Centre for Biomedical Engineering, Indian Institute of Technology, Hauz Khas, New Delhi, India.
Drug Dev Ind Pharm. 2009 Nov;35(11):1281-92. doi: 10.3109/03639040902882322.
Methotrexate (MTX) causes systemic toxicity thereby limiting its use; hence, transdermal delivery would be a possible alternative.
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.
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 1 hour. 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 18.79 microg/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.
The above results indicate that the above-mentioned enhancers are safe and well tolerated by the skin.
甲氨蝶呤（MTX）会导致全身性毒性，从而限制了其应用；因此，经皮给药可能是一种替代方法。
进行了一项比较体外/体内研究，以观察化学和物理增强剂的双层系统的效果。将 MTX 载入聚丙烯酰胺基水凝胶贴剂中，以观察增强剂的效果。
当使用乙酸乙酯：薄荷醇：乙醇（1:1:1）的三元混合物与方波离子电渗法联合使用 1 小时时，MTX 的通量增强（161%）。与被动给药相比，在体外使用纯乙酸乙酯、其与乙醇的二元混合物以及其与乙醇和薄荷醇的三元混合物，通量增强分别为 71%、83%和 93.5%。然而，使用方波离子电渗法，通量分别增加到 126%、140%和 161%。生物物理工具如衰减全反射-傅里叶变换红外光谱（ATR-FTIR）、扫描电子显微镜（SEM）和组织病理学支持了通量增强的机制。ATR-FTIR 研究表明，与萜烯和离子电渗法分别分裂不对称 C-H 振动和酰胺 II 带。此外，乙酸乙酯的二元和三元混合物均未显示出酯峰，表明存在脂质提取。经化学增强剂与方波电渗联合处理的皮肤样本的 SEM 显示，毛发滤泡均发生肿胀和增大，从而支持更高的渗透性。对白化病小鼠经处理的皮肤样本的组织病理学研究表明，表皮变薄和局灶性破坏、海绵状、真皮水肿和附属物扩张。在体内研究中，在与方波联合使用乙酸乙酯的三元混合物的情况下，在小鼠中证明了 18.79 微克/毫升的血浆浓度，是口服给药的两倍。在体内进行的可逆性研究表明，上述增强剂引起的组织学变化在 48 小时内是暂时和可逆的。
上述结果表明，上述增强剂对皮肤安全且耐受良好。
