Sustained-release multiparticulate formulations of Zileuton .1. In vitro and in vivo evaluation

Zileuton is an active 5-lipoxygenase inhibitor which has been shown to be useful in the treatment of asthma. However, it requires dosing four times per day. In order to investigate the feasibility of developing sustained-release formulations of zileuton, two multiparticulate matrix formulations (A and B) with different in vitro release rates were prepared using extrusion/spheronization techniques. Oral absorption from the two formulations was compared with a solution formulation in a three-way crossover study using fed beagle hogs. The results indicated sustained release of zileuton from both multiparticulate formulations with prolonged T-max (4.72 h for formulation A and 3.67 h for formulation B vs. 1.21 h for the oral solution) and decreased C-max (1.21 mu g/ml for formulation A and 4.14 mu g/ml for formulation B vs. 9.07 mu g/ml for the oral solution). Based on 90% confidence intervals, both matrix formulations were less bioavailable than the solution in terms of the extent of absorption. The estimates of relative bioavailability were 15 +/- 3% and 48 +/- 7% for formulation A and B, respectively. It is possible that these formulations may offer better bioavailability in humans due to inherent physiological differences between humans and animals. In vivo drug release from the sustained-release matrix formulations in dogs was estimated by deconvolution based on data of both formulations and correlated well with in vitro dissolution data.