The Construction And Penetration Evaluation Of Chiral 4-O-acylterpineol Derivatives As Novel Percutaneous Absorption Enhancers

Objectives The transdermal drug delivery system(TDDS)is a new type of drug delivery.The stratum corneum of the skin is the major biggest barrier limiting the effectiveness of the drug.Therefore,increasing the amount of drug permeation is of great significance for the development of transdermal dosage forms.The present study is to investigate the influence of d-4-O-aclyterpineol and l-4-O-aclyterpineol on transdermal delivery of SR-FP and its enantiomers both in vitro and in vivo to confirm its potential for clinical application.Methods 4-O-acylterpineol derivatives which were expected to enzymatically hydrolyzed into nontoxic metabolites by esterase in the living epidermis were synthesized from 4-terpineol(4-TER)enantiomers and straight chain fatty acids.Their promoting activity on the percutaneous absorption of flurbiprofen(FP)including SR-FP,S-FP,R-FP was tested in vitro across full thickness rabbit skin,as well as to investigated the skin irritation of enhancers by in vivo histological evaluation.Then FP enantiomer pharmacokinetic parameters were determined after intravenous administration and topical application of patches with the better promoting enhancers in rabbits.A deconvolution approach was employed to analyze the correlation between the in vitro and in vivo drug permeation.Attenuated total reflection-Fourier transform infrared spectroscopy(ATRFTIR),molecular simulation and FP release experiment were introduced to investigate the mechanism of enhancers in the skin permeability.Results Both in vitro and in vivo permeation studies indicated that some newly designed 4-O-acylterpineol derivatives had significant enhancing effect on the transdermal delivery of SR-FP and its enantiomers.The correlation coefficient indicated excellent correlation(r>0.8783).By comparison,l-4-T-d C18 had the most significant enhancing effect,and the attained Q24 h was 547.20±35.94 ?g/cm2,increasing the SR-FP in Q24 h by 4.45-fold.Additionally,d-4-O-aclyterpineol had higher enhancing effects than l-4-O-aclyterpineol,only l-4-T-d C18 has stronger penetration promoting activity than d-4-T-d C18.l-4-T-d C18 produced a relatively low skin irritation,compared with the 4-TER which was assumed to be a safe compound.The in vitro release experiment indicated chemical enhancers which could facilitate the permeant release from the patch played an important role in penetration process.Molecular simulation revealed that 4-Oacylterpineol could decrease the order of the alkyl chains in the skin lipids and facilitate the drug penetration across the skin.ATR-FTIR indicate that increased transdermal flux of FP by enhancers correlate with increased SC lipid mobility,the hydration of OH,and the SC protein interaction caused by exposure to 4-O-acylterpineol.Conclusions From the results of present investigations,chiral 4-O-acylterpineol significantly promoted the percutaneous permeation of SR-FP and its enantiomers both in vitro and in vivo,additionally l-4-T-d C18 was shown to be the most promising enhancer for increasing the transdermal amount of SR-FP and its enantiomers,with the superiorities of high flux and low skin irritation.Figure 12;Table 13;Reference 105...