Mouth ulcers are common oral lesions. Although several topical treatments are commercially available, their limited residence time requires frequent application, which remains a significant drawback. This study aimed to develop a novel mucoadhesive, thermosensitive, in situ gel-forming spray for local delivery of betamethasone sodium phosphate, thereby reducing systemic exposure. Formulations were optimized using the design of experiment approach to investigate the effects of thermosensitive polymers (Poloxamer 407 and Poloxamer 188), mucoadhesive polymer (hyaluronic acid), and drug incorporation on gelation temperature and time. The optimized formulation gelled at 33.3 ± 0.7 °C within 14.79 ± 1.87 s and showed a spray angle of 43.6 ± 0.62° at 3 cm (ovality ratio 1.1 ± 0.06), indicating consistent plume formation. This formulation demonstrated uniform spray dose delivery of ~99% drug content per actuation and exhibited good mucosal biocompatibility in histological studies. These findings suggest that the proposed in situ gel-forming spray is a promising localized delivery system for the effective management of aphthous ulcers.
