Proposal of a Transdermal Iontophoresis Patch and Sheet Mask Using the Principle of Magnesium-air Batteries

2.1 Principle and patch structure

Figure 3 illustrates the structure of a magnesium-air battery and its electrochemical reactions. A magnesium-air battery consists of an air electrode, which serves as the reaction site for oxygen as the cathode active material, a magnesium anode, and an electrolyte that facilitates ion transport. The fundamental structure of the proposed iontophoresis patches is based on replacing the electrolyte of the magnesium-air battery with the skin (Fig. 4).

Fig. 3. The structure of a magnesium-air battery.

Fig. 4. The structure of the iontophoresis patch researched and developed by NTT.

During battery reaction, ions flow from both the cathode and anode into the skin, and the resulting electro-osmosis is expected to enhance the penetration of active ingredients. The penetration rate of active ingredients in iontophoresis is given by Eq. (1) [5] and is proportional to the applied current. Therefore, increasing the penetration amount of active ingredients requires enhancing the output power of the magnesium-air battery.

To achieve higher power in a magnesium-air battery, it is necessary to promote the reactions described in Eqs. (2) and (3). However, since the cathode reaction often acts as the rate-limiting step, a key challenge is how to activate and stabilize the cathode reaction effectively.

2.2 Fabrication method of cellulose nanofiber carbon sheet

As in Eq. (2), the cathode reaction becomes more active when oxygen (gas), water (liquid), and electrons (in the carbon solid) coexist. To satisfy this condition, it is necessary to have a greater number of reaction sites where oxygen, electrolyte, and carbon coexist—known as three-phase interfaces. We focused on cellulose nanofiber (CNF) carbon, in which carbon nanofibers form a mesh-like structure, to increase the number of three-phase interfaces.

The fabrication process of a CNF carbon sheet is shown in Fig. 5. Cellulose nanofibers were rapidly frozen at −40°C, followed by vacuum drying for more than 1 week. Subsequently, heat treatment was conducted at 1200°C for 1 hour under a nitrogen atmosphere to obtain CNF carbon. The fabricated CNF carbon was then mixed and milled with CNF, filtered by suction, and dried to form a sheet.

Fig. 5. The fabrication process of the CNF carbon sheet and photographs and SEM images of the fabricated samples.

Figure 5 shows photographs and scanning electron microscope (SEM) images of the fabricated samples. The SEM images indicate that the mesh structure of the carbon was maintained both after carbonization of the CNF and after sheet formation.

3.1 Evaluation of current

Figure 6 shows a schematic diagram and photograph of the setup of evaluating current using pig skin. The pig skin used was 3 × 4 cm, and the electrodes had diameters of 16 mm each, with a center-to-center distance of 3 cm. A cotton pad was placed under the electrodes, onto which 300 μl of saline solution was applied.

Fig. 6. Schematic and photograph of the setup for current evaluation using pig skin.

Figure 7 shows the results of the current measurement. A current of over 200 μA was obtained, indicating that the output is sufficient for evaluating iontophoresis.

Fig. 7. The results of the current measurement through pig skin.

3.2 Permeation test

Figure 8 illustrates the setup for the permeation test using cultured skin. The cultured skin used was the three-dimensional artificial cultured skin “LabCyte EPI-MODEL12” from Japan Tissue Engineering Co., Ltd. The active ingredients used were saturated aqueous solutions of niacinamide and tranexamic acid, provided by Tokyo Chemical Industry Co., Ltd. The setup consisted of layers arranged in the following order: aluminum (conductive layer)/CNF carbon electrode/cotton/cultured skin/cotton/magnesium electrode/aluminum (conductive layer).

Fig. 8. Setup for the permeation test using cultured skin.

A saline solution was applied to the cotton on the magnesium-electrode side, while the prepared active ingredient solution was applied to the CNF carbon electrode. The setup was then sandwiched between glass slides and left stationary for one hour. The conductive layer, electrodes, and cotton were then gently removed, and the cultured skin was frozen at −18°C using a cryostat. The skin was embedded in a compound resin, sectioned into 10 μm-thick slices, and analyzed using time-of-flight secondary ion mass spectrometry (TOF-SIMS) to obtain ion image mapping of the cross-section of the cultured skin.

TOF-SIMS analysis was used to obtain data on PC₅H₁₅NO₄ (m/z = 184.1) derived from phospholipids, a marker derived from the cell layer, to distinguish the stratum corneum from the cellular layer in the cultured skin cross-section.

Figure 9 shows TOF-SIMS ion images of the cross-section for each active ingredient, while Figure 10 shows the TOF-SIMS line profile. A significant difference in approximately twice that of patches without iontophoresis was observed in the penetration of niacinamide with iontophoresis. In contrast, no significant difference was observed for tranexamic acid. This is attributed to the difference in their ionic properties; niacinamide is cationic with a pK_a (acidity constant) of 3.3, while tranexamic acid is amphoteric with a pK_a1 of 4.33 and pK_a2 of 10.65, leading to differences in penetration rates.

Fig. 9. TOF-SIMS ion images of the cross-section for each active ingredient.

Fig. 10. TOF-SIMS line profile for each active ingredient.