Development of arsenic trioxide sustained-release pellets for reducing toxicity and improving compliance

Abstract

Arsenic trioxide (ATO) is first-line drug for acute promyelocytic leukemia. Clinically, the continuously slow intravenous infusion is adopted to maintain effective blood concentration and reduce toxic effects, but it causes poor patient' compliance for a considerable infusion period. To overcome these disadvantages, we developed an oral ATO sustained-release preparation which was constructed via the ATO core pellets prepared by extrusion spheronization and followed by a coating membrane by fluid-bed technology. The prepared coated pellets displayed a round surface and uniform particle size. All in vitro release profiles of ATO pellets in different pH media and rotation speeds had no statistical difference. Importantly, the coated pellets can release completely in 12 h without obvious burst release. There was no distinct change in appearance and release behaviors in stability experiments. In vivo pharmacokinetics was studied by one-time intragastric administration of rats. Compared with free drug, the AUC0–∞ of the ATO coated pellets was 2.3-fold higher, indicating the oral bioavailability was significantly increased. Cmax decreased by about a half and Tmax extended about 15 h. In particularly, the ATO level at 96 h only decreased about 20% of Cmax , suggesting that the ATO sustained-release preparation could not only decrease the peak concentration, but also maintain a relatively constant blood concentration for a long period. Further, the in vivo absorption could be well predicted by in vitro release experiments. Therefore, the ATO sustained-release preparation formulated by the mature preparation technology, possessing satisfactory stability and improving bioavailability, had great application potentials for industrialization.