Yasuko Obata

Nanoemulsions are considered to have an advantage in improving the oral bioavailability of poorly absorbed drugs. However, studies on additives such as sur

Background/Objectives: Reverse iontophoresis (R-IP) is a technology that transdermally delivers components from inside the body to outside the body using electroosmotic flow (EOF) generated by applying a low electric current through the skin. It has attracted attention as a non-invasive sampling method for therapeutic drug monitoring (TDM). The purpose of this study was to determine whether urea and Tween 80 effectively enhance drug extraction from beneath the skin using R-IP. Methods: An in vitro drug extraction test using hairless mouse skin and R-IP was performed with a 3-chamber Franz cell and Ag|AgCl electrodes by applying a constant current (0.25 mA/cm²) for 6 h. Acetaminophen was chosen as the model drug, and its solution (30, 100, or 300 μg/mL) was placed in the subdermal compartment. The pH of both the electrode and subdermal compartment solutions was maintained at 7.4. Results: Acetaminophen was gradually extracted into the electrode compartment in a concentration-dependent manner and was more abundant in the cathode compartment than in the anode compartment. In addition, urea significantly promoted drug extraction, particularly on the cathode side, and a linear relationship was observed between the subdermal concentration and extracted amount. This effect is likely due to skin hydration caused by urea, which enhances EOF generation in the skin. Conversely, Tween 80 had no effect on drug extraction. Conclusions: R-IP combined with urea is expected to not only shorten the treatment time but also enable its application to drugs with low concentrations in blood.

In this study we have focused on three types of alcohols: ethanol (EtOH), 2-propanol (IPA), and 1-propanol (NPA), and examined the skin permeability of drugs with different physicochemical properties: ketoprofen (KPF; hydrophobic), cimetidine (CMT; slightly hydrophobic), and caffeine (CF; hydrophilic). The results revealed EtOH particularly enhanced the skin permeation of CF, while IPA enhanced skin permeation regardless of the type of drug. In contrast, NPA significantly increased the skin permeability of KPF and CMT, but had little effect on CF. The differing effects of the alcohols on skin permeation appear to be linked to the physicochemical properties of the drugs. KPF is more hydrophobic than the other drugs, suggesting that it uses the intercellular pathway in the stratum corneum for permeation. CMT has intermediate properties between hydrophilic and hydrophobic, resulting in low skin permeability and ineffective utilization of both the transepidermal and transappendageal pathways. CF mainly utilized the transappendageal pathways for skin permeation because of its smaller molecular weight and more hydrophilic as compared with the other drugs. These results suggest that the effect of different alcohols on enhancing drug skin permeation is not uniform and that the optimal alcohol for enhancing permeability may vary depending on the drug. Therefore, the selection of appropriate additives based on the physicochemical properties of the drug, such as hydrophilicity, hydrophobicity, and molecular weight, is crucial for developing effective transdermal formulation.

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Oral disulfiram (DSF) has been used clinically for alcohol dependence and recently has been found to have antitumor activity. A transdermal delivery system would be useful for maintaining drug concentration and reducing the frequency of administration of DSF for cancer treatment. Penetrating the stratum corneum (SC) barrier is a challenge to the transdermal delivery of DSF. Therefore, we investigated the promoting effects and mechanism of action of the combination of oleic acid (OA) and Tween 80 on the skin permeation of DSF. Hairless mouse skin was exposed to OA and Tween 80, combined in various ratios (1:0, 2:1, 1:1, 1:2, and 0:1). A permeation experiment was performed, and total internal reflection infrared spectroscopic measurements, differential scanning calorimetry, and synchrotron radiation X-ray diffraction measurements were taken of the SC with each applied formulation. The combination of OA and Tween 80 further enhanced the absorption-promoting effect of DSF, compared with individual application. The peak of the CH2 inverse symmetric stretching vibration near the skin surface temperature was shifted by a high frequency due to the application of OA, and DSF solubility increased in response to Tween 80. We believe that the increased fluidity of the intercellular lipids due to OA and the increased solubility of DSF due to Tween 80 promoted the absorption of DSF. Our study clarifies the detailed mechanism of action of the skin permeation and promoting effect of DSF through the combined use of OA and Tween 80, contributing to the development of a transdermal preparation of DSF.

Famotidine (FMT) is a competitive histamine-2 (H2) receptor antagonist that inhibits gastric acid secretion for the treatment of Gastroesophageal reflux disease. To study the promoting effect and mechanism of terpenes, including l-menthol, borneol, and geraniol, as chemical enhancers, FMT was used as a model drug. Attenuated total reflectance-Fourier transform IR spectroscopy (ATR-FTIR) and differential scanning calorimetry (DSC) were used to explore the effects of terpenes on the skin. Hairless mouse skin was mounted on Franz-type diffusion cell, and skin permeation experiment of FMT hydrogel was carried out. The results suggested that the thermodynamic activity influenced the permeability of the drug, and the main mechanism of terpenes to enhance skin permeation of the drug was based on increasing the fluidity of the intercellular lipids. Moreover, it was revealed that l-menthol simultaneously relaxed the packing structure and lamellar structure, whereas geraniol had a great influence on the lamellar structure only. Collectively, all terpenes had a promoting effect on skin permeation of FMT, indicating their potential as chemical enhancers to change the microstructure of stratum corneum and improve the permeation of FMT through the skin, and it has great potential to be used in transdermal formulations of FMT.

Intercellular lipids fill the interstices of corneocytes and serve a barrier function. The amount of transdermal water evaporation varies depending on the packing structure of intercellular lipids, as this structure is important for maintaining barrier efficacy. This packing structure consists of a mixture of crystals (orthorhombic and hexagonal) and liquid crystals (fluid phase), and the proportion of these phases is thought to affect barrier function. However, there have been no methods to visualize the actual distribution of the domains formed by packing structure in intercellular lipids. In this study, the planar distribution of intercellular lipid structures was determined using focal plane array (FPA)-based Fourier transform (FT) IR imaging analysis of stratum corneum cell units obtained by grid stripping. The lipid composition of ceramides was revealed by electrospray ionization tandem mass spectrometry (ESI-MS/MS)-based shotgun lipidomics. The distribution of domains formed by packing structures and the lipid composition of ceramides was compared in skin with high- or low-transepidermal water loss (TEWL). The orthorhombic proportion was lower in high-TEWL skin than in low-TEWL skin. ESI-MS/MS-based shotgun lipidomics analysis showed that the alpha-hydroxyceramide content in the low- and high-TEWL groups differed regarding the distribution of fatty acid chain lengths. The evaluation of stratum corneum cell units using FPA-based FTIR imaging is an innovative technology that can visualize the distribution of domains formed by intercellular lipid-packing structures. Increased proportions of alpha-hydroxyceramide subclasses such as alpha-hydroxy-sphingosine ceramide and alpha-hydroxy-phytosphingosine ceramide were associated with a reduced proportion of the orthorhombic packing structure domain.