Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 505

Sodium dodecyl sulfate is incorporated to enhance absorption of peptide drug vaso-
pressin across the CACO-2 cell monolayer. This is due to loosening of the tight junction,
thus easing paracellular transport [176] . Bile salts make up another important class of nat-
ural or semisynthetic surfactants. Some reports suggest bile salts also increase absorption
of proteins and peptides across the membrane. Sodium deoxycholate and sodium cholate
dissociates insulin from its complexes and makes it available for absorption [177] .
Mixed micellar systems, which are naturally formed during the absorption of lipids
from the GI tract, have also shown enhanced absorption of proteins and peptides [178] .
Absorption of hCT across the rat colon was increased ninefold when given as a mixed
micellar form. Mixed micelles enhance the absorption of peptides and proteins over the
MW range of 4000 to 40,000 without acute damage to the membrane [179] .
Cyclodextrin and its derivatives have been studied to check its effect on absorp-
tion of peptides and proteins. Cyclodextrins improves absorption of insulin from the
lower jejunum to the upper ileum segment. Citric acid and castor oil derivatives are
used to increase pharmacological activity of recombinant human granulocyte colony-
stimulating factor (rhG-CSF) in rats by affecting its absorption [180,181] .
Due to lack of specificity and destructive nature, penetration enhancers may have
long-term toxicities, and thus their use to increase absorption of proteins and pep-
tides can only be accepted after extensive chronic studies. They are prone to destruct
the membrane that is the barrier to external toxic chemicals and microorganisms.
Thus their use can only be established after solving their safety issues [178] .
10.6.6 Protease Inhibitors
Proteins are degraded by various proteases present in the GI tract and thus reduce its
absorption when given via oral route. Degradation of proteins by proteases is a major
drawback of the oral route for protein delivery. The GI tract presents a very unfavorable
environment for the peptides and proteins, due to the presence of plentiful proteolytic
enzymes at high concentration in the lumen and throughout the intestinal wall [182] .
Therefore, an enteric coating alone is not sufficient to protect peptides and proteins.
This problem is overcome by the use of protease inhibitors in a formulation that avoids
proteolytic degradation. Protease inhibitors may be classified as follows:
1. Polypeptide protease inhibitors (e.g., aprotinin)
2. Peptides and their derivatives (e.g., bacitracin, chymostatin, and amastatin)
3. Amino acids and their derivatives (e.g., -aminoboronic acid derivatives)
4. Miscellaneous (e.g., p -aminobenzamidine and camostat mesilate) [183] .
It was concluded in various studies that aminopeptidase inhibitor (puromycin)
was able to increase the absorption of metkephamid (MKA), a stable analog of met-
enkephalin, across the rat intestine. Endopeptidase inhibitor (thiorphan) was ineffec-
tive in the prevention of MKA metabolism because the enzyme participate in MKA
metabolism during absorption is aminopeptidase [184] . Hydrolysis of the pentapeptide,
leucine (Leu)-enkephalin (YGGFL) at a high pH was reported to be reduced by
amastatin [185] . The endopeptidase inhibitors such as tripeptides YGG and GGF
were found to be effective at lower pH (below 5.0).