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
• Administration, Cutaneous MeSH
• Hydroxyproline metabolism   MeSH
• Skin Absorption * MeSH
• Skin metabolism   MeSH
• Carboxylic Acids metabolism   MeSH
• Pharmaceutical Preparations metabolism   MeSH
• Humans MeSH
• Organic Chemicals metabolism   MeSH
• Permeability MeSH
• Proline * metabolism   MeSH
• Pyrrolidinones pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Hydroxyproline MeSH
• Carboxylic Acids MeSH
• Pharmaceutical Preparations MeSH
• Organic Chemicals MeSH
• Proline * MeSH
• Pyrrolidinones 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.

• Keywords
• dermal and transdermal drug delivery, morpholine derivatives, skin barrier, skin permeation enhancers,
• Publication type
• Journal Article MeSH

Ceramides (Cer) are essential components of the skin permeability barrier. To probe the role of Cer polar head groups involved in the interfacial hydrogen bonding, the N-lignoceroyl sphingosine polar head was modified by removing the hydroxyls in C-1 (1-deoxy-Cer) or C-3 positions (3-deoxy-Cer) and by N-methylation of amide group (N-Me-Cer). Multilamellar skin lipid models were prepared as equimolar mixtures of Cer, lignoceric acid and cholesterol, with 5 wt% cholesteryl sulfate. In the 1-deoxy-Cer-based models, the lipid species were separated into highly ordered domains (as found by X-ray diffraction and infrared spectroscopy) resulting in similar water loss but 4-5-fold higher permeability to model substances compared to control with natural Cer. In contrast, 3-deoxy-Cer did not change lipid chain order but promoted the formation of a well-organized structure with a 10.8 nm repeat period. Yet both lipid models comprising deoxy-Cer had similar permeabilities to all markers. N-Methylation of Cer decreased lipid chain order, led to phase separation, and improved cholesterol miscibility in the lipid membranes, resulting in 3-fold increased water loss and 10-fold increased permeability to model compounds compared to control. Thus, the C-1 and C-3 hydroxyls and amide group, which are common to all Cer subclasses, considerably affect lipid miscibility and chain order, formation of periodical nanostructures, and permeability of the skin barrier lipid models.

• MeSH
• Cell Membrane metabolism   MeSH
• Ceramides chemistry   metabolism   MeSH
• Skin metabolism   MeSH
• Membranes, Artificial * MeSH
• Permeability MeSH
• Water metabolism   MeSH
• Phase Transition MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Ceramides MeSH
• Membranes, Artificial * MeSH
• Water 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
• Alcohols chemistry   pharmacology   MeSH
• Administration, Cutaneous MeSH
• 3T3 Cells MeSH
• Cidofovir administration & dosage   chemistry   pharmacokinetics   MeSH
• Epidermis drug effects   metabolism   MeSH
• Esters chemistry   pharmacology   MeSH
• Chemistry, Pharmaceutical MeSH
• Pharmaceutic Aids chemistry   pharmacology   MeSH
• Hydrocortisone administration & dosage   chemistry   pharmacokinetics   MeSH
• Keratinocytes MeSH
• Humans MeSH
• Lipid Metabolism drug effects   MeSH
• Monoterpenes chemistry   MeSH
• Mice MeSH
• Permeability drug effects   MeSH
• Water Loss, Insensible drug effects   MeSH
• Drug Compounding methods   MeSH
• Terpenes chemistry   pharmacology   MeSH
• Toxicity Tests, Acute MeSH
• Theophylline administration & dosage   chemistry   pharmacokinetics   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alcohols MeSH
• Cidofovir MeSH
• Esters MeSH
• Pharmaceutic Aids MeSH
• Hydrocortisone MeSH
• Monoterpenes MeSH
• perillyl alcohol MeSH Browser
• Terpenes MeSH
• Theophylline MeSH

PURPOSE: To study new skin penetration/permeation enhancers based on amphiphilic galactose derivatives. METHODS: Two series of alkyl and alkenyl galactosides were synthesized and evaluated for their enhancing effect on transdermal/topical delivery of theophylline (TH), hydrocortisone (HC) and cidofovir (CDV), reversibility of their effects on transepidermal water loss (TEWL) and skin impedance, interaction with the stratum corneum using infrared spectroscopy, and cytotoxicity on keratinocytes and fibroblasts. RESULTS: Initial evaluation identified 1-(α-D-galactopyranosyl)-(2E)-pentadec-2-ene A15 as a highly potent enhancer - it increased TH and HC flux through human skin 8.5 and 5 times, respectively. Compound A15 increased the epidermal concentration of a potent antiviral CDV 7 times over that reached by control and Span 20 (an established sugar-based enhancer). Infrared spectroscopy of human stratum corneum indicated interaction of A15 with skin barrier lipids but not proteins. These effects of A15 on the skin barrier were reversible (both TEWL and skin impedance returned to baseline values within 24 h after A15 had been removed from skin). In vitro toxicity of A15 on HaCaT keratinocytes and 3T3 fibroblasts was acceptable, with IC50 values over 60 μM. CONCLUSIONS: Galactosyl pentadecene A15 is a potent enhancer with low toxicity and reversible action.

