The Evaluation Of Promoting Activity Of Chiral O-acylmenthol As Novel Percutaneous Absorption Enhancers

Objectives Chemical promoting infiltration method is most widely used and one of effective methods of drug transdermal penetration,but ideal penetration enhancer is rare.The research is to develop safer,more efficient,less volatile compounds as penetration enhancers through structure transformation of l-menthol and d-menthol.Methods Chiral O-acylmenthol ester derivatives were synthesized by l-menthol or dmenthol and different fatty acid and the structures were confirmed by 1HNMR and MS.Metoprolol(META)and flubiprofen(FP)were selected as the model drugs and chiral Oacylmenthol ester derivatives applied in the drugs as penetration enhancers were evaluated in isopropy myristatel(IPM)and adhesive(DIA)patches to screen the most promsing enhanser.The screened penetration enhancers were evaluated in skin irritation respect by self-control of left andright side after single and multiple administration on the intact skin of the rabbits.Results 1 Twelve chiral O-acylmenthol ester derivatives were synthesized by l-menthol or d-menthol and different fatty acid,including l-M-OA,d-M-OA,l-M-HEP,d-M-HEP,lM-DEC,d-M-DEC,l-M-DOD,d-M-DOD,l-M-TET,d-M-TET,l-M-STE,d-M-STE,and the structures were confirmed by1 HNMR and MS.2 Part of O-acylmenthol ester derivatives had a significant increase in accumulation amount of FP and META compared with control in IPM and adhesive patches.d-M-TET produced the highest increase of accumulation of FP(2.33-fold)and l-M-DEC provided the highest increase of accumulation of META(1.83-fold)in the receptor phase in DIA.3 The skin stimulative experimental results showed that l-M-DEC and d-M-DOD aspenetration enhancers had no allergic reaction including erythema edema and others.Conclusions Chiral O-acylmenthol ester derivatives as new type penetration enhancers can promote percutaneous absorption of META and FP in IPM and DIA.Chiral Oacylmenthol ester derivatives as penetration enhancers had the optimal length of hydrophobic chain and concentration,to the FP 3%(w)d-M-TET(14 tail chain length) was most effective and for META,5%(w)l-M-DEC(10 tail chain length)was most effective.The skin stimulative experimental results showed that chiral O-acylmenthol ester derivatives(l-M-DEC and d-M-DOD)as penetration enhancers had no skin irritation.