Investigation of the enhancement effect of the natural transdermal permeation enhancers from Ledum palustre L. var. angustum N. Busch: Mechanistic insight based on interaction among drug, enhancers and skin.

It has been reported that natural transdermal permeation enhancers (TPEs) are superior in safety compared with synthetic TPEs. The essential oil (EO) of Ledum palustre L. var. angustum N. Busch had a strong enhancement effect on drug skin permeation based on previous studies. However, their enhancement mechanisms and safety were still unclear. The composition of the EO was determined using GC-MS. By using donepezil (DNP) as a model drug, the enhancement effect of the constituents of the EO and the EO were evaluated by in vitro skin permeation test. Confocal laser scanning microscopy (CLSM), attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) and molecular docking were used to investigate the interaction among drug, enhancers and skin. Skin retention amount, apparent partition coefficient (K') and molecular simulation were used to reflect the effect of the enhancers on drug partition into skin. The skin irritation potential was evaluated using in vivo skin erythema analysis. The results showed that the main constituents of the EO were sabinene (SA), 4-terpineol (TE), p-cymene (CY) and cuminaldehyde (CU). CU was the main active constituent of the EO, which facilitated skin permeation of DNP. CU improved the skin permeation of DNP by increasing the mobility of the stratum corneum (SC) intercellular lipids, decreasing the interaction between DNP and the SC intercellular lipids, and improving the partition of DNP into the SC layer. Besides the superior enhancement effect, CU also showed a lower skin irritation potential compared with the EO. This work gave us some enlightenment that the effectiveness and safety of the natural transdermal permeation enhancers could be improved by understanding their composition and the enhancement mechanisms.