• Keywords
• galactoside, penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• Alkenes administration & dosage   chemistry   MeSH
• Administration, Cutaneous MeSH
• Cidofovir MeSH
• Cytosine administration & dosage   analogs & derivatives   chemistry   MeSH
• Epidermis metabolism   MeSH
• Fibroblasts drug effects   metabolism   MeSH
• Galactose analogs & derivatives   chemistry   MeSH
• Galactosides administration & dosage   chemistry   MeSH
• Hydrocortisone administration & dosage   chemistry   MeSH
• Keratinocytes drug effects   metabolism   MeSH
• Skin Absorption drug effects   MeSH
• Skin metabolism   MeSH
• Humans MeSH
• Lipids chemistry   MeSH
• Organophosphonates administration & dosage   chemistry   MeSH
• Permeability MeSH
• Theophylline administration & dosage   chemistry   MeSH
• Drug Liberation MeSH
• Water MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Alkenes MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Galactose MeSH
• Galactosides MeSH
• Hydrocortisone MeSH
• Lipids MeSH
• Organophosphonates MeSH
• Theophylline MeSH
• Water MeSH

PURPOSE: Skin permeation/penetration enhancers are substances that enable drug delivery through or into the skin. METHODS: To search for new enhancers with high but reversible activity and acceptable toxicity, we synthesized a series of D-glucose derivatives, both hydrophilic and amphiphilic. RESULTS: Initial evaluation of the ability of these sugar derivatives to increase permeation and penetration of theophylline through/into human skin compared with a control (no enhancer) or sorbitan monolaurate (Span 20; positive control) revealed dodecyl 6-amino-6-deoxy-α-D-glucopyranoside 5 as a promising enhancer. Furthermore, this amino sugar 5 increased epidermal concentration of a highly hydrophilic antiviral cidofovir by a factor of 7. The effect of compound 5 on skin electrical impedance suggested its direct interaction with the skin barrier. Infrared spectroscopy of isolated stratum corneum revealed no effect of enhancer 5 on the stratum corneum proteins but an overall decrease in the lipid chain order. The enhancer showed acceptable toxicity on HaCaT keratinocyte and 3T3 fibroblast cell lines. Finally, transepidermal water loss returned to baseline values after enhancer 5 had been removed from the skin. CONCLUSIONS: Compound 5, a dodecyl amino glucoside, is a promising enhancer that acts through a reversible interaction with the stratum corneum lipids.

• Keywords
• penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• Antiviral Agents administration & dosage   metabolism   MeSH
• Administration, Cutaneous MeSH
• Administration, Topical MeSH
• Cell Line MeSH
• Cidofovir MeSH
• Cytosine administration & dosage   analogs & derivatives   metabolism   MeSH
• Epidermis drug effects   metabolism   MeSH
• Chemistry, Pharmaceutical MeSH
• Glucosides chemical synthesis   pharmacology   MeSH
• Hexoses pharmacology   MeSH
• Hydrophobic and Hydrophilic Interactions MeSH
• Keratinocytes drug effects   metabolism   MeSH
• Skin Absorption MeSH
• Skin drug effects   metabolism   MeSH
• Drug Delivery Systems MeSH
• Humans MeSH
• Lipids physiology   MeSH
• Organophosphonates administration & dosage   metabolism   MeSH
• Permeability MeSH
• Theophylline administration & dosage   metabolism   MeSH
• Cell Survival MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antiviral Agents MeSH
• Cidofovir MeSH
• Cytosine MeSH
• Glucosides MeSH
• Hexoses MeSH
• Lipids MeSH
• Organophosphonates MeSH
• sorbitan monolaurate MeSH Browser
• Theophylline MeSH

PURPOSE: In this work, we investigate prodrug and enhancer approaches for transdermal and topical delivery of antiviral drugs belonging to the 2,6-diaminopurine acyclic nucleoside phosphonate (ANP) group. Our question was whether we can differentiate between transdermal and topical delivery, i.e., to control the delivery of a given drug towards either systemic absorption or retention in the skin. METHODS: The in vitro transdermal delivery and skin concentrations of seven antivirals, including (R)- and (S)-9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine (PMPDAP), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine ((S)-HPMPDAP), its 8-aza analog, and their cyclic and hexadecyloxypropyl (HDP) prodrugs, was investigated with and without the penetration enhancer dodecyl-6-(dimethylamino)hexanoate (DDAK) using human skin. RESULTS: The ability of ANPs to cross the human skin barrier was very low (0.5-1.4 nmol/cm(2)/h), and the majority of the compounds were found in the stratum corneum, the uppermost skin layer. The combination of antivirals and the penetration enhancer DDAK proved to be a viable approach for transdermal delivery, especially in case of (R)-PMPDAP, an anti-HIV effective drug (30.2 ± 2.3 nmol/cm(2)/h). On the other hand, lysophospholipid-like HDP prodrugs, e.g., HDP-(S)-HPMPDAP, reached high concentrations in viable epidermis without significant systemic absorption. CONCLUSIONS: By using penetration enhancers or lysolipid prodrugs, it is possible to effectively target systemic diseases by the transdermal route or to target cutaneous pathologies by topical delivery.

• MeSH
• 2-Aminopurine administration & dosage   analogs & derivatives   chemistry   MeSH
• Antiviral Agents administration & dosage   chemistry   MeSH
• Administration, Cutaneous MeSH
• Skin Absorption drug effects   physiology   MeSH
• Drug Delivery Systems methods   MeSH
• Humans MeSH
• Liposomes MeSH
• Organ Culture Techniques MeSH
• Prodrugs administration & dosage   chemistry   MeSH
• Check Tag
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 2-Aminopurine MeSH
• 2,6-diaminopurine MeSH Browser
• Antiviral Agents MeSH
• Liposomes MeSH
• Prodrugs MeSH