Colon-targeted pH-responsive tofacitinib beads improve ulcerative colitis outcomes with lower systemic exposure

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease resulting in mucosal inflammation and ulceration. Although tofacitinib, a Janus kinase inhibitor, is effective when administered systemically, its clinical use may be limited by systemic adverse effects. Thus, this study aimed to design and evaluate a colon‑targeted tofacitinib delivery system based on sodium alginate beads coated with Eudragit® S‑100 in a dextran sulfate sodium (DSS) induced colitis rat model. Tofacitinib was encapsulated within alginate beads and subsequently coated with Eudragit® S-100 for pH-dependent release. The beads were characterized for size, encapsulation efficiency, stability, and
in vitro
drug release. Therapeutic efficacy was evaluated in a 30-day DSS colitis model by histopathology, cytokine profiling, and drug concentrations in plasma and colon tissue. The colon-targeted beads exhibited minimal release under acidic gastric conditions and maximum release at the colonic pH.
In vivo
, the formulation significantly improved disease activity scores, preserved colonic architecture, and significantly reduced pro-inflammatory cytokines levels while increasing IL-10 levels. Colonic drug levels achieved with the formulated beads were substantially higher than those obtained with non‑formulated tofacitinib, accompanied by markedly reduced systemic exposure. As a conclusion, the colon-targeted tofacitinib delivery system may limit systemic exposure relative to conventional oral administration while maintaining therapeutic efficacy in experimental colitis. Nevertheless, comprehensive toxicological and long‑term safety studies are required before definitive conclusions regarding safety can be drawn.