Fabrication and Evaluation of Pemetrexed Disodium Transdermal Patches Using a DoE Approach

Pemetrexed disodium, a multi‐targeted antifolate, exhibits significant therapeutic potential for autoimmune diseases and cancers. However, its clinical application remains restricted due to poor oral bioavailability and severe systemic side effects. Transdermal drug delivery serves as a non‐invasive alternative that enhances localized drug action while minimizing systemic toxicity. This study develops and optimizes pemetrexed disodium‐loaded transdermal patches using hydrophilic polymers, including α‐tocopherol polyethylene glycol succinate and hydroxypropyl methylcellulose, to achieve controlled drug release while reducing systemic side effects. The solvent casting technique fabricates the transdermal patches, incorporating aloe vera gel as a permeation enhancer and polyethylene glycol 400 as a plasticizer. A Box–Behnken design optimizes formulation variables such as polymer concentration and temperature, assessing their effects on viscosity, patch thickness, and zeta potential. Characterization studies include physicochemical evaluation, in vitro drug release analysis, and scanning electron microscopy for surface morphology assessment. Drug release kinetics follow zero‐order, Higuchi, and Korsmeyer‐Peppas models. The optimized patches exhibit favorable mechanical properties, pH compatibility (5.2–5.6), tensile strength (9.4–12.2 kg/cm 2 ), and folding endurance (> 60 folds). In vitro studies confirm sustained drug release, with formulations OF4 and OF5 demonstrating superior efficiency. SEM analysis reveals a uniform, defect‐free surface. These transdermal patches offer a promising alternative for managing autoimmune diseases like psoriasis, with further in vivo studies needed for clinical validation.