Research On The Penetration-enhancing Effects Of Chiral O-acylmenthol To The Chiral Drugs And Its Mechanisms

Objectives Transdermal drug delivery system(TDDS)is designed to effectively delivery the active pharmaceutical ingredient via the skin into the systemic circulation.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 d-menthol and different fatty acid and the structures were confirmed by ~1HNMR and MS.S-Metoprolol(S-META),R-Metoprolol(R-META),S-flubiprofen(S-FP)and R-flubiprofen(R-FP)were selected as the model drugs and chiral O-acylmenthol 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.To investigate the permeation mechanism of chiral O-acylmenthol ester derivatives,morphological changes in the stratum corneum were observed by a confocal laser scanning microscopy(LSCM),and attenuated total reflectance Fourier transform infared(ATR-FTIR).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,l-M-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 by ~1HNMR and MS.2 Part of O-acylmenthol ester derivatives had a significant increase in accumulation amount of S-FP,R-FP,S-META and R-META compared with control in IPM and adhesive patches.d-M-TET produced the highest increase of accumulation of S-FP,R-FP and l-M-DEC provided the highest increase of accumulation of S-META,R-META in the receptor phase.Chiral O-acylmenthol ester derivatives resulted in significantly higher permeation enhancing effect on S-FP than on R-FP.3 The ATR-FTIR experiments revealed that the chiral O-acylmenthol ester derivatives could significantly decrease the order of the alkyl chains in the skin lipids and the LSCM experiments demonstrated that the chiral O-acylmenthol ester derivatives have significant promoting effect on the drug permeation through the skin.4 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 penetration enhancers had the optimal length of hydrophobic chain and concentration,to the S-FP and R-FP 3%(w/w)d-M-TET(14 tail chain length)was most effective and for S-META and R-MET,5%(w/w)l-M-DEC(10 tail chain length)was most effective.The enantioselective enhancing effect of chiral O-acylmenthol ester derivatives on S-FP and R-FP was attributed to sterespecific interactions among chiral drug,chiral enhancers or keratin or ceramides in stratum corneum.The ATR-FTIR and LSCM experiments both demonstrated that the chiral O-acylmenthol ester derivatives have significant promoting effect on the drug permeation through the skin.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.