Construction Of 4-O-acylterpineol And Research On Its Penetrative Activity

Objectives Structural modification of 4-terpineol(TEN)the aim is to find a new penetration enhancer with significant promoting effects to flurbiprofen(FP),low irritation to skin in isopropyl myristate(IPM)system and the drug-in-adhesive(DIA)patch system,evaluation of the correlation of transdermal administration in vitro and in vivo by evaluating the penetration-promoting activity of the penetration enhancer and a preliminary exploration on the mechanism of action of the penetration enhancer.Methods The 4-O-acylterpineol derivatives was synthesized by reacting TEN with different fatty acids,and its structure was confirmed by ~1H-NMR.The in vitro permeability test was carried out with two-chamber cells and excised rabbit skin as barrier to evaluate the penetration-enhancing activity of 4-O-acylterpineol derivatives derived from model drug FP in IPM and DIA.Skin irritant and histological experiments were used to preliminarily evaluate the safety of TEN and TEN-C7.Evaluation of the in vivo permeation activity of the preferred penetration enhancers TEN-C7,IPM,IVIVC studies of flurbiprofen patches containing different penetration enhancers by deconvolution.The mechanism of action of PE was investigated by laser scanning confocal microscope(LSCM),attenuated total reflection fourier transform infrared(ATR-FTIR),and molecular simulation.Results 1 Synthesis of seven kinds of 4-O-acylterpineol derivative penetration enhancers.2 In the IPM system,mass fraction of 3%TEN equimolar concentration of TEN-C14 had the best effect on the penetration of FP;In the DIA patch system,mass fraction of 5%IPM and mass fraction of 5%TEN equimolar concentration of TEN-C7 had the best effect on the penetration of FP,and the cumulative permeation of the drug within 24 h was 3.17times and 2.92 times higher than that of the control group(P<0.05).In the group with the combination mass fraction of 5%TEN equimolar concentration of TEN-C7 and mass fraction of 5%IPM,the cumulative penetration amount of FP within 24 h was 4.61 times higher than that of the control group(P<0.05).3 Skin irritation experiments showed that TEN-C7 had no erythema and edema to rabbit skin,and had high safety performance.4IVIVC studies showed that flurbiprofen patches containing the penetration enhancer TEN has low linear correlation,the other patches showed significant linear correlation in vitro and in vivo correlation(R~2>0.8783).5 LSCM,ATR-FTIR,and Molecular modeling experiments had shown that the drug penetrated into the skin mainly through the intercellular channel of horny cells,the penetration enhancer was that compete with the drug for the polar head of the stratum corneum ceramide or reversible change of skin epidermal barrier function to increase the skin permeability.The penetration enhancer can reduce the order of the spatial arrangement of the lipid side chains to increase the skin permeability.Conclusions In this study,the synthesized 4-O-acylterpineol derivative as a penetration enhancer can reversibly change the barrier function of the stratum corneum of the skin and promote the percutaneous absorption of the drug,which has low skin irritation and significantly promote the enhancing activity,and is expected to be used as a new penetration enhancer in transdermal administration.Significant linear correlation were observed in the drug permeation between in vitro and in vivo with the different penetration enhancers of flurbiprofen patches can be used to predict in vivo behavior through in vitro transdermal experiments,thereby reducing the number of in vivo studies and reducing the cost of new drug development.Figure 16;Table 11;Reference 94...