Tianjin Key Laboratory of Drug Delivery and High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, 300072 Tianjin, PR China.
Int J Pharm. 2011 Aug 30;415(1-2):169-74. doi: 10.1016/j.ijpharm.2011.05.069. Epub 2011 Jun 12.
The objective of this study was to investigate the percutaneous absorption of metronidazole (MTZ) in the topical formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol. Six formulations were studied in an in vitro hairless mouse skin model using Franz Diffusion Cell. MTZ was applied at infinite doses (50mg and 100mg of the formulations, which correspond to 375 and 750 μg of MTZ, respectively). Based on the flux values and retardation ratio (RR), a synergistic retardation effect on percutaneous absorption of MTZ was observed for the formulations containing a combination of 1,4-cyclohexanediol and 1,2-hexanediol (RRs are 0.40 for 375 μg dose and 0.69 for 750 μg dose, respectively). Interestingly, retention of MTZ in epidermis and dermis layer showed no significant differences (p>0.05) between the formulations containing the retardant combination and control formulations. In other words, the retardant combination in the formulation decreases MTZ fluxes while maintaining similar level of retention in epidermis and dermis layer when compared to the control formulations. These observations provide insight in formulating superior topical formulations with minimized potential systematic toxicity while maintaining therapeutic efficiency. A mechanistic explanation of the observed synergistic effect is proposed.
本研究旨在考察包含 1,4-环己二醇和 1,2-己二醇组合的局部制剂中甲硝唑（MTZ）的经皮吸收情况。在使用 Franz 扩散池的无毛小鼠皮肤模型中，研究了 6 种制剂。将 MTZ 以无限剂量（制剂的 50mg 和 100mg，分别相当于 MTZ 的 375 和 750μg）应用。基于通量值和阻滞比（RR），观察到包含 1,4-环己二醇和 1,2-己二醇组合的制剂对 MTZ 经皮吸收具有协同阻滞作用（RR 分别为 375μg 剂量时为 0.40，750μg 剂量时为 0.69）。有趣的是，在表皮和真皮层中 MTZ 的保留率在含有阻滞剂组合的制剂和对照制剂之间没有显著差异（p>0.05）。换句话说，与对照制剂相比，制剂中的阻滞组合降低了 MTZ 的通量，同时在表皮和真皮层中保持了相似的保留水平。这些观察结果为开发具有最小系统毒性潜在风险的改良局部制剂提供了思路，同时保持了治疗效率。提出了对观察到的协同作用的机制解释。
