Quality-by-design Driven Formulation Development of Propellent Free Foam Formulation for Effective Burn-related Wound Healing: A Comprehensive Preclinical Study.

Burn wound infections remain a major clinical challenge due to extensive tissue damage, delayed healing, and increased susceptibility to microbial contamination, which can limit the effectiveness of conventional topical formulations. This study aimed to develop and optimize a Quality-by-Design (QbD)-based non-propellant foam (NPF) containing silver nitrate, chlorhexidine, and asiaticoside for enhanced burn wound management. A sequential design of experiments strategy was employed, involving Taguchi L8 screening followed by Box-Behnken optimization to identify the critical formulation variables influencing foam performance and drug release. The optimized formulation exhibited desirable physicochemical characteristics, including a foam density of 0.192 ± 0.002 g/mL, a skin-compatible pH of 5.56 ± 0.04, uniform drug content (98-99%), and satisfactory foam stability. In-vitro studies demonstrated cumulative drug release of 94.69% chlorhexidine, 82.13% asiaticoside, and 78.63% silver nitrate within 6 h, with the release profiles predominantly following the Higuchi diffusion model. Accelerated stability studies indicated that the formulation remained stable over six months. In a Sprague-Dawley rat burn wound model, the optimized foam achieved 93.29 ± 1.75% wound contraction by day 14, outperforming both the untreated control and the marketed formulation. Furthermore, biochemical analyses revealed increased hydroxyproline, hexosamine, and hexuronic acid levels, while histopathological examination confirmed enhanced collagen deposition, neovascularization, and re-epithelialization. These findings demonstrate that the developed QbD-based non-propellant foam represents a promising preclinical topical delivery platform capable of supporting both antimicrobial protection and tissue repair during burn wound healing.