Silibinin-Loaded Proniosomal Gel for Cutaneous Application: Pharmaco-Technical Characterization and In Vitro–In Ovo Biocompatibility

The skin serves as the first line of defense, being highly prone to external damage. Silibinin (SIL) exerts skin-protective properties, but its topical use requires a suitable delivery system. Despite the growing interest in proniosomal platforms loaded with natural products, their application for the cutaneous delivery of SIL remains scarcely explored. This study proposes the pharmaco-technical characterization and preclinical safety evaluation of a SIL-loaded proniosomal gel (SIL-PG) for skin application. SIL-PG was produced using the coacervation phase separation technique, analyzed in terms of physicochemical and technological properties, and evaluated in vitro and in ovo for potential cytotoxic and irritant effects. SIL-PG retained a yellowish, creamy aspect, proper rheological behavior and spreadability, gradual in vitro drug release, sustained permeation, and an adequate safety profile, evidenced by the lack of cytotoxicity in HaCaT keratinocytes and spheroids and the absence of irritant potential in 3D EpiDerm™ reconstructed human tissues and on the chorioallantoic membrane. Overall, these findings emphasize SIL-PG as a potential pharmaceutical formulation for dermal use, with favorable pharmaco-technical characteristics and in vitro-in ovo biocompatibility.