Sun Yuting, Guo Ming, Zhao Xiaoxue, Wu Ronghui
College of Environmental and Resource Sciences, Zhejiang Agricultural & Forestry University, Hangzhou, Zhejiang, China.
College of Chemistry and Materials Engineering, Zhejiang Agricultural & Forestry University, Hangzhou, Zhejiang, China.
Turk J Chem. 2023 Apr 4;47(3):554-571. doi: 10.55730/1300-0527.3560. eCollection 2023.
In this paper, a new pharmaceutical cocrystal was synthesized using apigenin (AP) and pharmaceutically acceptable conformer nicotinamide (Nico), and the drug delivery between AP-Nico pharmaceutical cocrystal and human serum albumin (HSA) in vivo was studied at atomic scale. The pharmaceutical cocrystal was characterized using Fourier-transform infrared (FTIR) spectroscopy, H NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), and the self-assembling mechanism was explored. The dissolution and cumulative release in vitro were investigated. Molecular dynamic (MD) simulation combined with fluorescence spectroscopy was used to study the delivery mechanism of AP-Nico to HSA. The results showed that AP was pharmaceutically cocrystallized with Nico, which formed a pharmaceutical cocrystal mainly through hydrogen interaction between the -OH groups of AP and -NH groups of Nico. The solubility of the AP-Nico was 3 times higher than raw AP and the cumulative release rate was 71%. The fluorescence spectroscopy results showed that the AP-Nico pharmaceutical cocrystal bind with Sudlow's site I inside the HSA molecule with hydrogen-bond interaction as the main force. The Sudlow's site I of HSA conjugated with AP-Nico explains the conformational changes of HSA in-silico. This study provided a useful reference for synthesizing flavonoid pharmaceutical cocrystal to improve solubility and exploring the interaction mechanism while understanding its delivery mechanism in vivo.
本文利用芹菜素（AP）和药学上可接受的构象体烟酰胺（Nico）合成了一种新型药物共晶，并在原子尺度上研究了AP-Nico药物共晶与人血清白蛋白（HSA）在体内的药物传递。采用傅里叶变换红外（FTIR）光谱、核磁共振氢谱（H NMR）、差示扫描量热法（DSC）和粉末X射线衍射（PXRD）对药物共晶进行了表征，并探讨了其自组装机制。研究了其体外溶出度和累积释放度。采用分子动力学（MD）模拟结合荧光光谱法研究了AP-Nico对HSA的传递机制。结果表明，AP与Nico形成了药物共晶，主要通过AP的-OH基团与Nico的-NH基团之间的氢键相互作用形成药物共晶。AP-Nico的溶解度比原料药AP高3倍，累积释放率为71%。荧光光谱结果表明，AP-Nico药物共晶以氢键相互作用为主要作用力与HSA分子内部的Sudlow位点I结合。HSA的Sudlow位点I与AP-Nico共轭解释了计算机模拟中HSA的构象变化。本研究为合成黄酮类药物共晶以提高溶解度、探索相互作用机制并了解其体内传递机制提供了有益的参考。
