Biomedical Engineering Reference
In-Depth Information
criterion for mucoadhesion. Polymers containing hydrophilic functional groups such as carboxyl,
amine, hydroxyl, and sulfate can interact with mucus layer to form noncovalent interactions [75].
Polyanionic polymers such as PAA interacts with mucus by hydrogen and Van der Waals bonds
created between the carboxylic groups and the sialic acid residues of mucin glycoproteins [76,77].
On the other hand polycationic polymer such as chitosan exhibits strong mucoadhesive properties
due to the formation of hydrogen and ionic bonds between the positively charged amino groups
and the negatively charged sialic acid residues of mucin glycoproteins [78]. Polyacrylic acid-
based systems (including their commercial forms such as Carbopol, Polycarbophil) are widely
used in mucosal drug-delivery applications. Hydrogel microparticles of PAA or polymethacrylic
acid (PMAA) prepared by the free radical polymerization of corresponding monomers with
bifunctional cross-linking agents, such as ethylene glycol dimethacrylate, or similar bifunctional
reagents were investigated for developing mucoadhesive delivery systems [79,80]. It has been
proved that use of PEG-based adhesion promoters improves the chain fl exibility and mobility of
such delivery systems. Peppas and group used the strategy of PEG-grafted PMAA for the develop-
ment of mucoadhesive drug-delivery systems [81,82].
Recently a novel class of polymers, so-called thiomers, which in fact are capable of forming
covalent interactions with mucus layer, was introduced in this area [83]. Thiolated polymers display
thiol-bearing side chains and are based on thiol or disulfi de exchange reactions, and through a
simple oxidation process, disulfi de bonds are formed between polymers and cysteine-rich subdo-
mains of mucus glycoproteins. Mucoadhesive polymers such as PAA, alginate, and chitosan were
modifi ed with cysteine using water-soluble carbodimide to yield polymer-cysteine conjugate. It is
reported that adhesive properties of these polymers were signifi cantly enhanced with the immo-
bilization of thiol groups. Thiolated nano- and microparticles were introduced recently, and these
systems seem to be an attractive excipient for oral protein delivery [84,85].
However, a major problem is the absorption of peptides released from the polymer particles.
It is reported that some mucoadhesive polymers can enhance the permeability of epithelial tissues
by loosening the tight intercellular junctions. Basically there are two types of passive diffusion
processes through which a drug can be absorbed from the mucosal site into the bloodstream. The
fi rst mechanism is transcellular (intracellular) transport and is used by small molecules. The mol-
ecule diffuses from one side of the barrier, through the cell, to the other side. The second mecha-
nism of transport is paracellular transport (intercellular). Paracellular transport is the passage of
the molecules through adjacent cells in the layer . This movement is governed by the available space
and environment between the cells [78]. Increasing the area available between the cells allows the
molecules to move more easily across the layer. Paracellular transport is the primary route used by
hydrophilic and charged molecules. The paracellular pathway found along the intestinal wall is an
alternative pathway for peptide absorption [86]. This pathway normally does not allow the entry of
peptides and nutrients by a specialized regions called “tight junction.” In a current model of a tight
junction, two major integral membrane proteins are found—occludin and claudin—each with four
membrane spanning alpha-helices [87]. The junction depends upon extracellular calcium to main-
tain integrity. The permeability properties of tight junctions vary considerably in different epithelia,
and epithelial cells can transiently alter their tight junctions in order to allow increased fl ow of
solutes and water through breaches in the junction barriers. The tight junctions usually prevent the
transport of protein through the paracellular pathway [86].
Among hydrophilic polymers, PAA-based systems turned out to be of particular interest show-
ing the capability of opening epithelial tight junctions, which are mainly responsible for limited
paracellular uptake of hydrophilic macromolecules [88,89]. Calcium-binding ability of these poly-
mers seems to be a major reason for such effects. Calcium chelators might disturb cell-cell adhesion
by depleting extracellular calcium required for the interaction of components of adherent junctions.
Further chelation of calcium may activate intracellular protein kinases, which ultimately can lead to
the disruption of junctional integrity. Divalent ion-binding ability of these polymers may also help
in reducing the proteolytic degradation of proteins in GIT [90].
