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Studies on in vitro and in vivo transdermal flux enhancement of methotrexate by a combinational approach in comparison to oral delivery

Background: Methotrexate (MTX) causes systemic toxicity thereby limiting its use; hence, transdermal delivery would be a possible alternative. Method: A comparative in vitro/in vivo study was done to see the effect of the two-tier system of chemical and physical enhancers. MTX was loaded into polyacrylamide-based hydrogel patch to see the effect of enhancers. Result: Flux enhancement (161%) of MTX was achieved when ternary mixture of ethyl acetate:menthol:ethanol (1:1:1) was used in combination with square-wave iontophoresis for 1hour. Lower flux enhancement of 71%, 83%, and 93.5% was obtained in vitro with neat ethyl acetate, its binary composition with ethanol, and its ternary composition with ethanol and menthol, respectively, as compared to passive. However, with square-wave iontophoresis, it increased to 126%, 140%, and 161%, respectively. The mechanism of flux enhancement was supported by biophysical tools such as attenuated total reflectance–Fourier transform infrared spectroscopy (ATR–FTIR), scanning electron microscopy (SEM), and histopathology. ATR–FTIR studies demonstrated split in the asymmetric C–H vibration and amide II band with terpenes and iontophoresis, respectively. Additionally binary and ternary mixture of ethyl acetate demonstrated absence of ester peak accounting for lipid extraction. SEM of the skin samples treated with chemical enhancers in combination with square-wave iontophoresis showed both swelling and increased pore size of hair follicles, thus supporting higher permeation. Histopathological studies on treated skin samples of albino mice demonstrated epidermal thinning and focal disruptions, spongiosis, dermal edema, and appendageal dilatations. In vivo studies on mice demonstrated plasma concentration of 18.79μg/mL with ternary mixture of ethyl acetate in combination with square wave, which is twofold higher to oral delivery. The reversibility studies conducted in vivo on mice demonstrated that the histological changes induced by the above-mentioned enhancers were transient and reversible in 48 hours. Conclusion: The above results indicate that the above-mentioned enhancers are safe and well tolerated by the skin.