A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption

Abstract

To enhance the dissolution and oral absorption of poorly water-soluble itraconazole, self-emulsifying drug delivery system (SEDDS) composed of oil, surfactant and cosurfactant for oral administration of itraconazole was formulated, and its physicochemical properties and pharmacokinetic parameters of itraconazole were evaluated. Among the surfactants and oils studied, Transcutol (R), Pluronic (R) L64 and tocopherol acetate were chosen that showed the maximal solubility to itraconazole. The solubility of itraconazole was further improved by the addition of hydrochloric acid. Droplet size of itraconazole emulsion was kept constant both in simulated gastric fluid without pepsin (pH 1.2) and simulated intestinal fluid (pH 6.8) throughout 120-min incubation period. Itraconazole in the SEDDS rapidly dissolved in every dissolution medium whereas the Sporanox (R) showed different dissolution patterns during the 120-min incubation according to the dissolution media. In fasted and fed normal diet group, AUC(0 -> 24h) and the mean maximum plasma level (C-max) of itraconazole after oral administration of SEDDS in rats were comparable to those of itraconazole after oral dose of Sporanox (R). However, in fed lipidic diet group, AUC and C-max after oral administration of SEDDS in rats were 3.7- and 2.8-fold higher, respectively, compared with those of Sporanox (R). These results demonstrate that the SEDDS of itraconazole composed of Transcutol (R), Pluronic (R) L64 and tocopherol acetate greatly enhanced the bioavailability of itraconazole after the dose, particularly not influenced by food intake or not. Thus, this system may provide a useful dosage form for oral water-insoluble drug without food effect. (c) 2005 Elsevier B.V. All rights reserved.