In vivo and in vitro evaluation of a microencapsulated narcotic antagonist

Injectable microcapsules containing 75% (w/w) cyclazocine, a narcotic antagonist, were prepared with dl-poly(lactic acid) as the coating material. Capsule fractions falling between 105 and 295 mum released about 90% of their cyclazocine in 8 days of rotating-bottle extraction at 37 degrees in pH 7.4 phosphate buffer. Although larger capsules released the drug somewhat more slowly, all capsules released cyclazocine far more rapidly than an ideal capsule should. This rapid release is attributed to macroscopic defects located in the capsule walls. The ability of the capsules to block the action of morphine in vivo was assessed by injection of a sesame seed oil suspension into Holtzman rats. A hot-plate test procedure was used to evaluate animal behavior. Capsule doses of 100-250 mg/kg to rats caused significant antagonism of morphine's analgesic effect for 14 days after injection. By Day 17, no antagonism occurred, indicating that the capsules completely released the drug in vivo between 14 and 17 days after injection.