Pharmacokinetic evaluation of fulvic acid-ketoconazole complexes: A validation and line extension study

Abstract

Poor aqueous solubility and bioavailability of the drugs is the major impediment in the field of drug development. Amongst the various solubility enhancing techniques, complexation of the ketoconazole with the peat sourced fulvic acid was adopted in the current study. Phase solubility study revealed that at 4%w/v of fulvic acid, maximum amount of drug gets entrapped. Further the complex of fulvic acid with ketoconazole was prepared in a molar ratio of 1:1 (w/w) by freeze drying method and characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD) and Fourier Transforms Infra-Red Spectroscopy (FT-IR). All these studies confirm the formation of an amorphous inclusion complex. Phase solubility study with fulvic acid indicates that maximum percentage increase in solubility of the KTZ was found to be 621 ± 2.3%, whereas with the Shilajit derived HA it was reported as 645.2%. In 60 min, 45% release was obtained with the pure drug, 82% with the peat sourced fulvic acid complexed drug and 81% with the shilajit derived humic acid complex. It was found that 68% of the pure drug and 95% of the complexed drug gets permeated across the intestinal gut sac whereas it is reported that with shilajit derived humic acid 3.7 times drug gets permeated. With the pure drug Cmax, tmax and AUC was found to be as 2.64 µg/ml, 0.5 h and 7.39 µg/ml*h, whereas with the complexed drug Cmax, tmax and AUC was found to be as 5.1 µg/ml, 1.0 h and 15.51 µg/ml*h.Antifungal study conducted on Candida albicans and Tricophytonrubrum indicates that the fulvic acid alone does not have promising anti-fungal activity but when complexed with KTZ, it enhances the antifungal activity of the pure drug. Hence it can be concluded that peat sourced derived fulvic acid can be used as a promising complexing agent for enhancing the solubility and bioavailability of the ketoconazole.