POLYMER DELIVERY OF THE ACTIVE ISOMER OF MISOPROSTOL - A SOLUTION TO THE INTESTINAL SIDE-EFFECT PROBLEM

SC-53450 is a new polybutadiene-based polymer system with an acid labi le diisopropyl silyl ether linker to which the active isomer of misopr ostol (SC-30249) is attached covalently at position C-11. It was studi ed in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the s ystemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective a ctivity similar to misoprostol-HPMC, being protective against indometh acin-induced gastric, cysteamine/indomethacin-induced duodenal and ind omethacin-induced lower small bower damage. SC-53450, in contrast to m isoprostol-HPMC, was not diarrheagenic in the rat when administered in tragastrically. The observation that SC-53450 is more than 4 times mor e potent than misoprostol-HPMC suggests the possibility of sustained g astric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage i n normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, sugg esting SC-53450 will have reduced abuse potential in abortion inductio n. SC-53450 is a potential candidate to replace the present misoprosto l formulation in the marketplace for the prevention of nonsteroidal an ti-inflammatory drug-induced gastric damage.