In vivo studies using various types of laboratory animal models have suggested that orally administered insulin is available for absorption when protected from enzymatic degradation. The experiments also were performed in vitro to observe the effect of these agents in insulin-containing formulations. Oil and water bases were prepared by using absorption enhancers and promoters. Evaluation studies on various types of enzyme inhibitors, selected based on their availability and suitability in the insulin containing formulations, also were reviewed.
Some of these studies are described in this article, with an emphasis on the delivery of oral insulin formulations containing either promoters and enhancers alone or in combination with enzyme inhibitors. This article also reviews the current state of use of absorption promoters and enhancers and enzyme inhibitors and assesses the progress and limitations of studies and reports. The article concludes with an examination of clinical outcomes of these agents characterized by increased permeability and no toxic effect.Oral insulin delivery strategies
Enzyme-inhibiting agents. Enzyme inhibiting agents are becoming increasingly popular as a delivery strategy for oral insulin. Insulin, like many other protein and peptide drugs, may be degraded in the gastrointestinal tract (GIT) by digestive enzymes such as pepsin, proteases, peptidases, and other proteolytic enzymes. The proper selection of protease inhibitors depends on both the peptide and protein drug to be delivered and on the type of proteases and peptidases used to protect the drug in the GIT.
In the 1980s, Ziv and his colleagues studied bile acid (sodium cholate) as a protease inhibitor, along with aprotinin (a trypsin inhibitor), in an insulin-containing solution. This solution was injected into rats' ileums. The results suggest that the combination of both inhibitors could improve insulin absorption in the intestinal lumen of rats (1). Interestingly, acarbose, an intestinal alpha glucosidase inhibitor, also showed some positive effects in diabetic animals (2).
A potent and specific inhibitor, 4-(4-isopropylpiper-adinocarnonyl) phenyl 1, 2, 3, 4-tetrahydro-1-naphthoate methanesulphonate (FK-448) of chymotrypsin improved intestinal absorption of insulin and resulted in a reduction in blood glucose in rats and dogs (3). Fujii's study, which used soybean trypsin inhibitors in the ileum, confirmed the earlier findings of Ziv et al. and Kidron et al. (1, 4). There is no evidence that soybean trypsin inhibitor enhanced insulin absorption in the ascending colon, however. Further attempts to increase the hypoglycemic levels in diabetic animals were made by introducing enzyme inhibitors and protease inhibitors (aprotinin or the Bowman–Birk inhibitor) to prevent the degradation of insulin in the intestine by pancreatic enzymes (5, 6).