Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 653

aqueous pores and the cell structure perturbation of the tight paracellular junctions.
Actually, there are only a few reports available about the use of mixed micelles in the
rectal route.
EDTA and Egtazic Acid Strong chelating agents such as EDTA and egtazic acid
have been employed for the study of tight junctions between rectal epithelial cells.
In fact, these chelating agents increased the rectal absorption of insulin and DE--
E [179,208] . It was revealed that EDTA activates protein kinase C by depletion of
extracellular calcium through chelation, resulting in expansion of the paracellular
route in CaCo 2 cell monolayers [209-211] .
Other Absorption Enhancers The main issue in using other absorption enhancers is
local irritation and safety; as well, the variability of the efficacy should be verified.
Saponin is known to be surface-active, and may be involved in enhancing effects.
Nitric oxide donors NOR1 and NOR4 increase insulin absorption. Utoguchi et al.
reported that the nitric oxide donor S -nitroso- N -acetyl-D,L-penicillamine (SNAP)
induced a significant increase in the absorption of insulin and FITC-dextran (MW
4000) from the rabbit's rectum [167,170] . The absorption-enhancing effect of SNAP
was inhibited by simultaneous administration of the nitric oxide scavenger car-
boxy-PTIO. Thus, nitric oxide donors act as powerful absorption enhancers. Other
absorption enhancers such as diethylethoxy methylene malonate (DEEMM) [212] ,
phosphate derivative [213] , and glycerin ester [214] have been reported as well.
Thus, a number of absorption enhancers have been extensively developed for their
potential use.
12.4.4.1.3 Efficacy and Safety of Absorption Enhancers
A large number of absorption enhancers, including surfactants, bile salts, chelating
agents, and fatty acids, are used to improve the absorption of macromolecules like
proteins and peptides. For practical use, it is essential that these enhancers do not
affect the membrane integrity of the epithelium. However, some of these excipients
lead to membrane damage and irritate the rectal mucosal membrane. Thus, nontoxic
and effective enhancers should be urbanized.
12.4.4.2 Protease Inhibitors
The oral administration of peptides often results in very low bioavailability due to
extensive hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic
barrier) and poor membrane penetration characteristics (transport barrier). Of these
two barriers, the former is of great importance for certain unstable small peptides,
because these peptides can be transported across the intestinal membrane unless they
are degraded by various proteases enzymes. Because the use of protease inhibitors
could reduce the degradation of various peptides and proteins, this is a promising
approach for overcoming the delivery problems of peptides and proteins. Many com-
pounds have been used as protease inhibitors to improve the stability of various pep-
tides and proteins, for example, aprotinin, trypsin inhibitors, bacitracin, puromycin,
bestatin, and bile salts such as Na-glycholate.