Microbiological and physicochemical studies of ketokonazole:B-cyclodextrin:citric acid multicomponent inclusion compounds

ARIANA ZOPPI; AGUSTINA BRUNO; LONGHI MARCELA R; AIASSA VIRGINA

Buenos Aires

Otro; Reunión Conjunta de Sociedades de Biociencias; 2017

SAFE

Abstract: Candida is an opportunistic yeast that causes severe diseases in immunocompromised individuals. Ketoconazole (KET) is an antifungal agent suitable for the treatment of candidiasis and other systemic fungal infections, classified as a class II drug in the Biopharmaceutics Classification System because of its low solubility and high permeability. Cyclodextrins (CD) multicomponent complexation is used to improve the poor aqueous solubility of different drugs. As citric acid (CA) is a pH-modifier used to increase solubility of weakly basic compounds, the aim of this work was to assess the effect of KET:βCD:CA multicomponent complexation in the solubility and antifungal activity of KET. The effects of complexation on drug solubility, was determined in water, by means of phase-solubility studies. In solid state, the multicomponent systems, prepared by physical mixture (PM) or kneading (K), were studied by Fourier-transform infrared spectroscopy, thermal analysis and scanning electron microscopy. The microbiological activity was evaluated by the agar diffusion test.The presence of βCD and CA caused a significantly increase in KET solubility with S0 of 0.542 µg/ml in water, 2.6 mg/ml in presence of CA (10 mM) and Smax of 3.8 mg/ml with CA and βCD (13.2 mM). Taking into account the results obtained by the different techniques in solid state, it is possible to confirm the formation of inclusion complex between KET and βCD in presence of CA, in systems prepared by K. The PM shows a behaviour comparable with the pure compounds. Furthermore, the antifungal activity against Candida albicans y C.parapsilosis was significantly improved (p<0.05).In summary, the multicomponent system prepared in our study, with simultaneous enhancement of KET solubility and microbiological activity, might have an important pharmaceutical potential in the development of a better antifungal formulation of KET.Keywords: ketoconazole, cyclodextrin, citric acid, solubility, antifungal activity.