Biomedical Engineering Reference
In-Depth Information
7.3 STRATEGY FOR IMPROVED ORAL PROTEIN DELIVERY
Successful oral delivery of protein involves overcoming the barriers of enzymatic degradation,
achieving epithelial permeability, and taking steps to conserve bioactivity during formulation pro-
cessing. The coadministration of enzyme inhibitors and permeation enhancers is an approach used
to enhance the bioavailability of oral protein formulations [12,14-16]. Chemical modifi cation of
peptides and use of polymeric systems as carriers have also been attempted to overcome the inher-
ent barriers.
Coadministration of protease inhibitors may retard the rate of degradation of peptides [17].
The slow rate of degradation may enhance the amount of peptides available for absorption.
Enzyme inhibitors have been associated with systemic intoxication if they are absorbed and may
affect the normal digestion of nutritive proteins. Use of absorption enhancers such as fatty acids,
surfactants, and bile salts has been proposed to improve drug transport across intestinal epithe-
lium [18-23]. An increase in paracellular transport is mediated by modulating tight junctions of
the cells, and an increase in transcellular transport is associated with an increase in the fl uidity
of the cell membrane. Permeation enhancers that fall into the former category include calcium
chelators, and those that fall into the latter category include surfactants and fatty acids. Calcium
chelators act by inducing calcium depletion, thereby creating global changes in the cells, includ-
ing disruption of actin fi laments, disruption of adherent junctions, and diminished cell adhesion
[18]. Surfactants act by causing exfoliation of the intestinal epithelium, thus compromising its
barrier functions [23]. Use of these permeation enhancers has demonstrated that their enhance-
ment is dose- and time-dependent. The utility of this approach for oral drug delivery has remained
unexplored because of the limited understanding of tight junction physiology and the lack of sub-
stances capable of increasing the tight junction permeability without irreversibly compromising
their integrity and function.
Chemical modifi cation using poly(ethylene glycol) (PEG) and fatty acids has been proposed as
a promising approach. Site-specifi c attachment of PEG to proteins such as insulin can signifi cantly
enhance the physical and pharmacological properties without negatively affecting its biological
potency [24]. Moreover PEGylation may enhance the
in vivo
half-life of proteins, by protecting
them from receptor-mediated uptake by the reticuloendothelial system (RES) and preventing rec-
ognition and degradation by proteolytic enzymes. However, use of polymer matrixes as carriers
of proteins and peptides remains the most promising strategy in oral protein delivery [25]. In this
chapter, we discuss the problems and prospects associated with polymeric oral protein-delivery
systems.
7.4 POLYMERIC NANO/MICROPARTICLES AS A
POSSIBLE ORAL PEPTIDE-DELIVERY SYSTEM
Polymeric drug carriers are particularly useful for formulating new drugs developed using bio-
technology, because they can provide protection from degradation in the body and promote their
penetration across biological barriers. Numerous attempts were made in the last few decades for
formulating a suitable delivery system for peptides and proteins using polymeric carriers [26,27].
Polymeric carriers offer numerous advantages over conventional delivery systems, which include
low cost, nonimmunogencity, and versatility. The traditional delivery systems or the so-called fi rst
generation polymeric systems are capable of delivering the active ingredient at a specifi c site in the
body. However, application of such systems toward oral peptide delivery has been limited, since the
enzymatic and absorption barriers may hinder the uptake of these bioactive agents.
Development of advanced drug-delivery systems, based on polymeric particulate systems, is
an emerging area of research. These systems are designed to overcome the enzymatic and absorp-
tion barriers in the GIT. Recently much interest has been directed toward the development of small
