Oleic acid and oleyl alcohol are commonly used permeation and penetration enhancers to facilitate topical drug delivery. Here, we aimed to better understand the mechanism of their enhancing effects in terms of their interactions with the human skin barrier using diclofenac diethylamine (DIC-DEA), a nonsteroidal anti-inflammatory drug for topical pain management. Oleic acid promoted DIC-DEA permeation through ex vivo human skin more rapidly than oleyl alcohol (both applied at 0.75%) due to fluidization of stratum corneum lipids as revealed by infrared spectroscopy. After 12 h, the effect of these enhancers on DIC-DEA permeation leveled off, fluidization was no longer evident, and skin permeabilization was mainly due to the formation of fluid enhancer-rich domains. Contrary to oleyl alcohol, oleic acid adversely affected two indicators of the skin barrier integrity, transepidermal water loss and skin electrical impedance. The content of oleyl alcohol in the stratum corneum was lower than that of oleic acid (even 12 h after the enhancers were removed from the skin surface), but it caused higher DIC-DEA retention in both epidermis and dermis compared to oleic acid. The effects of oleyl alcohol and oleic acid on DIC-DEA permeation and retention in the skin were similar after a single and repeated application (4 doses every 12 h). Thus, oleyl alcohol offers several advantages over oleic acid for topical drug delivery.

• Klíčová slova
• diclofenac, infrared spectroscopy, lipid interactions, penetration enhancer, permeation enhancer, skin barrier, topical drug delivery,
• MeSH
• aplikace kožní MeSH
• kožní absorpce * MeSH
• kůže metabolismus   MeSH
• kyselina olejová * farmakologie   metabolismus   MeSH
• lidé MeSH
• mastné alkoholy metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyselina olejová * MeSH
• mastné alkoholy MeSH
• oleyl alcohol MeSH Prohlížeč

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 IC50 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.

• MeSH
• aplikace kožní MeSH
• hydroxyprolin metabolismus   MeSH
• kožní absorpce * MeSH
• kůže metabolismus   MeSH
• kyseliny karboxylové metabolismus   MeSH
• léčivé přípravky metabolismus   MeSH
• lidé MeSH
• organické látky metabolismus   MeSH
• permeabilita MeSH
• prolin * metabolismus   MeSH
• pyrrolidinony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hydroxyprolin MeSH
• kyseliny karboxylové MeSH
• léčivé přípravky MeSH
• organické látky MeSH
• prolin * MeSH
• pyrrolidinony MeSH