Skin Barrier Research Group, Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
Department of Biochemical Sciences, Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 50005, Hradec Králové, Czech Republic.
Sci Rep. 2022 Nov 14;12(1):19495. doi: 10.1038/s41598-022-24108-6.
Overcoming the skin barrier properties efficiently, temporarily, and safely for successful transdermal drug delivery remains a challenge. We synthesized three series of potential skin permeation enhancers derived from natural amino acid derivatives proline, 4-hydroxyproline, and pyrrolidone carboxylic acid, which is a component of natural moisturizing factor. Permeation studies using in vitro human skin identified dodecyl prolinates with N-acetyl, propionyl, and butyryl chains (Pro2, Pro3, and Pro4, respectively) as potent enhancers for model drugs theophylline and diclofenac. The proline derivatives were generally more active than 4-hydroxyprolines and pyrrolidone carboxylic acid derivatives. Pro2-4 had acceptable in vitro toxicities on 3T3 fibroblast and HaCaT cell lines with IC values in tens of µM. Infrared spectroscopy using the human stratum corneum revealed that these enhancers preferentially interacted with the skin barrier lipids and decreased the overall chain order without causing lipid extraction, while their effects on the stratum corneum protein structures were negligible. The impacts of Pro3 and Pro4 on an in vitro transepidermal water loss and skin electrical impedance were fully reversible. Thus, proline derivatives Pro3 and Pro4 have an advantageous combination of high enhancing potency, low cellular toxicity, and reversible action, which is important for their potential in vivo use as the skin barrier would quickly recover after the drug/enhancer administration is terminated.
有效地、暂时地和安全地克服皮肤屏障特性，以实现成功的经皮药物传递仍然是一个挑战。我们合成了三系列源自天然氨基酸脯氨酸、4-羟脯氨酸和吡咯烷酮羧酸（天然保湿因子的组成部分）的潜在透皮促进剂。使用体外人皮研究鉴定出具有 N-乙酰基、丙酰基和丁酰基链的十二烷基脯氨酸（Pro2、Pro3 和 Pro4）作为茶碱和双氯芬酸等模型药物的有效促进剂。脯氨酸衍生物通常比 4-羟脯氨酸和吡咯烷酮羧酸衍生物更活跃。Pro2-4 在 3T3 成纤维细胞和 HaCaT 细胞系上的体外毒性可接受，IC 值为数十µM。使用人体角质层的红外光谱表明，这些促进剂优先与皮肤屏障脂质相互作用，降低整体链序而不会引起脂质提取，而它们对角质层蛋白结构的影响可以忽略不计。Pro3 和 Pro4 对体外经皮水分损失和皮肤电导率的影响是完全可逆的。因此，脯氨酸衍生物 Pro3 和 Pro4 具有高增强效力、低细胞毒性和可逆作用的有利组合，这对于它们作为皮肤屏障的潜在体内应用很重要，因为在药物/促进剂给药结束后，皮肤屏障会迅速恢复。
