Sguizzato Maddalena, Agosta Federica, Ciancetta Antonella, Grassi Mario, Cortesi Rita, di Cagno Massimiliano Pio
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy.
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari, 46, 44121 Ferrara, Italy.
Int J Pharm. 2025 Feb 10;670:125170. doi: 10.1016/j.ijpharm.2025.125170. Epub 2025 Jan 3.
The use of in vitro markers able to reproduce the in vivo permeability and diffusivity of orally administered drugs, could represent an innovative starting point for the formulation of delivery systems, in particular for low soluble and low permeable drugs belonging to BCS class II and IV. Considering the great interest in the green pharmaceutical approaches and the increasing use of natural molecules as novel therapeutic drugs, in this study, rutin, hesperidin and curcumin have been selected as lipophilic model drugs to investigate their possible enhancement of their permeability and bioavailability after oral administration. As the low solubility of the three drugs hinders their application, β-cyclodextrins (CD), amphiphilic natural moieties able to form stable inclusion complexes, have been considered to promote their solubilization. Notably, hydroxypropyl-β-CD (HPBCD) and methyl-β-CD (MBCD), have been selected and the formation of the inclusion complexes with a stoichiometric ratio of 1:1 has been detected through phase-solubility studies and rationalized via docking calculations, revealing a strong complexation and an increased hydrophilicity of the systems. The diffusion experiments performed through the novel UV-Vis localized spectroscopy method confirmed a the extremely high stability of the CD-drugs complexes, especially in the cease of curcumin, which makes this as the predominant chemical specie to diffuse and permeates. The PermeaPad® plate, an in vitro cell-free assay, allowed to investigate the permeability behavior of the drugs, demonstrated that the type of β-cyclodextrins can influence the permeability through the biomimetic membrane, reflecting the effect of the unstirred water layer (UWL). Moreover, in the case of curcumin, the spectroscopic-mathematical approach suggested the formation of nano-supramolecular systems, detected by DLS, supporting the precision of the fitting model.
使用能够重现口服药物体内渗透性和扩散性的体外标志物，可为给药系统的制剂研发提供创新起点，特别是对于属于BCS II类和IV类的低溶解性和低渗透性药物。考虑到绿色制药方法备受关注以及天然分子作为新型治疗药物的使用日益增加，本研究选择芦丁、橙皮苷和姜黄素作为亲脂性模型药物，以研究口服给药后它们的渗透性和生物利用度可能的提高情况。由于这三种药物的低溶解性阻碍了它们的应用，β-环糊精（CD），一种能够形成稳定包合物的两亲性天然部分，已被考虑用于促进它们的溶解。值得注意的是，已选择羟丙基-β-环糊精（HPBCD）和甲基-β-环糊精（MBCD），并通过相溶解度研究检测到了化学计量比为1:1的包合物的形成，并通过对接计算进行了合理化分析，揭示了系统的强络合作用和增加的亲水性。通过新型紫外-可见局部光谱法进行的扩散实验证实了CD-药物络合物具有极高的稳定性，特别是对于姜黄素而言，这使得它成为扩散和渗透的主要化学物种。PermeaPad®板，一种无细胞体外测定法，可用于研究药物的渗透行为，结果表明β-环糊精的类型可影响通过仿生膜的渗透性，反映了未搅拌水层（UWL）的作用。此外，对于姜黄素，光谱-数学方法表明形成了纳米超分子体系，通过动态光散射（DLS）检测到，支持了拟合模型的准确性。
