Bai/HA Co，以黄芩苷增溶倍数和载药量为指标，通过单因素实验结合Box-Behnken设计-响应面法优化复合物的处方及工艺，对其体外溶出和体内药动学进行研究，并应用傅里叶变换红外光谱法（Fourier transform infrared spectroscopy，FT-IR）、差示扫描量热法（differential scanning calorimeter，DSC）、粉末X射线衍射法（powder X-ray diffraction，PXRD）、分子动力学（molecular dynamics，MD）模拟研究复合物中黄芩苷的存在状态及与透明质酸的相互作用，探讨Bai/HA Co的增溶机制。结果 分子模拟和增溶实验结果表明，透明质酸能更好地改善黄芩苷的水溶性，增溶效果较好。透明质酸质量浓度和加热温度对Bai/HA Co的增溶倍数和载药量影响较大，优化得到的处方工艺为透明质酸质量浓度2 mg/mL、水浴加热温度65 ℃、搅拌速度900 r/min、搅拌时间1 h。制得的Bai/HA Co使增溶倍数达到23.37倍，载药量为17.09%。Bai/HA Co能明显增加黄芩苷在pH 1.2盐酸溶液、pH 4.5醋酸盐缓冲液和去离子水中的溶出度，提高黄芩苷的生物利用度。FT-IR、DSC、PXRD和MD模拟结果表明，复合物中黄芩苷与透明质酸产生氢键相互作用使得黄芩苷能够以非结晶状态分散在透明质酸分子链中。结论 分子模拟结合增溶实验，为复合物载体多糖的筛选提供了一种更加精准的方法，加热搅拌结合冷冻干燥法制备的Bai/HA Co能够较好地改善黄芩苷的水溶性、溶出度和生物利用度。

Objective To improve the water solubility, dissolution and bioavailability of baicalin and explore the solubilization mechanism, molecular simulation combined with a solubilization experiment was applied to screen the carrier material of baicalin/ polysaccharide complex, and the baicalin/hyaluronic acid complex (Bai/HA Co) was prepared. Methods Firstly, the binding free energies of baicalin with different polysaccharides were calculated by molecular docking and simulation, and the solubilization effect of these polysaccharides on baicalin was evaluated by solubilization experiment to screen proper polysaccharide as carrier material of the complex. Secondly, Bai/HA Co was prepared by stirring under heating combined with the freeze-drying method. Using solubilization ratio of baicalin and drug loading as indicators, the process was optimized by single factor experiments combined with Box-Behnken design-response surface methodology. Thirdly, the in vitro dissolution of Bai/HA Co in different media and in vivo pharmacokinetics in SD rats were investigated. Finally, the solubilization mechanism of Bai/HA Co was explored by Fourier transform infrared spectrometry (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and molecular dynamics (MD) simulation. Results The results of molecular docking, molecular simulation and solubilization experiment showed that hyaluronic acid could improve the water solubility of baicalin and exhibited the best solubilization effect. The solubilization ratio and drug loading of Bai/HA Co were greatly affected by the heating temperature and the concentration of hyaluronic acid. The results showed that the optimal process for preparing Bai/HA Co was as follows: hyaluronic acid concentration of 2 mg/mL, heating temperature of 65 ℃, stirring speed of 900 r/min and stirring time of 1 h. The Bai/HA Co prepared showed a great solubilization effect on baicalin, which was 23.37 times higher than that of baicalin, and its drug loading was 17.09%. The results of in vitro dissolution indicated that Bai/HA Co could significantly improve the dissolution of baicalin in pH 1.2, 4.5 media and deionized water, and the bioavailability of baicalin. The results of FT-IR, DSC, PXRD and MD simulations revealed that the H-bond interaction between baicalin and hyaluronic acid enabled baicalin to disperse into the hyaluronic acid molecular chain in an amorphous state. Conclusion Molecular simulation combined with solubilization experiment provides a more accurate method for screening polysaccharides as carrier materials for complex. The Bai/HA Co prepared by the method of stirring under heating combined with freeze-drying can improve the water solubility, dissolution of baicalin and bioavailability of baicalin.

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