HYPOGLYCEMIC EFFECT OF NOVEL ORAL MICROSPHERES OF INSULIN WITH PROTEASE INHIBITOR IN NORMAL AND DIABETIC RATS

The effectiveness of an oral administration of insulin microspheres (IMS) containing a protease inhibitor was evaluated in normal and diabetic rats. The dosage form is based on the incorporation of insulin with protease inhibitor into polyacrylic polymer (Eudragit L100). These preparations were administered orally with a 20 U/kg insulin dose by force-feeding to rats. Insulin absorption was evaluated by its hypoglycemic effect. IMS without protease inhibitor and with trypsin inhibitor (TI) or chymostatin (CS) produced no marked hypoglycemic response in both groups of rats. A significant continuous hypoglycemic effect was obtained after oral administration of IMS containing aprotinin (AP) or Bowman-Birk inhibitor (BBI) in both normal and diabetic rats when compared with controls. To calculate the relative efficacy, log dose/effect curves for i.v. insulin were obtained in both groups of rats. The efficacy of oral administration, relative to i.v., was assessed by measuring the cumulative percentage of change in serum glucose levels during the experimental period. The efficacy order of four protease inhibitors incorporated into IMS was AP greater-than-or-equal-to BBI > CS = TI. The results suggest that the use of protease inhibitors as pharmaceutical adjuvants for IMS has the advantage of enhancing the efficacy of insulin.