Poluri Koteswari*

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor with limited therapeutic options, largely due to poor drug penetration across the blood–brain barrier (BBB). Capecitabine, a prodrug of 5-fluorouracil, has demonstrated potential against glioblastoma; however, its short half-life and limited brain delivery may restrict its therapeutic efficacy. This study aimed to develop and evaluate a thermoresponsive intranasal nanoemulsion-based in situ gel of capecitabine for potential nose-to-brain delivery in GBM therapy. Capecitabine-loaded nanoemulsion in situ gels were prepared using triolein, egg lecithin, and Pluronic F127 and F68 by emulsification followed by probe sonication. The formulations were evaluated for physicochemical characteristics, drug content, thermal compatibility, morphology, and in vitro drug release. The optimized formulation (F5) exhibited a gelation temperature of 33.2 ± 0.45 °C and a pH of 6.4, indicating suitability for intranasal administration. F5 showed an average droplet size of 219.7 nm, polydispersity index of 0.12, and zeta potential of −16.6 mV, indicating a uniform and stable nanoemulsion system. The drug content was 97.67 ± 1.564%. Differential scanning calorimetry confirmed compatibility between capecitabine and the formulation excipients, while scanning electron microscopy revealed spherical lipid droplets dispersed within the gel matrix. The optimized formulation demonstrated sustained drug release, achieving 99.64 ± 0.119% cumulative release over 8 h. Drug release kinetics followed the Higuchi and Korsmeyer–Peppas models, suggesting diffusion-controlled release. Overall, the developed thermoresponsive intranasal nanoemulsion-based in situ gel demonstrates promising physicochemical and drug-release characteristics for potential nose-to-brain delivery of capecitabine in glioblastoma therapy.