Biomedical Engineering Reference
In-Depth Information
TABLE 7.1
Commonly Used Biotech-Derived Pharmaceutical Products
Products
Application
Human insulin
Treatment of diabetes mellitus
Interferon-α
Leukemia, AIDS, and renal cell carcinoma
Interferon-β
AIDS, multiple sclerosis, and cancer
Erythropoietin
Anemia and chronic renal failure
Interleukin-2
Cancer treatment
Streptokinase
Heart attack
Monoclonal antibodies
Cancer treatment and septic shock
Tissue plasminogen activator
Acute myocardial infarction
Human growth hormone
Growth defi ciency
Hepatitis B
Hepatitis B vaccine
Calcitonin
Osteoporosis
7.2 BARRIERS TO ORAL DELIVERY OF PROTEINS/PEPTIDES
Peptide-based biotechnology products are subject to the same hostile environment faced by all
peptides in the GIT. The major problems associated with oral peptide delivery are the susceptibility
to degradation by the hostile gastric environment; metabolism by luminal, brush border, and cyto-
solic peptidases; and poor permeability across the intestinal epithelium because of size, charge,
and hydrophilicity [10,11]. Intestinal epithelium serves as a major barrier for the absorption of
orally administered drugs and peptides into the systemic circulation. High-resistance epithelial
cell barriers restrict the passage of various hydrophilic compounds from the small intestine into
the human body. The high resistance is due to the formation of well-organized tight junctions that
connect the cell plasma membranes by a network of apical localized seams. As the name implies,
tight junctions exclude the paracellular passage of ions, peptides, and proteins. The paracellular
route is the dominant pathway for passive transepithelial solute fl ow in the small intestine, and its
permeability depends on the regulation of intercellular tight junctions.
The utility of the paracel-
lular route for oral drug delivery has remained unexplored because of a limited understanding of
tight junction physiology and the lack of substances capable of increasing the tight junction per-
meability without irreversibly compromising intestinal integrity and function. The attempts made
so far to fi nd ways to increase paracellular transport by loosening intestinal tight junctions have
been hampered by unacceptable side effects induced by the potential absorption enhancers [12].
Physiological considerations, such as gastric transit time, dilution, and interaction with intestinal
debris, also infl uence peptide absorption across the intestinal epithelium. Furthermore, peptides
absorbed through the hepatic portal vein have to negotiate with the fi rst-pass metabolism in the
liver [9].
The nature of these barriers has now been expanded to include intracellular metabo-
lism by cytochrome P450-3A4 as well as apically polarized effl ux mediated by ATP-dependent
P-glycoproteins [13]. Although, P-glycoprotein-mediated effl ux systems are most commonly
observed in tumor cells, they are also present in normal intestinal cells and act to reduce the
intracellular accumulation or the transcellular fl ux of a wide variety of drugs, including peptides.
Furthermore, peptides are associated with potential physical and chemical instability, and formu-
lating peptide drugs are much more complex and demanding. Hence formulating a proper delivery
system for proteins and peptides with optimal therapeutic effect and shelf life is an elusive goal for
pharmaceutical scientists.
