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

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
• chemie farmaceutická MeSH
• cidofovir aplikace a dávkování   chemie   farmakokinetika   MeSH
• epidermis účinky léků   metabolismus   MeSH
• estery chemie   farmakologie   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