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.

• Klíčová slova
• penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• antivirové látky aplikace a dávkování   metabolismus   MeSH
• aplikace kožní MeSH
• aplikace lokální MeSH
• buněčné linie MeSH
• chemie farmaceutická MeSH
• cidofovir MeSH
• cytosin aplikace a dávkování   analogy a deriváty   metabolismus   MeSH
• epidermis účinky léků   metabolismus   MeSH
• glukosidy chemická syntéza   farmakologie   MeSH
• hexosy farmakologie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• keratinocyty účinky léků   metabolismus   MeSH
• kožní absorpce MeSH
• kůže účinky léků   metabolismus   MeSH
• lidé MeSH
• lipidy fyziologie   MeSH
• organofosfonáty aplikace a dávkování   metabolismus   MeSH
• permeabilita MeSH
• systémy cílené aplikace léků MeSH
• theofylin aplikace a dávkování   metabolismus   MeSH
• viabilita buněk MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antivirové látky MeSH
• cidofovir MeSH
• cytosin MeSH
• glukosidy MeSH
• hexosy MeSH
• lipidy MeSH
• organofosfonáty MeSH
• sorbitan monolaurate MeSH Prohlížeč
• theofylin 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.

• Klíčová slova
• galactoside, penetration enhancers, sugar, topical drug delivery, transdermal drug delivery,
• MeSH
• alkeny aplikace a dávkování   chemie   MeSH
• aplikace kožní MeSH
• cidofovir MeSH
• cytosin aplikace a dávkování   analogy a deriváty   chemie   MeSH
• epidermis metabolismus   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• galaktosa analogy a deriváty   chemie   MeSH
• galaktosidy aplikace a dávkování   chemie   MeSH
• hydrokortison aplikace a dávkování   chemie   MeSH
• keratinocyty účinky léků   metabolismus   MeSH
• kožní absorpce účinky léků   MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• lipidy chemie   MeSH
• organofosfonáty aplikace a dávkování   chemie   MeSH
• permeabilita MeSH
• theofylin aplikace a dávkování   chemie   MeSH
• uvolňování léčiv MeSH
• voda MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alkeny MeSH
• cidofovir MeSH
• cytosin MeSH
• galaktosa MeSH
• galaktosidy MeSH
• hydrokortison MeSH
• lipidy MeSH
• organofosfonáty MeSH
• theofylin MeSH
• voda MeSH

A film-forming system (FFS) represents a convenient topical dosage form for drug delivery. In this study, a non-commercial poly(lactic-co-glycolic acid) (PLGA) was chosen to formulate an FFS containing salicylic acid (SA) and methyl salicylate (MS). This unique combination is advantageous from a therapeutic point of view, as it enabled modified salicylate release. It is beneficial from a technological perspective too, because it improved thermal, rheological, and adhesive properties of the in situ film. DSC revealed complete dissolution of SA and good miscibility of MS with the polymer. MS also ensures optimal viscoelastic and adhesive properties of the film, leading to prolonged and sustained drug release. The hydrolysis of MS to active SA was very slow at skin pH 5.5, but it apparently occurred at physiological pH 7.4. The film structure is homogeneous without cracks, unlike some commercial preparations. The dissolution study of salicylates revealed different courses in their release and the influence of MS concentration in the film. The formulated PLGA-based FFS containing 5 % SA and 10 % MS is promising for sustained and prolonged local delivery of salicylates, used mainly for keratolytic and anti-inflammatory actions and pain relief.

