POLYMERIC DELIVERY OF THE ACTIVE ISOMER OF MISOPROSTOL REDUCES SYSTEMIC AVAILABILITY AND UTEROTONIC ACTIVITY

SC-30249 is the active isomer of misoprostol responsible for its mucos al protective effects against nonsteroidal anti-inflammatory drugs (NS AIDS). Linkage of SC-30249 to a polybutadiene polymer results in a del ivery system (SC-55307) that releases the active component only under the acidic conditions of the stomach. This approach could be used to m inimize side effects and systemic availability of synthetic prostaglan dins. These studies were done to determine whether uterotonic activity could be recorded after treatment with SC-55307. Female beagles were implanted with uterine strain gauge force transducers, allowed 10 days for recovery and treated with estrogen to sensitize the uterus to the actions of prostaglandins. Base-line responses were determined with S C-30249, i.v., and then a randomized series of four treatments were gi ven: SC-30249, IG, 10 mu g/kg; SC-55307, IG, equivalent to 30 and 100 mu g/kg of SC-30249; and a blank polymer control. HCl was given IG to provide an acid environment in the stomach, uterine responses were obt ained for up to 4 h and plasma concentrations of SC-30249 free acid we re determined. No uterotonic effect was seen after a low dose of SC-55 307, whereas the high dose caused a brief but statistically significan t increase equal to 8.8% and 17.8% of the responses to SC-30249, i.v. and IG, respectively. Peak plasma levels of SC-30249 free acid were 17 6.4 +/- 17.4 and 59.5 +/- 10.6 pg/ml after SC-30249, i.v. and IG, resp ectively, but were only 3.9 +/- 1.7 and 15.5 +/- 6.6 pg/ml after low a nd high doses of SC-55307, respectively. Controlled release of SC-3024 9 from SC-55307 resulted in lower plasma levels of SC-30249 free acid and reduced uterotonic activity.