Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 489

The absorbed drug molecule enters into either the blood or the lymphatic circula-
tion. Because the blood flow rate is 1000-2000 times higher than that of lymphatic
flow in humans, lymphatic absorption is not as important [72] . The advantage of
lymphatic absorption, however, is that a drug can bypass the liver and enter directly
into the circulation.
10.5 Factors Affecting Peptides and Proteins Absorption
10.5.1 Molecular Weight and Size of Molecule
Diffusion of the drug across the epithelial layer largely depends on MW and molecular
size of the drug. Very large molecules have lower diffusion than small molecules (75-
100 Da), which cross the mucosa barrier rapidly [73] . Drug diffusion decreases markedly
with increase in molecular size. There are several reports showing the effects of MW on
mucosal absorption of various hydrophilic compounds [74-76] . It was found that the
apparent permeability coefficient of fluorescein isothiocyanate dextrans (FITCD), a neu-
tral polysaccharide, decreased as MW increased [75-77] . Generally, absorption decreased
exponentially with MWs above 300 Da [78] . MW varies largely among therapeutically
used peptides and proteins, ranging from less than 600 to greater than 100,000 Da so
that a direct comparison is not possible [79] . In vivo permeation studies on humans dem-
onstrated that peptides such as protirelin (MW: 362 Da) and oxytocin (MW: 1007 Da)
crossed the human buccal mucosa barrier, whereas buserelin (MW: 1239 Da) and calcito-
nin (MW: 3500 Da) did not [80] . Outcomes of such studies led Merkle et al. [81] to pro-
pose that the transfer of peptides with MWs above 500-1000 Da through mucosa would
require use of an absorption enhancer. Peptides and proteins having a wide variety of
MWs showed different absorption patterns [82-87] ( Table 10.3 ).
10.5.2 Three-Dimensional Structure and Immunogenicity
Peptide drugs may have primary, secondary, and tertiary structures, and in solution
they may exist in several different conformations depending upon their size [88-90] .
Change in conformation influences membrane permeability, and this phenomenon
can be utilized during formulation, but the potential problem is the preservation of
the pharmacologically active conformation [91] . Stereoselectivity exists in the pro-
cess of permeation, so care must be taken to preserve stereospecificity during for-
mulation [45,92] . Peptides are also recognized as often being immunogenic, and the
use of inert polymers for peptide delivery, for example, polyethylene glycol (PEG),
dextran, polyvinylpyrrolidone (PVP), and albumin, has been shown to increase resis-
tance to proteolysis and simultaneously decrease peptide immunogenicity [90,93] .
10.5.3 Charge Distribution
Proteins and peptides exist as zwitterions at their isoelectric point (p I ) and have
a negative effect on membrane permeability [45] . The electrostatic charge on the