• Klíčová slova
• Bioadhesion, Film-forming system, Methyl salicylate, PLGA, Salicylic acid, Sustained drug release,
• MeSH
• aplikace kožní MeSH
• aplikace lokální MeSH
• chemie farmaceutická metody   MeSH
• koncentrace vodíkových iontů MeSH
• kopolymer kyseliny glykolové a mléčné * chemie   MeSH
• kůže metabolismus   MeSH
• kyselina mléčná * chemie   MeSH
• kyselina polyglykolová * chemie   MeSH
• kyselina salicylová * aplikace a dávkování   chemie   farmakokinetika   MeSH
• léky s prodlouženým účinkem MeSH
• rozpustnost MeSH
• salicylany * aplikace a dávkování   chemie   farmakokinetika   MeSH
• systémy cílené aplikace léků * metody   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• methyl salicylate MeSH Prohlížeč

Nanosized materials offer promising strategy for topical drug delivery due to their enhancing effect on drug percutaneous transport across the stratum corneum barrier. In this work, polymeric micelles made from hydrophobized hyaluronic acid (HA) were probed for skin delivery. Compared to non-polymeric micelle solutions containing similar drug amount, in vitro skin penetration analysis indicated 3 times larger deposition of drug in the epidermis and 6 times larger drug deposition in the dermis after 5h of topical treatment in Franz diffusion cells. The drug deposition was further increased with prolonged time of topical treatment. Laser confocal microscopy revealed the accumulation of both, the HA forming the vehicle and the payload, in the epidermis and dermis. Although fluorescent labeling of the HA would suggest co-transport of the HA and the drug, loading FRET pair dyes in the micellar core clearly demonstrated gradual micelle disruption with increasing skin depth. Transcellular penetration was the predominant pathway for the loaded drug. The HA polymeric micelles also demonstrated increased bioactivity of loaded compound in vitro and in vivo. In addition, the loaded micelles were found to be stable in cream formulations and thus they have great potential for topical applications for cosmetic and pharmaceutical purposes.

• Klíčová slova
• Hyaluronan, Polymeric micelle, Skin penetration,
• MeSH
• buněčné linie MeSH
• dospělí MeSH
• kožní absorpce * MeSH
• kyselina hyaluronová chemie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• micely * MeSH
• nosiče léků chemie   MeSH
• pleťový krém MeSH
• polymery MeSH
• prasata MeSH
• techniky in vitro MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyselina hyaluronová MeSH
• micely * MeSH
• nosiče léků MeSH
• polymery MeSH

Owing to their complicated pathophysiology, the treatment of skin diseases necessitates a complex approach. Conventional treatment using topical corticosteroids often results in low effectiveness and the incidence of local or even systemic side effects. Nanoformulation of potent anti-inflammatory drugs has been selected as an optimal strategy for enhanced topical delivery of corticosteroids. In order to assess the efficiency of various nanoformulations, we formulated hydrocortisone (HC) and hydrocortisone-17-butyrate (HCB) into three different systems: lipid nanocapsules (LNC), polymeric nanoparticles (PNP), and ethosomes (ETZ). The systems were characterized using dynamic light scattering for their particle size and uniformity and the morphology of nanoparticles was observed by transmission electron microscopy. The nanosystems were tested using ex vivo full thickness porcine and human skin for the delivery of HC and HCB. The skin penetration was observed by confocal microscopy of fluorescently labelled nanosystems. ETZ were proposed as the most effective delivery system for both transdermal and dermal drug targeting but were also found to have a profound effect on the skin barrier with limited restoration. LNC and PNP were found to have significant effects in the dermal delivery of the actives with only minimal transdermal penetration, especially in case of HCB administration.

• Klíčová slova
• PLGA nanoparticles, dermal and transdermal delivery, ethosomes, hydrocortisone, hydrocortisone-17-butyrate, lipid nanocapsules,
• Publikační typ
• časopisecké články MeSH

