Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 654

The effect of protease inhibitors on the stability of peptides
It was found that the protease inhibitors may reduce the degradation of insulin
in the large intestinal homogenate, thereby improving large intestinal absorption of
insulin. These findings suggest that coadministration of protease inhibitors would be
useful for improving large intestinal absorption of insulin.
The effect of protease inhibitors on the intestinal absorption of peptides
Information on the relative potential of proteolytic activity at different regions
along the GI tract is required for the use of a protease inhibitor as an absorption
enhancer. The activities of various proteases in the small intestine are generally
higher than those in the large intestine. This tendency is more remarkable in the case
of endopeptidases such as trypsin, chymotrypsin, and elastase, because little activity
of these enzymes is in the large intestine. Of all proteases, aminopeptidase B had a
more uniform distribution pattern than the other proteases used.
Absorption-enhancing mechanisms of protease inhibitors
Protease inhibitors are one of the most useful approaches to improve the stability
and absorption of peptides and proteins, although the mechanism by which peptides
and proteins are stabilized by these inhibitors is not fully understood. Because some
protease inhibitors may also have absorption-enhancing activities in addition to their
protease inhibitory action, when they are applied in practical use, it is essential that
these inhibitors do not affect the membrane integrity of the epithelium.
12.4.4.3 Chemical Modification of Protein and Peptide Drugs
Alternative methods are needed for peptide delivery via the GI tract because absorp-
tion enhancers and protease inhibitors improve the absorption of usually nonabsorbed
substances from the GI tract. Normally, peptides and proteins have been coadminis-
tered with absorption enhancers and protease inhibitors in order to promote the passage
through GI epithelial barriers and to reduce degradation in the gut [215] . But limita-
tions, for instance, local irritation of the mucosa and nonselective absorption of other
antigenic compounds, are considered a negative aspect in the use of absorption enhanc-
ers. A potentially useful approach to solve these delivery problems may be chemical
modification of peptides and proteins to produce analogues and prodrugs. So, it is
likely that this chemical approach may protect peptides against degradation by the pres-
ence of peptidases and other enzymes at the mucosal barrier, leaving the peptides and
proteins more lipophilic, resulting in augmented permeability. From these standpoints,
some novel lipophilic derivatives of TRH, tetragastrin, human calcitonin, insulin, and
lysozyme can be synthesized through chemical modification by various fatty acids.
12.5 Conclusion
Various routes have been explored to achieve therapeutic concentration, such as trans-
dermal, topical, uterine, and rectal. Low oral bioavailability is often recorded for pro-
teins and peptides because of some limiting factors. Development of a transdermal