Cilurzo Francesco, Vistoli Giulio, Selmin Francesca, Gennari Chiara G M, Musazzi Umberto M, Franzé Silvia, Lo Monte Matteo, Minghetti Paola
Department of Pharmaceutical Sciences, Università degli Studi di Milano , via G. Colombo, 71 20133 Milan, Italy.
Mol Pharm. 2014 Mar 3;11(3):1014-21. doi: 10.1021/mp400675d. Epub 2014 Jan 30.
This work aims to elucidate the mechanism by which N-methylpyrrolidone (NMP) enhances the skin permeation of a compound by combining experimental data with molecular dynamic (MD) simulations. The addition of 10% NMP significantly increased the propranolol (PR) permeation through the human epidermis (∼ 15 μg/cm(2) vs ∼ 30 μg/cm(2)) while resulting inefficacious on hydrocortisone (HC) diffusion. No significant alterations in the stratum corneum structure were found after the in vitro treatment of human epidermis with NMP dispersed in mineral oil or water by attenuated total reflectance Fourier transform infrared (ATR-FTIR) analyses. MD simulations revealed the formation of a complex by H-bonds and the π-π stacking interactions between the NMP's amido group and the drug's aromatic systems. The size of the depicted NMP/PR clusters was in line with the hydrodynamic radius derived by dynamic light scattering analyses (∼ 2.00 nm). Conversely, no interaction, and consequently cluster formation, between NMP and HC occurred. These results suggest that NMP is effective in enhancing the drug permeation through human epidermis by a cotransport mechanism when NMP/drug interaction occurs.
本研究旨在通过将实验数据与分子动力学（MD）模拟相结合，阐明N-甲基吡咯烷酮（NMP）增强化合物皮肤渗透性的机制。添加10%的NMP可显著增加普萘洛尔（PR）透过人表皮的渗透率（约15μg/cm²对约30μg/cm²），而对氢化可的松（HC）的扩散无效。通过衰减全反射傅里叶变换红外光谱（ATR-FTIR）分析，用分散在矿物油或水中的NMP对人表皮进行体外处理后，未发现角质层结构有明显变化。MD模拟揭示了NMP的酰胺基团与药物的芳香体系之间通过氢键和π-π堆积相互作用形成了复合物。所描绘的NMP/PR簇的大小与动态光散射分析得出的流体动力学半径一致（约2.00nm）。相反，NMP与HC之间未发生相互作用，因此也未形成簇。这些结果表明，当NMP/药物相互作用发生时，NMP通过共转运机制有效增强药物透过人表皮的渗透率。
