Abstract
The recent rapid progress in molecular biology makes it possible to produce peptides in sufficient quantities at reasonable cost. The development of the oral peptides delivery system is highly desirable ; however, poor absorbability and low stability of peptides in the gastrointestinal(GI) tract make it difficult. In order to develop successful strategies for enhancement of the oral bioavailability of peptide drugs, we have investigated various pharmaceutical approaches using insulin, one of the typical peptide drugs. As the first step, insulin absorption from various sites in the rat intestine was compared using the in situ ligated loop technique. The results suggest that the ileum seems to be the most useful region in the small intestine for insulin absorption ; however, insulin must be protected from proteolysis to enhance its absorption. Further, we evaluated the effectiveness of an oral administration of Eudragit insulin microspheres (IMS) containing a protease inhibitor. A significant continuous hypoglycemic effect was obtained after the oral administration of IMS containing aprotinin or Bowman-Birk inhibitor in both normal and diabetic rats. However, the efficacy of oral administration, relative to i, v., remains low. Thus, as the next step we prepared water-in-oil-in-water (w/o/w) emulsions by a two-step emulsification procedure and liposomes by a reverse-phase evaporation method. These preparations were expected to protect insulin against proteolysis in the GI tract. A significant hypoglycemic effect was observed at the ileum and colon loops after administration of the filtered emulsions containing 5% w/w gelatin in the inner phase. In the colon, the hypoglycemic effect of the emulsion containing fatty acids such as oleic acid, linoleic acid or linolenic acid in the oily phase was markedly increased. After enteral or oral administration of liposomes prepared with dipalmitoylphosphatidylcholine and cholestelol, a significant continuous hypoglycemic effect was observed. Our findings suggest that these pharmaceutical approaches offer much improvement bioavailability of insulin via oral route.
