The enhancing effect and promoting mechanisms of the stereoisomeric monoterpene alcohol esters as enhancers for drugs with different physicochemical properties  

作　　者：Heping Wang Yan Li Chunyan Wang Jing Wang Bo Ren Xiaona Li Mingzhu Li Dandan Geng Chensi Wu Ligang Zhao 

机构地区：[1]School of Pharmacy,North China University of Science and Technology,Tangshan 063000,China [2]Dept of Pharmacy,Tangshan Maternal and Child Health Hospital,Tangshan 063000,China [3]Tangshan key laboratory of novel preparations and drug release technology,Tangshan 063000,China

出　　处：《Asian Journal of Pharmaceutical Sciences》2022年第1期139-152,共14页亚洲药物制剂科学（英文）

基　　金：The Natural Science Foundation of Hebei Province [grant numbers H2019209254];North China University of Science and Technology Foundation for Distinguished Young Scholars[grant numbers JQ201713];Distinguished Young Scholars of Hebei Province。

摘　　要：To explore the structure-activity connections of amphiphilic permeation enhancers containing the length of the hydrophobic chains as well as the properties of the polar head,O-acylgeraniol and O-acylnerol derivatives were synthesized from geraniol/nerol(cis-isomer of geraniol) and pharmaceutical excipient acids in this research. Their promotion of the percutaneous absorption of three drugs as the model, flurbiprofen(FP), isosorbide dinitrate(ISDN) and donepezil(DNP), which were selected based on their physicochemical properties,was tested by in vitro skin penetration and in vivo. Molecular simulation, ATR-FTIR, CLSM and histological observation were implement to evaluate the mode of action of the enhancers.The results indicated that(E)-3,7-dimethyl-2,6-octadien-1-yl tetradecanoate(GER-C14, trans-)achieved the highest enhancement ability for the three drugs;additionally, the in vivo results obtained were in good correlation with the in vitro data. Molecular docking results suggested that enhancers loosen the hydrogen bonds between ceramides, and the results of molecular simulation indicated that GER-C14, NER-C14 could insert into the middle of the lipid bilayer to form an independent phase. According to ATR-FTIR and histological evaluation, the enhancers extracted lipids and influenced the protein region, thereby disturbing the skin array. In addition, CLSM described the dynamic effects of enhancers on lipids between stratum corneum(SC) cells. In conclusion, GER-C14 had a better penetration promotion effect, which broadened our understanding of stereoisomeric penetration enhancers.

关 键 词：O-acylgeraniol derivatives O-acylnerol derivatives Transdermal drug delivery system In vitro and in vivo correlation Enhancing mechanism 

分 类 号：R943[医药卫生—药剂学]