Polymer Delivery of the Mucosal Protective Prostaglandin Misoprostol

Abstract

Misoprostol is currently marketed throughout the world for the prevention of non-steroidal anti-inflammatory drug-induced gastric/duodenal damage. Although safe and effective, intestinal side-effects, namely diarrhoea and cramping, can limit its use. We have developed and studied polybutadiene-based polymeric delivery systems for misoprostol to address side-effect problems. These systems were designed to slowly release drug in the stomach (pH 1–3) but not in the intestine (pH > 5). A covalent silicon ether bond from the polymer to the C-11 hydroxy group of misoprostol is the key element for selective gastric release. Initial polymer/misoprostol studies showed that (1) increasing the steric hinderance around the silyl ether reduced the in-vitro release rate of prostaglandin, (2) diarrhoea was absent following intrajejunal and intracolonic administration of these materials, (3) reducing the gastric release rate of drug from the polymer reduced intestinal side-effects without affecting antilesion activity, and (4) polymer delivery reduced the systemic availability of prostaglandin. Consequently, a polymer system (SC-53450) carrying the active isomer of misoprostol (SC-30249) was studied relative to misoprostol/hydroxypropyl methylcellulose (HPMC) in both rats and dogs. This material has a spectrum of mucosal protective activity in rats similar to misoprostol/HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. In contrast to misoprostol/HPMC, SC-53450 was not diarrhoeagenic in the rat when administered intragastrically.