Improved solubility and activity against Candida species of ketoconazole by complexation with β-cyclodextrin and proline

BRUNO A; AIASSA V; LONGHI MR; ZOPPI A

Rosario

Otro; 4° Reunión Internacional de Ciencias Farmacéuticas.; 2016

Fac. de Ciencias Químicas UNC-UNR

Introduction:Ketoconazole (KET) is an antifungal agent suitable for the treatment of candidiasis and other systemic fungal infections. The major drawback in the therapeutic efficacy of KET is its very low aqueous solubility. Multicomponent complexation with cyclodextrins (CD) has been used to improve the poor aqueous solubility of different drugs. In addition, the antimicrobial activity of nitric oxide (NO) against a wide array of microorganisms is well documented resulting synergistic with azoles. As proline (PRO) is considered a NO source, the objective of this work was to asses the effect of KET:βCD:PRO multicomponent complexation in the solubility and antifungal activity of KET.Materials and Methods:The effects of complexation on drug solubility, affinity constant (KC) and the stoichiometry for the complex were determined in water, by means of phase-solubility studies. In solid state, the ternary systems, prepared by physical mixture (PM) or freeze-drying (FD), were studied by fourier-transform infrared spectroscopy and scanning electron microscopy. The microbiological activity was evaluated by the agar diffusion test.Results and Discussion:The increase in solubility occurred as a linear function of βCD concentration, corresponding to an AL-type profile, with KC=5087±139 M-1, S0=(9±2)x10-3 mg/ml, Smax=0,61±0,01 mg/ml and ES (Smax/S0)=67,8. Taking into account the results obtained by the different techniques in solid state, by the different techniques, it is possible to confirm the formation of inclusion complexes between KET and βCD in presence of PRO, in systems prepared by FD. The PM shows a behaviour comparable with the pure compounds. Furthermore, the antifungal activity was improved.Conclusion:The complexation of KET with βCD and PRO is an effective strategy to increase its solubility and antifungal activity. Furthermore, the complex in solid state can be prepared by FD method, which might be useful on an industrial scale.