| Skin drug delivery remains to be challenging due to the excellent barrier posed by stratum corneum.In order to improve skin drug absorption,penetration enhancers(PEs)have been widely employed in skin delivery for a long time because of their easy formulation,simplicity in application.The good correlation between skin permeability to hydrophilic permeant and skin barrier integrity was found in the presence of diverse chemical PEs(CPEs).However,it has rarely been investigated whether or not such skin permeability-barrier integrity correlations can hold true for physical PEs or peptide PEs.Further,the skin drug delivery is a complicated process,involving not only the drug delivery across the skin but also the drug accumulation in different desired skin layers.The correlations between skin barrier integrity and the skin drug distribution,including the drug deposition in stratum cormeun(SC),in viable epidermis(VE)and in dermis(D),have not been studied in the presence of different types of PEs and their combinations.In this study,we investigated the impact on the skin barrier integrity of different type of PEs,including chemical PEs(1%SDS,30%Ethanol,10%Tween 80),physical PE(sponge Haliclona sp.Spicules,SHS),or peptide PE(5%SPACE peptide,ACTGSTQHQ-CG with a disulfide bridge 2-10).We studied the impact of these PEs and PE combinations on the skin barrier integrity,and the distribution profiles of two hydrophilic model drugs,Fluorescein sodium(FNa,MW=3 76.27 Da)and Fluorescein isothiocyanate-dextrans 10(FD-10K,MW=10 KDa).For the first time,We studied the corrections between skin barrier integrity and total skin absorption/deposition in different skin layers.The results indicated that:1.The impact of different PEs on the skin barrier integrity decreased in the following order:SHS01>>SDS1>ET30>TW10>SP5≈ PBS.These PE combinations did not lead to a synergistic effect on the integrity of skin barrier.2.The drug deposition in different skin layers was not only dependent on PE applied but also its own molecular weight.Two excellent correlations here were found:one(R2=0.9388)between skin barrier integrity and total skin absorption of FNa,andanother one(R2=0.9212)between skin barrier integrity and the deposition of FNa in dermis and receptor in presence of chemical or physical PEs and their combinations.However,such correlations did not hold true for either large hydrophilic drugs such as FD-10K or peptide PE.Meanwhile,we evaluated the effect of PE combination-SHS and SPACE peptide on the skin delivery of lidocaine hydrochloride(LH).The following conclusions were obtained:1.The results of in vitro experiments indicated that SHS combined with SPACE could reduce anaesthetic onset time significantly.The permeation of LH induced by combination at 0.5 h was equal as control group at 2 h(0.34±0.11μg/cm2 compared with 0.37 ± 0.02μg/cm2,p>0.05),which was significant for clinical treatment.The results of the LH deposition at 24 hours showed that SHS could enhanced the delivery of LH(p<0.05).The sustained-release effect of SPACE could not be seen obviously.There was no interaction between SPACE and LH in the mass spectrometry analysis2.SHS could reduce the onset time of lidocaine hydrochloride significantly in tailflick test.We have a tendency to find the local anesthetic that can band with SPACE and to evaluate the effect of SHS and SPACE on the delivery of local anesthetic.Above all,These findings provide insights into the rational design of a suitable PE or PE combination to enhance skin delivery of hydrophilic drugs,especially small hydrophilic ones.Also SHS combined with SPACE could be an effective way for skin delivery of local anesthetics. |
