Optimization, Characterization, and In Vitro Evaluation of Fusidic Acid‐Hydroxypropyl β‐Cyclodextrin Polymeric Complex Encapsulated Within a pH and Thermo‐Responsive N‐Isopropylacrylamide‐Itaconic Acid Nanogel
The emergence of antimicrobial resistance (AMR) necessitates the development of innovative delivery systems capable of maintaining enhanced therapeutic concentrations at the infection site. This study presents an innovative dual temperature and pH‐responsive nanogel system encapsulating poorly water‐soluble antibiotic fusidic acid, complexed with hydroxypropyl‐beta‐cyclodextrin (HPβCD) to improve solubility and facilitate controlled topical drug release. The fusidic acid‐HPβCD inclusion complex was synthesized to improve drug loading, and the resulting complex was encapsulated within nanogels (NGs). Fabricated via free radical polymerization, the optimized formulation (NIB‐7) demonstrated high drug entrapment efficiency (75.1% ± 1.7%) and exceptional pH responsiveness, exhibiting up to 600% ± 3.0% swelling at pH 7.4 compared to pH 1.2 (109.5% ± 3.0%). Characterization by Fourier Transform Infrared (FTIR) and Differential Scanning Calorimetry‐Thermogravimetric (DSC‐TGA) analysis demonstrated successful complexation and inclusion of the complex into a thermally stable nanogel matrix. A sustained release profile was demonstrated by in vitro release studies, with 76.5% ± 4.5% cumulative release observed over 48 h, prolonging the retention interval relative to the unencapsulated control. Kinetic modeling demonstrated that the drug release mechanism adheres to anomalous (non‐Fickian) transport ( n = 0.68, R 2 = 0.95), indicating that release is actively influenced by both fusidic acid diffusion and the reversible swelling/deswelling of the N‐Isopropylacrylamide‐Itaconic acid (NIPAM‐IA) polymer network in response to environmental stimuli (pH and temperature). This dual‐responsive system provides a promising foundation for localized and regulated antibiotic administration. The synergistic pairing of enhanced solubility by cyclodextrin complexation and the smart sustained release mechanism provided by thermo‐ and pH‐responsive nanogels offers significant possibilities to increase patient adherence and deal with antimicrobial resistance in the management of bacterial skin infections.