A systematic investigation is performed on structural transformations in small neutral gold clusters (Au3–Au12) induced by O2 adsorption, with the use of the fully automated reaction path search techniques, i.e., anharmonic downward distortion following (ADDF) and artificial force induced reaction (AFIR) methods, implemented in the global reaction route mapping (GRRM) program. For each size of Au cluster, the most stable structure, low-energy isomers, and a network of isomerization pathways are determined. The located Au n –O2 adsorption forms can be classified into two groups: η1-Au n O2, where only one oxygen atom is adsorbed on Au n , and η2-Au n O2, where both oxygen atoms are adsorbed on Au n in a bridged manner. These two adsorption forms can be transformed to each other with a low barrier. The isomerization pathways of gold clusters upon O2 adsorption are compared with those obtained for the pure gold clusters without O2. It is demonstrated that O2 adsorption promotes structural transformations in gold clusters considerably by lowering the isomerization barriers. The presence of the unpaired electron is a necessary condition for O2 adsorption in the η1-Au n O2 form, as well as the subsequent cluster isomerization and the O–O bond activation. These conclusions are consistent with the recent experimental results by Fielicke et al.

Ethanol (EtOH) is one of the bases in topically applied medicines that promote the skin permeation of drugs. Although the effects of EtOH have been attributed to structural modifications in the stratum corneum, the underlying mechanisms, especially the influence of different concentrations of EtOH, have not been examined extensively. Structural modifications in the stratum corneum of hairless mouse due to the application of EtOH/water mixture were herein investigated at the molecular level using synchrotron X-ray diffraction. The results revealed that all EtOH concentrations examined greatly modified the short lamellar structures containing the aqueous layer in intercellular lipids and the structure of keratin fibrils in corneocytes, which can take up hydrophilic compounds. However, the long lamellar and the hydrocarbon-chain packing structures were unaffected by EtOH. Changes to the short lamellar structures were not proportional to the concentration of EtOH. However, the keratin fibril structures changed gradually with increasing EtOH concentration. The X-ray diffraction experiments enabled the effects of different EtOH concentrations on the morphology of the stratum corneum to be assessed by using a number of experimental samples to avoid variations due to individual differences. The results indicated that alterations to the short lamellar structures appeared to be related to the skin permeability of drugs with the application of EtOH/water mixture, and monotonous structural changes in the keratin fibrils with an increase in EtOH concentration may contribute to this permeation as supplement. These results will be useful for the development of new drug formulations containing EtOH.

It has been demonstrated that ethanol (EtOH) can enhance skin permeation of drugs when simultaneously applied with drugs. However, only a few studies have reported on the pretreatment effect of EtOH on skin permeations. In this study, the pretreatment effects of EtOH on skin permeation of drugs were investigated by measuring changes in skin permeation and electrical skin resistance. Permeabilities of deuterium oxide (D 2 O), isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), calcein sodium (CA-Na), and fluorescein isothiocyanate-dextran 4 kDa (FD-4, 3.3-4.4 kDa) were evaluated through Yucatan micropig skin pretreated with different concentrations of EtOH solution. From the results, almost constant skin permeabilities of D 2 O and ISDN were observed independent of EtOH concentration. Skin permeabilities of ISMN, CA, and FD-4 increased with low concentrations of EtOH, but decreased with high concentrations of EtOH. At 99.5% EtOH pretreatment, skin permeabilities of hydrophilic compounds (ISMN, CA, and FD-4) decreased to non-detectable levels. In addition, low molecular ion transports were almost constant at any EtOH concentration. Since molecular (ion) sizes of ISMN, CA, and FD-4 are larger than Na , Cl , and D 2 O, permeation pathway sizes for hydrophilic compounds in the skin barrier may be remarkably decreased by pretreatment with high concentrations of EtOH. However, the permeability coefficient of ISDN was not influenced by any EtOH concentration, since ISDN is a lipophilic, low-molecular compound that permeated through the lipophilic stratum corneum pathway. The present results show useful information for repeatedly and topically applied formulations containing EtOH, and also contribute to the effective use of alcohol formulations.Key words skin permeation; ethanol; pretreatment; electrical skin resistance; enhancer; permeation route Ethanol (EtOH) is well known as an ingredient of alcoholic beverages and has been utilized as a medicine for humans with different efficacies since ancient times. Currently, several skin disinfectants containing EtOH are frequently utilized in hospitals and public facilities for preventive purposes against viral infections. EtOH is a commonly used solvent just like water in pharmaceutical formulations, and is applied as a skin permeation enhancer, a skin disinfectant, and a solubilizer for poorly-soluble drugs. Tinctures, lotions, gels and liniments are dosage forms containing EtOH. Transdermal drug delivery systems and topical formulations often have the problem of low skin permeation of active ingredients. The skin barrier is mainly constituted by the outermost layer of skin, the stratum corneum, which dramatically restricts skin permeability of drugs. EtOH in topical formulations greatly enhances skin permeation of drugs. Estradiol and fentanyl dermal patches are typical examples developed using EtOH to enhance their transdermal deliveries.1-3) It has been proposed that the mechanisms of EtOH effects on the stratum corneum are extraction of lipids, increases in lipid...

The hf pathway must be important for the skin permeation of ionized compounds and hydrophilic high molecular compounds. hf-plugging is also a useful method for assessing the skin permeability of compounds through the hf pathway.

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