Enhanced antifungal activity of itraconazole by the supercritical antisolvent technique

Itraconazole is broad spectrum antifungal drug that have problems of poor solubility and bioavailability of conventional dosage forms. Attempts to overcome the solubility problems are solubilisation with mixed micelles or... [ view full abstract ]

Itraconazole is broad spectrum antifungal drug that have problems of poor solubility and bioavailability of conventional dosage forms. Attempts to overcome the solubility problems are solubilisation with mixed micelles or forming a complex using cyclodextrins but these approaches are of limited success. One tried to improve the in vivo performances of poorly soluble drug by reducing the particles size using supercritical antisolvent technique (SAA). Micronization of itraconazole dissolved in acetone, dimethyl sulfoxide and ethanol with supercritical carbon dioxide as antisolvent was successfully performed using a supercritical antisolvent technique. The effect of a few process parameters such as precipitation temperature, the pressure and solute concentration in the liquid solution has been studied to evaluate their influence on morphology and size of particles. The micronised itraconazole were evaluated for drug content, particle size analysis and in vitro dissolution profiles. Fourier transform infrared spectroscopy, differential scanning calorimetry and PXRD patterns was used to study the possible changes after micronization of itraconazole. The dissolution rate was increased after micronized compared with pure itraconazole in distilled water, pH 1.2 buffer and pH 7.0 buffer. Micronized and pure itraconazole were evaluated for their therapeutic efficacy in the treatment of experimental oral candidiasis induced by Candida albicans in immunosuppressed rats. This antifungal activity was analyzed by microbiological and histopathological techniques. Microbiologically, micronized itraconazole significantly (p<0.05) reduced the number of colony forming units (CFU) sampled from the oral cavity of rats treated for eight consecutive days, compared to untreated control rats. Histologically, the untreated control animals showed numerous hyphae on the epithelium of the dorsal surface of the tongue. In contrast no hyphal colonization of the epithelium was seen in micronized itraconazole-treated animals indicating improved bioavailability of micronised itraconazole as compared with pure itraconazole. In conclusion, SAA process could be a useful method for the micronization of itraconazole and its solubility, dissolution rate and antifungal activities were significantly increased by micronization. Improve the in vivo performances of poorly soluble drug by reducing the particles size using supercritical antisolvent technique (SAA) is a novel approach.