10.22376/ijpbs.2019.10.1.p1-12 Volume 3 Issue 4 2012(October - December) Transdermal delivery system was the best alternative to oral dosage forms. Methotrexate was formulated in transdermal patches with different ratios of Ethyl cellulose and Hydroxy propyl methyl cellulose E15. Different chemical enhancers Tween-80, Span-80, Di-methyl sulphoxide, and Isopropyl myristate are used to enhance the drug delivery and its mechanism. The formulations were evaluated for lessThan i greaterThan In vitro lessThan /i greaterThan release, lessThan i greaterThan Ex-vivo lessThan /i greaterThan permeation studies. Further albino rats are used to study the skin irritation and pharmacokinetic parameters for optimized formulations. The mechanism of drug release follows the Higuchi kinetics and shows significance (p lessThan 0.01) with in the test formulations so, the drug release be both diffusion and erosion controlled rate release. DMSO shows prominent 7 fold increase of flux than the patches without enhancer. From the pharmacokinetic study it was observed that the bioavailability of patches significantly improved due to low elimination rate constant and high mean residence time of MTX (p lessThan 0.01). B.RAMA AND A.SHANTHA Methotrexate, Flux, SEM, Skin irritation, Pharmacokinetic, two-way Anova 36-47