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
- Názvy látek
- alkoholy MeSH
- cidofovir MeSH
- estery MeSH
- farmaceutické pomocné látky MeSH
- hydrokortison MeSH
- monoterpeny MeSH
- perillyl alcohol MeSH Prohlížeč
- terpeny MeSH
- 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
Photocatalytic degradation of pharmaceuticals (hydrocortisone, estradiol, and verapamil) and personal care product additives (parabens-methyl, ethyl, and propyl derivatives) was investigated in the homogeneous phase (with ferric ions as the catalyst) and on TiO2. Ferric ions in concentrations corresponding to concentrations in natural water bodies were shown to be a significant accelerator of the degradation in homogeneous reaction mixtures. In heterogeneous photocatalytic reactions on TiO2, lower reaction rates, but mineralisation to higher extents, were observed.
- MeSH
- estradiol chemie MeSH
- fotolýza účinky záření MeSH
- hydrokortison chemie MeSH
- katalýza MeSH
- léčivé přípravky chemie MeSH
- parabeny chemie MeSH
- spektrofotometrie ultrafialová MeSH
- titan chemie MeSH
- ultrafialové záření * MeSH
- verapamil chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- estradiol MeSH
- hydrokortison MeSH
- léčivé přípravky MeSH
- parabeny MeSH
- titan MeSH
- titanium dioxide MeSH Prohlížeč
- verapamil MeSH
Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder, mostly occurring in the third trimester. ICP is defined as an elevation of serum bile acids, typically accompanied by pruritus and elevated activities of liver aminotransferases. ICP is caused by impaired biliary lipid secretion, in which endogenous steroids may play a key role. Although ICP is benign for the pregnant woman, it may be harmful for the fetus. We evaluated the differences between maternal circulating steroids measured by RIA (17-hydroxypregnenolone and its sulfate, 17-hydroxyprogesterone, and cortisol) and GC-MS (additional steroids), hepatic aminotransferases and bilirubin in women with ICP (n = 15, total bile acids (TBA) >8 μM) and corresponding controls (n = 17). An age-adjusted linear model, receiver-operating characteristics (ROC), and multivariate regression (a method of orthogonal projections to latent structure, OPLS) were used for data evaluation. While aminotransferases, conjugates of pregnanediols, 17-hydroxypregnenolone and 5β-androstane-3α,17β-diol were higher in ICP patients, 20α-dihydropregnenolone, 16α-hydroxy-steroids, sulfated 17-oxo-C19-steroids, and 5β-reduced steroids were lower. The OPLS model including steroids measured by GC-MS and RIA showed 93.3% sensitivity and 100% specificity, while the model including steroids measured by GC-MS in a single sample aliquot showed 93.3% sensitivity and 94.1% specificity. A composite index including ratios of sulfated 3α/β-hydroxy-5α/β-androstane-17-ones to conjugated 5α/β-pregnane-3α/β, 20α-diols discriminated with 93.3% specificity and 81.3% sensitivity (ROC analysis). These new data demonstrating altered steroidogenesis in ICP patients offer more detailed pathophysiological insights into the role of steroids in the development of ICP.
- MeSH
- 17-alfa-hydroxypregnenolon krev chemie MeSH
- 17-alfa-hydroxyprogesteron krev chemie MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- dospělí MeSH
- gestační stáří MeSH
- hydrokortison krev chemie MeSH
- intrahepatální cholestáza diagnóza metabolismus patologie MeSH
- jaterní testy MeSH
- komplikace těhotenství diagnóza metabolismus patologie MeSH
- lidé MeSH
- nuclei raphe dorsalis MeSH
- plocha pod křivkou MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí MeSH
- radioimunoanalýza MeSH
- ROC křivka MeSH
- steroidy krev chemie metabolismus MeSH
- těhotenství MeSH
- žlučové kyseliny a soli analýza MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 17-alfa-hydroxypregnenolon MeSH
- 17-alfa-hydroxyprogesteron MeSH
- alanintransaminasa MeSH
- aspartátaminotransferasy MeSH
- hydrokortison MeSH
- steroidy MeSH
- žlučové kyseliny a soli MeSH
A novel reversed-phase high-performance liquid chromatographic method with UV spectrophotometric detection was developed and validated for the determination of compounds in topical cream. The method describes determination of active component hydrocortisone acetate (HCA), its degradation products hydrocortisone (HC) and cortisone acetate (occurring in formulation after long-term stability tests) and two preservatives presented in the cream-methylparaben and propylparaben, using dexamethasone as an internal standard. The chromatographic separation was performed on a 5 microm SUPELCO Discovery C18 125 x 4-mm ID column. The optimised mobile phase for separation of all the compounds consists of methanol, acetonitrile and water (15:27:58, v/v/v), with the analysis time less than 13 min. The method was applicable for routine analysis (assays and stability tests) of active compound HCA, preservatives and degradation products in pharmaceutical product--topical cream Hydrocortizone cream 1%.
- MeSH
- aplikace lokální MeSH
- emoliencia analýza chemie MeSH
- farmaceutická technologie metody MeSH
- hydrokortison analogy a deriváty analýza chemie MeSH
- parabeny analýza chemie MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- emoliencia MeSH
- hydrocortisone acetate MeSH Prohlížeč
- hydrokortison MeSH
- methylparaben MeSH Prohlížeč
- parabeny MeSH
- propylparaben MeSH Prohlížeč
