Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Palackeho 1946/1, 612 42 Brno, Czech Republic.
Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic.
Molecules. 2019 Feb 4;24(3):566. doi: 10.3390/molecules24030566.
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. ()-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig ( f. ) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (/) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3,6)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
（-）-8-甲基-6,9-二氮杂螺[4.5]癸-7,10-二酮（阿普肽）已被研究作为一种有潜力的化学渗透增强剂。基于其结构，通过多步合成途径合成了四个选定的哌嗪-2,5-二酮。所有化合物均考察了其从亲水性介质丙二醇：水（1：1）中增强模型药物茶碱渗透的能力。在恒定温度 34 ± 0.5°C 下使用垂直 Franz 扩散池进行体外实验，并使用全厚猪（f.）耳皮。用 RP-HPLC 分析取出的样品，以测定茶碱的渗透量。所有化合物的应用比例为 1:10（/）相对于茶碱的量。应用 1 小时后，阿普肽和（3,6）-3,6-二甲基哌嗪-2,5-二酮的制剂中茶碱的渗透量分别约为无测试化合物制剂的 15-和 12 倍。尽管两种增强剂在稳定状态下的增强比约为 2.3，但在 1 至 3 小时的时间范围内的伪增强比为 4.4。这些增强比表明这些化合物能够增强药物通过皮肤的渗透；然而，两种化合物制剂的短期应用似乎更有利。此外，使用三种细胞系对所有制备化合物的细胞毒性进行了筛选，结果表明这些化合物没有显示出任何显著的毒性作用。
