Formulation and Pharmacological Evaluation of Budesonide-Loaded Zinc-Crosslinked Chitosan Nanocomposite Spheroids in TNBS-Induced Colitis

Abstract

Background: Inflammatory bowel disease, particularly ulcerative colitis, requires effective delivery of anti-inflammatory drugs to the inflamed colonic mucosa while minimizing systemic exposure. Budesonide is a potent topical corticosteroid; however, its low oral bioavailability and extensive first-pass metabolism limit its therapeutic availability. The present study aimed to develop and optimize budesonide-loaded zinc-crosslinked chitosan (Zn-CS-BUD) nanocomposite spheroids for pH-responsive, mucus-penetrating, and sustained colonic drug delivery. Methods: Zn-CS-BUD nanocomposite spheroids were prepared using a modified ionic gelation technique followed by zinc crosslinking. A 3² full factorial design was employed to investigate the effects of CS:TPP ratio and ZnCl₂ concentration on particle size and entrapment efficiency. The optimized formulation was characterized for particle size, PDI, zeta potential, entrapment efficiency, drug loading, swelling behavior, morphology, mucus penetration, and pharmacokinetic performance. Results: Numerical optimization identified a CS:TPP ratio of 1.5:1 and ZnCl₂ concentration of 0.55% w/v as the optimum formulation. The optimized spheroids exhibited a particle size of 245.3 ± 8.2 nm, PDI of 0.23 ± 0.02, zeta potential of −18.2 ± 1.3 mV, entrapment efficiency of 78.6 ± 3.4%, and drug loading of 12.4 ± 1.2%. The formulation demonstrated pH-responsive swelling, with a swelling index of 218.4 ± 8.2% at pH 7.4 after 12 h. Mucus penetration was significantly enhanced, with 62.4 ± 5.8% translocation through mucus compared with 22.3 ± 3.2% for conventional positively charged chitosan nanoparticles. Pharmacokinetic evaluation demonstrated a prolonged Tmax of 6 h, increased AUC₀–₂₄ to 3218.5 ± 245.2 ng·h/mL, and prolonged elimination half-life to 8.2 ± 0.6 h compared with budesonide suspension. Conclusion: The optimized zinc-crosslinked chitosan nanocomposite spheroids demonstrated favorable physicochemical characteristics, pH-responsive swelling, enhanced mucus penetration, and sustained pharmacokinetic behavior. The findings support Zn-CS-BUD spheroids as a promising platform for targeted and sustained colonic delivery of budesonide in inflammatory bowel disease.