The Optimized Fabrication of a Polymeric Porous Microneedle for Effective Iontophoresis

Abstract

Iontophoresis has been widely studied to improve transdermal drug administration and transdermal extraction of interstitial fluids without patient’ stress. The stratum corneum (SC), outermost layer of skin, has the barrier functions preventing contamination of harmful molecules into a body, and also hinders the iontophoresis due to its high electrical resistance. Previously, we have reported the porous microneedle (PMN) prepared by a molding process and porogen method, which has a potential to lower the total resistance of the skin and improves the effect on iontophoresis [1]. However, the reproducibility of PMN’s porosity had room for further improvement since the solution of porogen used in the previous method could evaporate and change its volume. Here, we studied a few kinds of porogen solution with different boiling point to create the PMN with higher reproducibility. Furthermore, the ionic resistance of the electrolyte-containing PMN and that of the skin with the PMN were evaluated in order to design an efficient iontophoretic PMN patch.The PMN was fabricated by the combination of a molding process and the porogen method [1]. Briefly, a female mold for the PMN was made with PDMS by duplicating an acrylic plate drilled with an end mill and drill. The PMNs were made by using two stock solutions. A monomer stock solution was prepared by mixing the monomer glycidyl methacrylate, crosslinker trimethylolpropane trimethacrylate, and crosslinker triethylene glycol dimethacrylate. A porogen stock solution was prepared by dissolving 4.0 g polyethylene glycol (10 kDa) in 20 g diethylene glycol monomethyl ether (DEG) at 50 °C. The mixed solution composed of monomer, porogen and photoinitiator, was filled to the mold by removing the air between the mold and the solution in a vacuum desiccator. After that, UV irradiation was performed in a nitrogen environment to polymerize the solution, and finally the obtained needle was immersed in a mixed solution of water and ethanol to elute the porogen. The 2-methoxyethanol (2ME) was also employed to compare with DEG.The porosity of PMN using each solvent was calculated from the difference of weight of PMN in dry and wet conditions (pure water). The experimental porosity of the PMN using DEG was closer to the theoretical value and the shape of that was closer to the mold, indicating that DEG can contribute the reproducibility of the PMN fabrication owing to its higher boiling point than that of 2ME.In order to determine the mechanical strength of the PMN, the load test was performed by the force gauge. The load value at which the PMN broke was recorded. In addition, to verify the load when inserted to a pig skin, the PMN was placed on a pig skin and the load test was performed. We found that the PMN could withstand 11 N (0.297 N/needle), indicating it is possible to insert human skin without break because the necessary load for insertion is known to be 0.098 N/needle [2]. The PMN was inserted to the pig skin at ca. 6.5 N and no broken structure was observed after the insertion.The ionic resistance of the PMN soaked in Ringer’s solution was measured by using the AC impedance at high frequency (10-100 kHz), where 100-µm tip of the PMN was stuck to a 3 wt% agarose gel and a couple of electrodes made of carbon fabric was placed on the PMN and agarose gel. The PMN was inserted into human skin, and the resistance value of the skin before and after insertion were compared. The resistance value was calculated from the voltage value when a constant current of 1 µA was applied for 10 seconds.The resistance value of PMN was found to be about 250 Ω. By comparing the resistance values of the skin before and after PMN insertion, it was found that the resistance of intact skin was 1-6 MΩ, but decreased to several hundred kΩ. It was also found that the dispersion of the resistance value by individuals is smaller when PMN was used. In conclusion, we successfully fabricated PMN that is useful for effective iontophoresis with highly reproducibility.