An investigation on percutaneous permeation of flurbiprofen enantiomers: The role of molecular interaction between drug and skin components

This work aimed to investigate skin permeation profiles of chiral flurbiprofen and clarify the molecular mechanism of transdermal permeation difference of enantiomers. The in vitro transdermal permeation of enantiomers through rat skin was studied by diffusion cells. Physicochemical parameters of model chiral drugs were determined. Molecular interaction between chiral flurbiprofen and ceramides of skin was investigated by FTIR, 13C NMR and molecular docking. The skin permeation mechanism of chiral drugs was characterized by ATR-FTIR, Raman spectra, DSC and molecular dynamic simulation. The results showed that the amount of the permeation and retention amount of (S)-flurbiprofen was 1.5 times over that of (R)-flurbiprofen. And it was proven that the difference was not induced by physicochemical properties but the molecular interaction between drug-skin components. (S)-flurbiprofen was easy to form stronger hydrogen bonding with –CONH group of skin lipids due to its steric configuration, which disturbed lipids arrangement more easily according to the results of ATR-FTIR (ΔνasCH2 = 1.00 cm−1), Raman spectra (ΔI2882/I2853 = 0.32) and the DSC (ΔTm stratum corneum = 11.75 °C). It was demonstrated more obvious effect on the second structure of keratin by ATR-FTIR study (Δ Amide I = 3.60 cm−1 and Δ Amide II = 3.38 cm−1). Better compatibility between (S)-flurbiprofen and lipids was confirmed quantificationally by thermodynamic analysis. In conclusion, the higher interaction between (S)-flurbiprofen and skin components, the higher skin permeation, which contributes to decrease the administration dose and increase the therapeutic effect.