School of Pharmacy , Shenyang Pharmaceutical University , 103 Wenhua Road , Shenyang 110016 , China.
Department of Pharmaceutical Sciences , Beijing Institute of Radiation Medicine , 27 Taiping Road , Beijing 100850 , China.
Mol Pharm. 2018 Aug 6;15(8):3121-3132. doi: 10.1021/acs.molpharmaceut.8b00209. Epub 2018 Jul 24.
Transdermal delivery is one of important controlled drug release strategies for drug development. Cubic phases are the assemblies of amphiphilic molecules in water with the hydrophilic-hydrophobic interpenetrating network for transdermal delivery of both hydrophilic and hydrophobic drugs. However, many details about the transdermal delivery of drugs from cubic phases remain unclear. Here, metformin hydrochloride (Met) cubic phases were prepared with glyceryl monooleate (GMO), ethanol, and water. The cubic structure was identified with the polarizing light microscopy and small-angle X-ray scattering method. Dissipative particle dynamics (DPD) was used for building the microstructures of the cubic phases to explore the mechanism of drug release that mainly depended on drug diffusion from the water channels of cubic phases in accordance with the Higuchi equation of in vitro release experiments. The coarse-grained model and molecular docking method showed that GMO could enhance drug permeation through the skin by disturbing the interaction between Met and the skin proteins, and increasing the fluidity of skin lipids, which was confirmed with the Fourier transform infrared spectroscopy, Langmuir monolayer, and immunohistochemistry. Furthermore, in vitro permeation experiments showed the high Met transdermal improvement of cubic phases. Cubic phases are an ideal transdermal delivery system of Met. In silico methods are very useful for analyzing the molecular mechanisms of transdermal formulations.
经皮给药是药物开发中重要的控制药物释放策略之一。立方相是两亲分子在水中的组装体，具有亲水-疏水相互贯穿的网络，可用于经皮递亲水和疏水药物。然而，关于药物从立方相向皮肤的经皮传递的许多细节仍不清楚。本文采用甘油脂单油酸酯（GMO）、乙醇和水制备盐酸二甲双胍（Met）立方相。用偏光显微镜和小角 X 射线散射法确定立方结构。耗散粒子动力学（DPD）用于构建立方相的微观结构，以探索药物释放的机制，主要依赖于根据体外释放实验的 Higuchi 方程从立方相的水通道中扩散药物。粗粒模型和分子对接方法表明，GMO 可以通过干扰 Met 与皮肤蛋白之间的相互作用以及增加皮肤脂质的流动性来增强药物透过皮肤的渗透，傅里叶变换红外光谱、Langmuir 单层和免疫组织化学证实了这一点。此外，体外渗透实验表明，立方相具有很高的 Met 经皮改善作用。立方相是 Met 理想的经皮给药系统。计算方法对于分析经皮制剂的分子机制非常有用。
