Preparation and in vitro–in vivo evaluation of none gastric resident dipyridamole (DIP) sustained-release pellets with enhanced bioavailability

Abstract

The objective of this study was to develop none gastric resident sustained-release pellets loaded with dipyridamole with a high bioavailability. Two different kinds of core pellets, one containing citric acid as a pH-modifier (CAP) and, the other without pH-modifier (NCAP) were prepared by extrusion-spheronization and then coated with mixtures of enteric soluble and insoluble polymers (referred to as CAP 1 and NCAP 1) or insoluble polymer alone (referred to as CAP 2 and NCAP 2). The relative bioavailability of the sustained-release pellets was studied in fasted beagle dogs after oral administration using a commercially available immediate release tablet (IRT) as a reference. The in vitro release, in vivo absorption and in vitro–in vivo correlation were also evaluated. Results revealed that the plasma drug concentrations after administration of CAP 2, NCAP 1 and NCAP 2 were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The C max, T max and AUC (0→24) of CAP 1 were 0.78 ± 0.23 (μg/ml), 3.80 ± 0.30 (h), and 6.74 ± 0.47 (μg/ml h), respectively. While the corresponding values were 2.23 ± 0.32 (μg/ml), 3.00 ± 0.44 (h) and 9.42 ± 0.69 (μg/ml h) for IRT. The relative bioavailability of CAP 1 was 71.55% compared with IRT. By combined incorporation of a pH-modifier into the core of pellets to modify the inner micro-environment and employing mixtures of enteric soluble and insoluble polymers as a retarding layer, drugs with high solubility in stomach and limited solubility in small intestine, such as DIP, could be successfully formulated as sustained release preparations with no pH-dependence in drug release and enhanced bioavailability.