Dual-Cross-Linked Alginate Hydrogels as a Strategy to Improve the Antifungal Properties of Posaconazole

<b>Background/Objectives</b>: Despite the continuous development of medicine, the treatment of dermatological fungal infections is difficult due to their chronic nature, recurrence, and resistance of some pathogens to standard therapies. In order to improve the effectiveness of treatment, not only are new active substances with antifungal activity synthesized, but new, unconventional carriers are also developed for substances already used. <b>Methods</b>: Therefore, the focus of this research was to evaluate the possibility of using a combination of two cross-linking techniques for sodium alginate ionic cross-linking with Zn²⁺ ions and electrostatic interaction with ε-poly-L-lysine. The pharmaceutical properties, antifungal activity against <i>Candida</i> strains, and compatibility with human fibroblasts of the designed hydrogels were assessed. <b>Results</b>: It was shown that the double cross-linking process increased the viscosity of the developed hydrogels, improved bioadhesive properties to hairless mice skin, and provided an extended release profile of the active substance. In addition, obtained formulations were characterized by improved antifungal effect against <i>C. albicans</i>, <i>C. krusei</i>, and <i>C. parapsilosis</i>. Prepared hydrogels expressed biocompatibility with human fibroblasts. <b>Conclusions</b>: Dual-cross-linked alginate hydrogels are a promising dermatological formulation that might improve the efficacy of posaconazole in the treatment of antifungal infections.