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.

Development of novel itraconazole-loaded solid dispersion without crystalline change with improved bioavailability

“…The solid dispersion gave higher plasma concentrations of drug compared to itraconazole power (not detected). Our results suggested that the higher initial plasma concentrations of itraconazole were due to the increased dissolution rate of drug in the solid (Yoo et al, 2000;Li et al, 2008). However, the total plasma concentrations of itraconazole in solid dispersion were not significantly different from those in commercial product in rats.…”

Studies on Formulation Development of Mucoadhesive Sustained Release Itraconazole Tablet Using Response Surface Methodology

“…7. A linear relationship was established between the peak area and Itraconazole in the concentration range of 0.1 and 20 μg mL The prepared mucoadhesive formulation exhibited C max 1898±75.23 ng/ml which is comparable to reported value of standard formulation sporanox (16), t max of the formulation was 2 h. The plasma concentrations of itraconazole were followed for 48 h and the AUC was observed to be 28,604.9 ng h/ml (Fig. 8), which is slightly better as compared to reported value for sporanox (23,382.2±6,326).…”

“…In vivo evaluation was carried out in rabbits of the optimized formulation of itraconazole tablets to establish the bioavailability of the formulation (16).…”

Development of self emulsifying drug delivery system of itraconazole for oral delivery: formulation and pharmacokinetic consideration

“…Thus, in spite of the high antifungal activity, the bioavailability of unformulated crystalline ITZ is extremely low (Jung et al 1999;Verreck et al 2003). In order to enhance its solubility and dissolution rate and thereby bioavailability, various formulations have been developed and ample literature is available (Miyake et al 1999;Peeters et al 2002;Jung et al 1999;Yoo et al 2000;Verreck et al 2003;Lee et al 2005;Janssens et al 2008;Hassan et al 2004;Nakarani et al 2010;Uch et al 1999;Gilis et al 1997).…”