DESIGN OF SUSTAINED-RELEASE MATRIX SYSTEMS FOR A HIGHLY WATER-SOLUBLECOMPOUND, ABT-089

ABT-089 is a potent cholinergic channel modulator under investigation for treatment of cognitive disorders. It is a highly water soluble com pound with a short elimination half-life of 1.7 h in dogs. Hydrophilic and hydrophobic matrix systems were designed to investigate the feasi bility of prolonged oral delivery of ABT-089 and to explore the prelim inary in vitro and in vivo correlations. The sustained-release single and layered matrix tablets were prepared by compression. In vitro rele ase testing using a USP apparatus II was performed for formulation scr eening. The release rates were modulated by varying concentrations of different types of rate controlling materials and by restricting surfa ce area available for drug release. The transport mechanism of the com pound from different types of systems typically followed Fickian diffu sion. Based on the in vitro release characteristics, two types of prot otype matrix systems were evaluated in beagle dogs. Both formulations provided prolonged plasma levels of ABT-089 above the minimum effectiv e concentration for over 22 h with reduced fluctuation of plasma level s. In vivo drug release from the tablet matrix estimated by deconvolut ion correlated well with drug release in vitro. In conclusion, prolong ed oral delivery of highly soluble ABT-089 was achieved using diffusio n controlled matrix systems. The hydrophobic matrix was found to be mo re effective than hydrophilic matrix in extending the release of the c ompound. Linear relationships between in vitro and in vivo drug releas e indicated by the initial results for both types of systems can provi de useful information for further formulation development. (C) 1997 El sevier Science B.V.