Development of novel formulations for mucosal delivery of protein ...

significant decline in blood glucose levels. However, these enzyme inhibitors (Figure 1.4)
have a toxic potential caused by the inhibition of digestive enzymes, which can further cause
incomplete digestion of the nutrient proteins. In addition, the inhibitory action can cause
increased secretion of these enzymes by a feed-back regulatory mechanism (Bernkop-
Schnürch, 1998; Reseland et al., 1996). Studies have shown that this feed-back regulation
leads to both hypertrophy and hyperplasia of the pancreas and prolonged administration of
soybean trypsin inhibitor may lead to invasive carcinoma (Bernkop-Schnürch, 1998). One of
the recent additions to the class of absorption enhancers is zonula occludens toxin (Zot), a
protein secreted by Vibrio cholerae (Baudry et al., 1992). This toxin induces modifications of
cytoskeletal organization, specifically at the actin filament of the zonula occludens which
leads to opening of the tight junctions causing increased permeability. This increase in
permeability is reversible, time and dose-dependent and is restricted to the jejunal and ileal
sections of the small intestine owing to the presence of receptors for the protein in those
sections (Fasano & Uzzau, 1997).
Figure 1.4: Schematic diagram showing the mechanism of enzyme inhibition. Available at
[Accessed; 20/03/2011]
Studies with diabetic animals have shown that INS administered with 5 g Zot and
NaHCO 3 to neutralize the gastric acidity, induced a hypoglycaemic effect comparable to that
caused by subcutaneously administered INS. This is a promising approach to improving oral
bioavailability of INS, but it suffers from the same safety and specificity issues that limit the
use of permeation enhancers discussed above. Thus, attempts to increase the oral