Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 492

from various studies that cyclosporine is more favorably absorbed from the duode-
num, and tetragastrin, from the upper GI tract and rectum. Other studies showed that
the junction of the duodenum and the ileocecal is the most ideal site of absorption for
desmopressin, and the upper GI tract is the ideal site for octreotide [117,118] . Due to
less enzymatic activity and higher paracellular permeability, distal intestinal segments
are the preferred zone over the proximal small intestine for absorption of oxytocin and
vasopressin [119] . Experiments showed that absolute bioavailability for insulin when
administered to the distal region of the rat intestine (0.133%) was higher than that
absorbed from a proximal region (0.059%) of the intestine [120] . As described earlier,
proteolytic enzymes are also present in the cytosol and brush border of the GI tract.
Proteolytic ruin the ingested peptides and proteins within the cytosol remains the same
throughout the GI tract, except in the brush border or for luminal fluid. The harshest
circumstances for the proteins and peptide inside the GI tract exist in the stomach. Very
low pH and high protease (mainly pepsin) enzyme activity make the condition inauspi-
cious for proteins. The problem of peptide and protein degradation in the stomach is
overcome by the use of an enteric coating technique, in which the release of peptides in
such an unkind environment is prevented. Surface area is reduced when moving from
the proximal to the distal region of the intestine, because of the reduced presence of
small villi in the distal part.
10.6.1.1 Colon Targeting
Delivery of peptide to the colon offers the advantage of low enzymatic activity but
suffers from drawbacks such as variable pH and interference of fecal matter. It was
concluded from earlier studies that calcitonin degrades more in the small intestine
than in the colon [121] . Peptides and proteins, when administered to the upper half
of the colon, will be taken up by hepatic portal veins and delivered to the liver, thus
reducing degradation. Polypeptides reach to the lymphatic circulation when absorbed
from the lower colon and hence, hepatic first pass metabolism is avoided. Thickness
and nature of the composition may be varied to get the drug to release in the lower
colon, bypassing the hepatic vein. The pH-dependent properties of Eudragit have
been utilized for improving delivery of insulin to lower colon [122] . Delivery of
insulin-like growth factor I (IGF-I) to rat and minipig colonic mucosae under in vitro
conditions has been investigated [123] . A novel time-based drug release system for
colon-specific delivery has also been investigated, where the release of peptide starts
after a predetermined lag time. This lag time is equal to the transit time of the deliv-
ery system (from time of ingestion to time it takes to reach the colon). The lag time
is independent of physiological conditions such as pH, digestive state, and the level
of digestive enzymes.
The colon has a high population of anaerobic bacteria species. These bacteria
have the capacity to reduce azo bonds, and this capacity can be utilized to develop
a formulation where a peptide or protein is coated with polymers crosslinked with
azo-aromatic groups to protect the peptide in the stomach and intestine. When the
formulation reaches the colon, the azo bond is reduced by such flora and releases the
peptide, which is absorbed through the mucosa [13,124] .