Topical chemotherapy approaches are relevant for certain skin cancer treatments. This study observes that cabazitaxel (CTX), a broad-spectrum second-generation taxane cytotoxic agent, can be dissolved in α-tocopherol at high concentrations exceeding 100 mg mL-1 . 2D nuclear magnetic resonance (NMR) analysis and molecular dynamics (MD) are used to study this phenomenon. The addition of 30% dimethyl sulfoxide (DMSO) to the α-tocopherol/CTX solution improves its working viscosity and enhances CTX permeation through human skin in vitro (over 5 µg cm-2 within 24 h), while no detectable drug permeates when CTX is dissolved in α-tocopherol alone. In a transepidermal water loss assay, the barrier impairment induced by CTX in 30% DMSO in α-tocopherol, but not in pure DMSO, is reversible 8 h after the formulation removal from the skin surface. Antitumor efficacy of the topical CTX formulation is evaluated in nude mice bearing A431 human squamous carcinoma skin cancer xenografts. With topical application of concentrated CTX solutions (75 mg mL-1 ), tumor growth is significantly suppressed compared to lower concentration groups (0, 25, or 50 mg mL-1 CTX). Taken together, these findings show that topical delivery of CTX using a DMSO and α-tocopherol solvent warrants further study as a treatment for skin malignancies.

• Klíčová slova
• cabazitaxel, skin cancer, transdermal delivery, α-tocopherol,
• MeSH
• alfa-tokoferol * chemie   MeSH
• dimethylsulfoxid terapeutické užití   MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádory kůže * farmakoterapie   MeSH
• taxoidy MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alfa-tokoferol * MeSH
• cabazitaxel MeSH Prohlížeč
• dimethylsulfoxid MeSH
• taxoidy MeSH

In this work, amphiphilic hyaluronan was synthesized by grafting succinylated N-oleoyl-phytosphingosine via esters bonds. Succinylated N-oleoyl-phytosphingosine (sCER) was first prepared by esterification of hydroxyl moieties of the ceramide with succinic anhydride. The esterification of hyaluronan was governed by crowding effect. The oligomeric HA-sCER derivatives exhibited a strong self-aggregation as evidenced by a very low critical aggregation concentration (1.9 μg mL-1), higher pyrene binding constant (KB), and the smallest particle size (30 nm) in solution. The self-aggregation properties demonstrated to be a function of the substitution degree and molecular weight of HA. The prepared derivatives were non-cytotoxic towards cell lines NIH-3T3. Nanoparticles prepared using oligomeric HA-sCER derivatives improved the penetration of Nile red dye through the stratum corneum due to their smaller size (≤50 nm). The fluorescence intensity localized at the stratum corneum was higher for oligomeric HA-sCER. A significant inhibition of the pro-inflammatory cytokine interleukin-6 production was observed in vitro in macrophages differentiated from THP-1 cells. These findings showed that HA-sCER constituted a promising active ingredient for cosmetics use.

• Klíčová slova
• Amphiphilic polysaccharides, Ceramides, Hyaluronan, IL-6, Self-assembling, Skin penetration,
• MeSH
• ceramidy MeSH
• esterifikace MeSH
• kyselina hyaluronová * MeSH
• systémy cílené aplikace léků * MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ceramidy MeSH
• kyselina hyaluronová * MeSH
• phytosphingosine MeSH Prohlížeč

PURPOSE: Acyclic nucleoside phosphonates possess unique antiviral and antineoplastic activities; however, their polar phosphonate moiety is associated with low ability to cross biological membranes. We explored the potential of transdermal and topical delivery of 2,6-diaminopurine derivative cPr-PMEDAP. METHODS: In vitro diffusion of cPr-PMEDAP was investigated using formulations at different pH and concentration and with permeation enhancer through porcine and human skin. RESULTS: Ability of 0.1-5% cPr-PMEDAP to cross human skin barrier was very low with flux values ~40 ng/cm(2)/h, the majority of compound found in the stratum corneum. The highest permeation rates were found at pH 6; increased donor concentration had no influence. The permeation enhancer dodecyl 6-dimethylaminohexanoate (DDAK, 1%) increased flux of cPr-PMEDAP (up to 61 times) and its concentration in nucleated epidermis (up to ~0.5 mg of cPr-PMEDAP/g of the tissue). No deamination of cPr-PMEDAP into PMEG occurred during permeation studies, but N-dealkylation into PMEDAP mediated by skin microflora was observed. CONCLUSIONS: Transdermal or topical application of cPr-PMEDAP enabled by the permeation enhancer DDAK may provide an attractive alternative route of administration of this potent antitumor and antiviral compound.

