Formulation and Characterisation of Azathioprine-Loaded Nanosponges for Topical Gel Delivery

Objective: The present study aimed to formulate, optimise, and characterise azathioprine-loaded nanosponges and incorporate them into a topical nanogel system to achieve sustained in vitro drug release and improved topical delivery. Methods: Compatibility of azathioprine with β-cyclodextrin, 1,2,3,4-butanetetracarboxylic acid (BTCA), and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was evaluated using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Azathioprine-loaded nanosponges were prepared by the emulsion-solvent evaporation method and optimised using a Box–Behnken design (BBD). Concentrations of β-cyclodextrin, BTCA, and TPGS were selected as independent variables, whereas particle size, polydispersity index (PDI), and entrapment efficiency (%EE) were considered dependent responses. The optimised nanosponges were incorporated into a Carbopol-based nanogel and evaluated for physicochemical characteristics, rheological behaviour, in vitro drug release, and accelerated stability. Results: Among 15 formulations, F10 was selected as the optimised formulation, exhibiting a particle size of 276.3 nm, PDI of 0.136, zeta potential of −25.6 mV, and %EE of 84.14%. FTIR, DSC, and XRD analyses indicated excipient compatibility and reduced azathioprine crystallinity. Scanning electron microscopy (SEM) revealed spherical nanosponges with an average dry particle size of 231.4±28.7 nm. Sustained drug release was observed for 12 h, reaching 96.31±1.18% (n = 3). Release kinetics followed the Higuchi model based on the highest adjusted R² and lowest Akaike information criterion (AIC). The nanogel exhibited a pH of 5.52±0.01, viscosity of 1035±2.27 cP, drug content of 91.41±0.19%, and spreadability of 93.49±1.09%. The formulation remained physicochemically stable during a three-month preliminary accelerated study conducted under International Council for Harmonisation (ICH) conditions of 40±2 °C/75±5% relative humidity (RH). Longer-term ICH stability studies are required to establish shelf life. Conclusion: The optimised azathioprine-loaded nanosponge gel exhibited sustained drug release, favourable physicochemical and rheological properties, and promising potential for prolonged topical drug delivery.