Investigation On Enhancing Kinetics Of Amphiphilic Transdermal Permeation Enhancers

Purpose:Transdermal drug delivery system(TDDS)is designed to deliver an effective dose of drug through the skin and into the bloodstream for the topical or systemic therapeutic and preventive purpose.Transdermal permeation enhancers are usually used for facilitating the skin permeation of drugs.The effectiveness and duration of transdermal preparations are directly affected by the enhancement effect of chemical enhancers.However,there is still a lack of knowledge about how the enhancement effect changes over time.The purpose of this work is to explore the dynamic enhancement process of enhancers,to clarify the relationship between the changes of drug release and interaction,and to explore the molecular mechanism of the dynamic enhancement effect on the skin and the dynamic skin irritation of enhancers.Method:Using drug release study,the effect of Azone and menthyl esters on the drug release were investigated,and the interaction among drug,pressure sensitive adhesive and enhancers was explored by FTIR,molecular docking and rheology study.The enhancement effect on the skin of Azone(AZ)and menthyl decanoate(MT-10)was evaluated with in vitro-permeation experiment and further confirmed by confocal laser scanning microscopy(CLSM).Based on the kinetic parameters(ERmax,Tmax and Teff),the molecular mechanism of enhancement effect was explored with ATR-FTIR,skin retention and molecular dynamic simulation.Moreover,dynamic skin irritation was evaluated by TEWL and erythema index analysis.Finally,the enhancing kinetics was verified and further discussed with in vivo drug pharmacokinetics study.Results:Drug release kinetic constant was enhanced by AZ and MT-10.The stronger the binding between enhancers and drug was,the higher the release amount ratio was.The enhancement effect of AZ and MT-10 on the skin permeability of drug included three periods,an increase,a plateau and a decline.The dynamic enhancement effect was caused by the variation of the diffusion coefficient of intercellular lipid in the stratum corneum(SC),which was dependent on the affinity between enhancers and lipid.Moreover,the skin barrier function recovered although a large amount of enhancers still existed in the SC.The dynamic effect of AZ on the skin protein induced skin irritation.Enhancing kinetics of MT-10 in vivo was also consisted of an increase,a plateau and a decline.Conclusion:Drug release kinetics were enhanced by amphiphilic enhancers through the disturbance of the interaction between drug and pressure sensitive adhesive.Dynamic enhancement effect on the skin permeability of drug was caused by the dynamic effect on the SC intercellular lipid,and the skin barrier function recovered by accepting the enhancer as a new component of the lipid bilayer.Both of in vitro and in vivo study verified the existence of enhancing kinetics of transdermal permeation enhancers.The research proposed a novel hypothesis about skin barrier function recovery,provided kinetic parameters for the evaluation of enhancing kinetics and provided more comprehensive understanding about the mechanism of transdermal penetration enhancers.