• MeSH
• adenin aplikace a dávkování   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• antivirové látky aplikace a dávkování   MeSH
• aplikace kožní MeSH
• dimethylaminy MeSH
• dodekanol MeSH
• kapronáty metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• kůže metabolismus   MeSH
• lidé MeSH
• methylaminy metabolismus   MeSH
• organofosfonáty aplikace a dávkování   MeSH
• permeabilita MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• antitumorózní látky MeSH
• antivirové látky MeSH
• dimethylaminy MeSH
• dodecyl 6-(dimethylamino)hexanoate MeSH Prohlížeč
• dodekanol MeSH
• kapronáty MeSH
• methylaminy MeSH
• N(6)-cyclopropyl-9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine MeSH Prohlížeč
• organofosfonáty MeSH

Adefovir (9-(2-phosphonomethoxyethyl)adenine) is an acyclic nucleoside phosphonate currently used for the treatment of hepatitis B. The aim of this study was to evaluate the effect of permeation enhancer DDAK (6-dimethylaminohexanoic acid dodecyl ester) on the transdermal and topical delivery of adefovir. In porcine skin, DDAK enhanced adefovir flux 42 times with maximum at pH 5.8 suggesting ion pair formation. DDAK increased thermodynamic activity and stratum corneum/vehicle distribution coefficient of adefovir, as well as it directly decreased the skin barrier resistance. Maximal flux was observed already at 2% adefovir+1% DDAK. The results were confirmed in freshly excised human skin where DDAK enhanced adefovir flux 179 times to 8.9 microg/cm(2)/h. This rate of percutaneous absorption would allow for reaching effective plasma concentrations. After the topical application, adefovir concentrated in the stratum corneum with low penetration into the deeper skin layers from either aqueous or isopropyl myristate vehicle without the enhancer. With 1% DDAK, adefovir concentrations in the viable epidermis and dermis were 33-61 times higher. These results offer an attractive alternative to established routes of administration of adefovir and other acyclic nucleoside phosphonates.

• MeSH
• adenin aplikace a dávkování   analogy a deriváty   chemie   metabolismus   MeSH
• antivirové látky aplikace a dávkování   chemie   metabolismus   MeSH
• aplikace kožní MeSH
• chemie farmaceutická MeSH
• difuzní komory kultivační MeSH
• dimethylaminy MeSH
• dodekanol MeSH
• druhová specificita MeSH
• farmaceutická vehikula chemie   MeSH
• kapronáty chemie   farmakologie   MeSH
• kinetika MeSH
• koncentrace vodíkových iontů MeSH
• kožní absorpce účinky léků   MeSH
• kůže účinky léků   metabolismus   MeSH
• lidé MeSH
• methylaminy chemie   farmakologie   MeSH
• organofosfonáty aplikace a dávkování   chemie   metabolismus   MeSH
• permeabilita MeSH
• prasata MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• antivirové látky MeSH
• dimethylaminy MeSH
• dodecyl 6-(dimethylamino)hexanoate MeSH Prohlížeč
• dodekanol MeSH
• farmaceutická vehikula MeSH
• kapronáty MeSH
• methylaminy MeSH
• organofosfonáty MeSH

Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.

• MeSH
• anthraceny MeSH
• antitumorózní látky terapeutické užití   MeSH
• aplikace lokální MeSH
• bazocelulární karcinom farmakoterapie   MeSH
• Bowenova nemoc farmakoterapie   MeSH
• dospělí MeSH
• fotochemoterapie metody   MeSH
• fytoterapie MeSH
• keratóza farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádory kůže farmakoterapie   MeSH
• perylen analogy a deriváty   terapeutické užití   MeSH
• pilotní projekty MeSH
• rostlinné přípravky terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• třezalka * chemie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anthraceny MeSH
• antitumorózní látky MeSH
• hypericin MeSH Prohlížeč
• perylen MeSH
• rostlinné přípravky MeSH