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

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 CAP1 and NCAP1) or insoluble polymer alone (referred to as CAP2 and NCAP2).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 CAP2, NCAP1 and NCAP2 were undetectable, indicating that the drug release was almost zero from the preparations throughout the gastro-intestinal tract. The Cmax, Tmax and AUC(0→24) of CAP1 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 CAP1 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.

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