Design and preclinical evaluation of a pH-responsive combined drug in situ gel for management of cellulitis.

Global disease patterns are being rapidly reshaped by environmental changes such as rising temperatures, pollution, and more frequent natural disasters. Notable effects include a rise in skin infections, such as cellulitis, as well as upper respiratory and urinary tract infections. Cellulitis, an acute bacterial infection predominantly caused by S. aureus and Streptococcus species, is clinically challenging due to recurrence, primarily because of antimicrobial resistance and limitations of standard systemic therapies. Oral antibiotics like ofloxacin, though effective, are associated with significant suboptimal drug localization, systemic adverse effects and necessitate reliable and more targeted therapeutic approaches. This study reports the development and optimization of a pH-sensitive nanoparticle-loaded in situ gel for the local management of cellulitis. As the encapsulating polymer, Eudragit® S100 was used to load Ofloxacin via the nanoprecipitation method and optimized through Design of Experiments, achieving high entrapment efficiency of ∼96% and a nano size of 85-110 nm. These nanoparticles were incorporated into a Carbopol-HPMC-based in situ gel containing lidocaine to provide immediate pain-relieving action. The system exhibited pH-triggered sol-gel transition, enhanced viscosity under simulated wound conditions, and sustained drug release following controlled kinetics. In vitro and ex vivo studies demonstrated prolonged drug release post permeation, effective antimicrobial activity driven by MIC and MBC tests, and improved retention. In vivo evaluation in S. aureus-infected rat models confirmed reduced lesion severity, absence of skin irritation, inflammation and accelerated healing. Overall, this dual-delivery platform renders a promising scheme for concurrent pain management and sustained antimicrobial therapy, potentially improving patient compliance by altering therapeutic outcomes in cellulitis treatment.