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

Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers' mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10-14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.

• Klíčová slova
• dermal and transdermal drug delivery, morpholine derivatives, skin barrier, skin permeation enhancers,
• Publikační typ
• časopisecké články MeSH

Disrupted skin barrier, one of the severe attributes of inflammatory skin diseases, is caused by lower content and pathological changes of lipids in the uppermost skin layer-stratum corneum (SC). Restoring skin barrier with native skin lipids, especially ceramides (Cers), appears to be a promising therapy with minimum side effects. For testing the efficiency of these formulations, suitable in vitro models of the skin with disrupted barriers are needed. For the similarity with the human tissue, our models were based on the pig ear skin. Three different ways of skin barrier disruption were tested and compared: tape stripping, lipid extraction with organic solvents, and barrier disruption by sodium lauryl sulfate. The level of barrier disruption was investigated by permeation studies, and parameters of each method were modified to reach significant changes between the non-disrupted skin and our model. Fourier transform infrared (FTIR) spectroscopy was employed to elucidate the changes of the skin permeability on the molecular scale. Further, the potential of the developed models to be restored by skin barrier repairing agents was evaluated by the same techniques. We observed a significant decrease in permeation characteristics through our in vitro models treated with the lipid mixtures compared to the untreated damaged skin, which implied that the skin barrier was substantially restored. Taken together, the results suggest that our in vitro models are suitable for the screening of potential barrier repairing agents.

• Klíčová slova
• FTIR spectroscopy, ceramides, liposomes, permeation experiment, skin barrier disruption models, stratum corneum lipids, topical treatment,
• MeSH
• ceramidy * MeSH
• epidermis MeSH
• kůže * MeSH
• lipidy MeSH
• permeabilita MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ceramidy * MeSH
• lipidy MeSH

Skin penetration/permeation enhancers are compounds that improve (trans)dermal drug delivery. We designed hybrid terpene-amino acid enhancers by conjugating natural terpenes (citronellol, geraniol, nerol, farnesol, linalool, perillyl alcohol, menthol, borneol, carveol) or cinnamyl alcohol with 6-(dimethylamino)hexanoic acid through a biodegradable ester linker. The compounds were screened for their ability to increase the delivery of theophylline and hydrocortisone through and into human skin ex vivo. The citronellyl, bornyl and cinnamyl esters showed exceptional permeation-enhancing properties (enhancement ratios up to 82) while having low cellular toxicities. The barrier function of enhancer-treated skin (assessed by transepidermal water loss and electrical impedance) recovered within 24 h. Infrared spectroscopy suggested that these esters fluidized the stratum corneum lipids. Furthermore, the citronellyl ester increased the epidermal concentration of topically applied cidofovir, which is a potent antiviral and anticancer drug, by 15-fold. In conclusion, citronellyl 6-(dimethylamino)hexanoate is an outstanding enhancer with an advantageous combination of properties, which may improve the delivery of drugs that have a limited ability to cross biological barriers.

• MeSH
• alkoholy chemie   farmakologie   MeSH
• aplikace kožní MeSH
• buňky 3T3 MeSH
• cidofovir aplikace a dávkování   chemie   farmakokinetika   MeSH
• epidermis účinky léků   metabolismus   MeSH
• estery chemie   farmakologie   MeSH
• farmaceutická chemie MeSH
• farmaceutické pomocné látky chemie   farmakologie   MeSH
• hydrokortison aplikace a dávkování   chemie   farmakokinetika   MeSH
• keratinocyty MeSH
• lidé MeSH
• metabolismus lipidů účinky léků   MeSH
• monoterpeny chemie   MeSH
• myši MeSH
• permeabilita účinky léků   MeSH
• perspiratio insensibilis účinky léků   MeSH
• příprava léků metody   MeSH
• terpeny chemie   farmakologie   MeSH
• testy akutní toxicity MeSH
• theofylin aplikace a dávkování   chemie   farmakokinetika   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alkoholy MeSH
• cidofovir MeSH
• estery MeSH
• farmaceutické pomocné látky MeSH
• hydrokortison MeSH
• monoterpeny MeSH
• perillyl alcohol MeSH Prohlížeč
• terpeny MeSH
• theofylin MeSH