Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, China.
Int J Pharm. 2021 May 15;601:120503. doi: 10.1016/j.ijpharm.2021.120503. Epub 2021 Mar 19.
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, C 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 (ΔνCH = 1.00 cm), Raman spectra (ΔI/I = 0.32) and the DSC (ΔT = 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 and Δ Amide II = 3.38 cm). 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.
本工作旨在研究手性氟比洛芬的皮肤渗透特性，并阐明其对映体经皮渗透差异的分子机制。通过扩散池研究了对映体通过大鼠皮肤的体外经皮渗透。测定了模型手性药物的物理化学参数。通过傅里叶变换红外光谱（FTIR）、C 核磁共振（C NMR）和分子对接研究了手性氟比洛芬与皮肤神经酰胺的分子相互作用。采用衰减全反射傅里叶变换红外光谱（ATR-FTIR）、拉曼光谱、差示扫描量热法（DSC）和分子动力学模拟等方法对手性药物的皮肤渗透机制进行了表征。结果表明，（S）-氟比洛芬的渗透量和滞留量是（R）-氟比洛芬的 1.5 倍。并且证明这种差异不是由物理化学性质引起的，而是药物-皮肤成分之间的分子相互作用所致。（S）-氟比洛芬由于其立体构型，容易与皮肤脂质的-CONH 基团形成更强的氢键，根据 ATR-FTIR（ΔνCH=1.00 cm）、拉曼光谱（ΔI/I=0.32）和 DSC（ΔT=11.75°C）的结果，更容易扰乱脂质排列。ATR-FTIR 研究表明，它对角蛋白的二级结构有更明显的影响（Δ酰胺 I=3.60 cm 和 Δ酰胺 II=3.38 cm）。通过热力学分析定量证实了（S）-氟比洛芬与脂质之间更好的相容性。总之，（S）-氟比洛芬与皮肤成分之间的相互作用越强，皮肤渗透越高，有助于减少给药剂量，提高治疗效果。
