The early years of oral insulin research inspired pharmaceutical polymer and biomedical researchers to explore the possibility
of improving the oral bioavailability of insulin and other peptide and protein drugs. A historical retrospective of oral insulin
delivery methods shows that the oral absorption of both native and modified insulin in animals significantly increases with
the incorporation of absorption enhancers and promoters and enzyme inhibitors, alone and in combination. Many authors have
suggested that various pharmaceutical excipients in different chemical forms and concentrations could help enhance the absorption
of insulin in an oral dosage form. These excipients have improved insulin absorption in laboratory animal experiments. Studies
were performed to observe if any of these agents have a toxic effect on the cellular structure of the intestinal epithelium.
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.
Several studies support using protease inhibitors as a protective cover to prevent the degradation of insulin by digestive
enzymes, which are mostly located in the upper part of the intestine (see Table I). Investigators should conduct more in vitro experiments to evaluate the potential for cytotoxicity or other gastrointestinal side effects. Most studies cited in this
article show increased permeability with little or no toxic effect.
Table I: Select penetration and permeation enhancers and enzyme inhibitors used in various studies.
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