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Controlled drug release using stimuli-responsive systems to electrical stimulation has gained attention as one of the novel strategies in the development of intelligent drug delivery systems. In this study, a portable electrochemical drug delivery system based on a paper substrate modified with polypyrrole was designed an‎d fabricated for loading an‎d controlled release of methotrexate under voltage stimulation combined with the iontophoresis effect. In this system, the paper-based drug delivery electrode was first coated with carbon ink, an‎d then a polypyrrole layer an‎d a polypyrrole layer containing methotrexate were successively deposited on the surface by electropolymerization. The optimal electropolymerization conditions for the first layer were (0.20 M pyrrole, 0.20 M sodium chloride at a potential of 0.90 V for 250 seconds), an‎d for the second layer (0.10 M pyrrole, 0.10 M sodium chloride, 0.0050 M methotrexate at a potential of 0.75 V for 1200 seconds), under which the drug loading capacity reached 103 μg/cm². In vitro release studies showed that applying the optimal potential (–1.2 V) significantly increased drug release, an‎d the prepared drug delivery electrodes exhibited considerable passive leakage reduction in the absence of potential. HPLC/MS analysis confirmed that the chemical structure of methotrexate was preserved after release. FTIR spectroscopy an‎d FESEM images also confirmed the successful formation of the polypyrrole layer an‎d the interaction of the drug with the polymer matrix. The ability to precisely control drug dosage an‎d prevent unwanted release (temporal an‎d spatial resolution) of the electro-responsive drug delivery system was demonstrated by stepwise drug release at the optimal potential (–1.2 V) in artificial sweat with pH 5.4 using four consecutive 1.5 minute stimulation cycles. Furthermore, the portability of the drug delivery electrodes was verified by eva‎luating system performance under different release conditions (potentiostatic an‎d battery-powered). Skin permeability studies using Franz cells showed that the combination of electrochemical release an‎d the iontophoresis effect increased methotrexate permeation through the stratum corneum to 20.8 μg/cm².h. The 20 day stability eva‎luation of the system indicated preservation of loading capacity an‎d release performance over time. Animal studies on a mouse model of psoriasis demonstrated that paper-based patches containing methotrexate with electrical stimulation delivered the drug locally an‎d in a controlled manner, leading to reduced inflammation an‎d improved skin symptoms. This low-cost, wearable system with high efficacy an‎d low side effects offers a novel perspective for non invasive an‎d personalized treatment of psoriasis.

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