School of Pharmacy, Keck Graduate Institute, Claremont, CA 91711, United States.
College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States.
Carbohydr Polym. 2019 Jan 15;204:68-77. doi: 10.1016/j.carbpol.2018.09.080. Epub 2018 Oct 4.
Cyclodextrin complex of nintedanib was prepared aiming for increased bio-activity and improved transport across intestinal membrane with reduced p-glycoprotein (p-gp) efflux. Based on preliminary phase solubility studies and molecular modeling, sulfobutyl ether derivative of β-cyclodextrin (SBE-β-CD, Captisol) was selected to prepare inclusion complex. Complexation was confirmed using FTIR, 1H NMR, DSC, and XRD. Bioactivity of the formed complex was tested using lung fibroblast cells, WI-38 for anti-proliferative activity and effect on collagen deposition and cells migration. In-vitro permeability studies were performed using epiIntestinal tissue model to assess the effect of complexation on transport and p-gp efflux. Results of the study demonstrated that cyclodextrin complexation increased stability of nintedanib in PBS (pH 7.4) and simulated intestinal fluid (SIF). Further, bioactivity of nintedanib also improved. Interestingly, complexation has increased transport of nintedanib across intestinal membrane and reduced efflux ratio, suggesting the role of cyclodextrin complexation in modulating p-gp efflux.
为了提高生物活性和改善跨肠细胞膜的转运，同时减少 P-糖蛋白（p-gp）外排，制备了尼达尼布的环糊精包合物。基于初步的相溶解度研究和分子建模，选择磺丁基醚-β-环糊精（SBE-β-CD，卡泊三醇）作为制备包合物的辅料。使用傅里叶变换红外光谱（FTIR）、1H NMR、差示扫描量热法（DSC）和 X 射线衍射（XRD）确认了包合物的形成。使用肺成纤维细胞 WI-38 评估了形成的复合物的抗增殖活性和对胶原蛋白沉积和细胞迁移的影响，以测试其生物活性。使用 EpiIntestinal 组织模型进行了体外渗透研究，以评估复合物对转运和 p-gp 外排的影响。研究结果表明，环糊精包合增加了尼达尼布在 PBS（pH7.4）和模拟肠液（SIF）中的稳定性。此外，尼达尼布的生物活性也得到了提高。有趣的是，复合物增加了尼达尼布在肠膜上的转运并降低了外排比，表明环糊精复合物在调节 p-gp 外排方面发挥了作用。
