QbD-Based Development of a pH-Responsive SLN-Loaded Hydrogel for Topical Management of Biofilm-Associated Diabetic Foot Ulcers.

Abstract

Introduction: Diabetic foot ulcers (DFUs) are difficult to treat due to biofilm formation, poor drug penetration, and elevated wound pH. This study aimed to develop a pH-responsive solid lipid nanoparticle (SLN)-loaded hydrogel for targeted ciprofloxacin delivery using a Quality-byDesign (QbD) approach.

Methods: SLNs were formulated via solvent emulsification-ultrasonication and optimized using a Box-Behnken design to study the effects of lipid concentration, surfactant concentration, and sonication time on particle size and entrapment efficiency. Optimized SLNs were coated with pHsensitive Eudragit L100 and incorporated into a Carbopol 974P hydrogel. The formulation was evaluated for particle size, zeta potential, entrapment efficiency, rheology, spreadability, occlusion, drug release, antimicrobial activity, and three-month stability.

Results: Optimized SLNs showed a particle size of 141.24 ± 2.19 nm, polydispersity index (PDI) 0.236 ± 0.019, zeta potential -26.28 ± 1.31 mV, and an entrapment efficiency of 62.55 ± 1.07%. The hydrogel exhibited pseudoplastic flow, good spreadability, and enhanced occlusivity. Drug release was sustained and pH dependent, with greater release at pH 7.4 than at pH 5.5. The SLNloaded hydrogel showed stronger antibacterial activity than the free drug gel against E. coli, S. aureus, and P. aeruginosa. The formulation remained stable for three months at 4 °C with minimal variation in physicochemical properties.

Discussion: The pH-responsive coating enabled targeted release in alkaline DFUs, and the SLN- hydrogel system improved drug retention, antibacterial activity, and formulation stability.

Conclusion: A stable, pH-responsive SLN-loaded hydrogel was successfully developed, demonstrating strong potential for targeted topical treatment of biofilm-associated DFUs and future clinical application.