Leflunomide (LEF), a disease-modifying anti-rheumatic drug, has been widely explored for its anti-inflammatory potential in skin disorders such as psoriasis and melanoma. However, its poor stability and skin irritation pose challenges for topical delivery. To surmount these issues, LEF-loaded solid lipid nanoparticles (SLNs) integrated with hydrogels have been developed in the present investigation. SLNs developed by microemulsion techniques were found ellipsoidal with 273.1 nm particle size and −0.15 mV zeta potential. Entrapment and total drug content of LEF-SLNs were obtained as 65.25 ± 0.95% and 93.12 ± 1.72%, respectively. FTIR and XRD validated the successful fabrication of LEF-SLNs. The higher stability of LEF-SLNs (p < 0.001) compared to pure drug solution was observed in photostability studies. Additionally, in vitro anti-inflammatory activity of LEF-SLNs showed good potential in comparison to pure drugs. Further, prepared LEF-SLNs loaded hydrogel showed ideal rheology, texture, occlusion, and spreadability for topical drug delivery. In vitro release from LEF-SLN hydrogel was found to follow the Korsmeyer-Peppas model. To assess the skin safety of fabricated lipidic formulation, irritation potential was performed employing the HET-CAM technique. In conclusion, the findings of this investigation demonstrated that LEF-SLN hydrogel is capable of enhancing the photostability of the entrapped drug while reducing its skin irritation with improved topical delivery characteristics.
