Formulation of a Modified Aloe vera-Based Emulgel for Sustained Release of Methotrexate: Integrated Experimental and Theoretical Approaches.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by chronic inflammation of synovial joints, for which methotrexate remains the first-line therapy. However, conventional methotrexate administration is often limited by systemic toxicity and uncontrolled drug release. In this study, a methotrexate-loaded Aloe vera-based emulgel was developed to achieve sustained drug delivery and enhanced anti-inflammatory efficacy. Four emulgel formulations with varying compositions were prepared and evaluated for physicochemical characteristics, including appearance, rheological behavior, spreadability, average globule size, zeta potential, drug content, and in vitro drug release. Aloe vera-containing formulations demonstrated sustained methotrexate release, with more than 60% of the drug released over 6 h, and the release kinetics were best described by the Weibull model. In contrast, non-Aloe vera formulations exhibited rapid drug release (>80% within 2 h) following Michaelis-Menten kinetics, indicating the critical role of Aloe vera in modulating release behavior. The optimized emulgel showed significant anti-inflammatory activity by inhibiting protein denaturation, achieving up to 93% inhibition of bovine serum albumin and 95% inhibition of egg albumin, comparable to diclofenac. Cytotoxicity studies revealed minimal to negligible toxicity toward normal peripheral blood mononuclear cells and splenocytes over 24-96 h, confirming good biocompatibility. Density functional theory calculations indicated stable adduct formation between methotrexate and bioactive constituents of Aloe vera, supporting their role as effective drug carriers. Molecular docking studies further suggested enhanced binding affinity of these adducts toward cyclooxygenase-2 compared to methotrexate alone. Overall, the findings suggest that methotrexate-loaded Aloe vera-based emulgel is a safe and promising therapeutic platform for improved management of rheumatoid arthritis.