Bioavailability of Itraconazole in Rats and Rabbits After Administration of Tablets Containing Solid Dispersion Particles

Abstract

A tablet dosage form containing solid dispersions of itraconazole (Asd tablets) was prepared by using the spray-drying and wet granulation methods. The dissolution rate of itraconazole from Asd tablets was fast, with more than 90% released within 10 min, compared to less than 20% for a marketed product, Sporanox® capsules. The oral absorption of itraconazole from Asd tablets was determined in rats and rabbits and was compared with that for Sporanox capsules. In the rat, there was no difference between the Asd tablets and Sporanox capsules in the mean area under the curve (AUC) (3089.5 ± 4332.8 ng · hr/ml and 3653.9 ± 2348.9 ng · hr/ml, respectively) and Cmax (295.0 ± 344.5 and 390.5 ± 169.4 ng/ml, respectively). Also, in the rabbit, no difference was found between the two products in the mean AUC (AUMC; 19357.9 ± 5117.5 ng · hr/ml and 23382.2 ± 6236.5 ng · hr/ml, respectively) and Cmax (766.4 ± 276.5 and 1127.5 ± 577.9 ng/ml, respectively). Despite the rapid in vitro release characteristics of itraconazole from the Asd tablets, the in vivo absorption of itraconazole was comparable to that of Sporanox capsules, with no difference in Tmax in both animal species. Serum levels of the major active metabolite hydroxyitraconazole were also measured. Itraconazole was rapidly converted to hydroxyitraconazole in both rats and rabbits, but there were species-specific differences in their pharmacokinetics. It is concluded that, in addition to drug solubility and dissolution characteristics, other formulation factors such as the physical state of the drug and the granulation process, may also need to be considered in the prediction of the in vivo absorption of itraconazole based on in vitro data.