NEW SOLID KETOCONAZOLE: SALICYLIC ACID DEVELOPMENT, CHARACTERIZATION AND EVALUATION ANTIBIOFILMS

Rosario

Otro; 7ma Reunión Internacional de Ciencias Farmacéuticas; 2023

Reunión Internacional de Ciencias Farmacéuticas

Invasive fungal infections caused by Candida spp. are a major cause of morbidity andmortality, especially in immunocompromised and critically ill patients. The progressive increase inantimicrobial drug resistance, combined with the ability of fungi to form biofilms, complicates thissituation. Moreover, it represents an additional challenge for the effective treatment of Candidaspp. infections.A promising strategy to overcome this challenge is the development of drug combinationscontaining one compound with known antifungal action and another compound that has reportedantifungal capacity.Ketoconazole (KTZ) is a synthetic imidazole antifungal agent widely used to treat fungal infections,characterized by its low aqueous solubility. Salicylic acid (SA), which is used in skin care products,has been shown to have activity against Candida spp.In this context, the preparation and characterization of systems combining KTZ and SA in anequimolar ratio (1:1) were carried out. In addition, the solubility of this system and its antibiofilmactivity compared to pure KTZ were determined.The new KTZ:SA solids in a 1:1 molar ratio were obtained by melting and physical mixing (PM) of thecomponents. They were characterized by infrared spectroscopy (FTIR), hot-stage microscopy (HSM),powder X-ray diffraction (PXRD), and thermogravimetric analysis (TGA). The saturation solubility ofsystems was determined by equilibrating excess powder in water for 72 h on a mechanical shakerat 37 °C. The minimum inhibitory concentration (MIC) was determined by the microdilution methodaccording to the Clinical Laboratory Standards Institute (CLSI). The antibiofilm activity wasdetermined by the MTT assay and by confocal laser scanning microscopy (CLSM) against clinicalstrains of C. albicans and C. tropicalis.The melting process produced a solid with a red color. FTIR analysis suggests ionic drug-druginteractions, and PXRD studies evidence the amorphous state of the solid formed. The solid has aglass transition temperature of 70 °C, according to HSM analysis, while TGA studies show that thesystem's thermal degradation begins at 186°C. There was a 520-fold increase in solubility comparedto pure KTZ. Further, KTZ:SA showed a decrease in biofilm formation in the clinical strains of C.albicans and C. tropicalis compared to pure KTC. These results were contrasted in C. tropicalis bythe CLMS studies: pure KTZ only alters fungal cell morphology, whereas KTZ:SA alters morphologyand reduces notably the number and density of cells per field.In conclusion, a new solid KTZ:SA system was obtained, and it was characterized as a promisingcombination against a form of resistance to antimicrobials, such as biofilm formation.