Design of sustained-release matrix systems for a highly water-soluble compound, ABT-089

Abstract

ABT-089 is a potent cholinergic channel modulator under investigation for treatment of cognitive disorders. It is a highly water soluble compound with a short elimination half-life of 1.7 h in dogs. Hydrophilic and hydrophobic matrix systems were designed to investigate the feasibility of prolonged oral delivery of ABT-089 and to explore the preliminary in vitro and in vivo correlations. The sustained-release single and layered matrix tablets were prepared by compression. In vitro release testing using a USP apparatus II was performed for formulation screening. The release rates were modulated by varying concentrations of different types of rate controlling materials and by restricting surface area available for drug release. The transport mechanism of the compound from different types of systems typically followed Fickian diffusion. Based on the in vitro release characteristics, two types of prototype matrix systems were evaluated in beagle dogs. Both formulations provided prolonged plasma levels of ABT-089 above the minimum effective concentration for over 22 h with reduced fluctuation of plasma levels. In vivo drug release from the tablet matrix estimated by deconvolution correlated well with drug release in vitro. In conclusion, prolonged oral delivery of highly soluble ABT-089 was achieved using diffusion controlled matrix systems. The hydrophobic matrix was found to be more effective than hydrophilic matrix in extending the release of the compound. Linear relationships between in vitro and in vivo drug release indicated by the initial results for both types of systems can provide useful information for further formulation development.