Biomedical Engineering Reference
In-Depth Information
7.4.3 N
ATUR AL
AND
P
ROTEIN
-B
ASED
P
OLYMERS
FOR
O
RAL
P
EPTIDE
D
ELIVERY
Polysaccharides are among the most versatile polymers because of their vast structural diversity and
nontoxicity. Among polysaccharides, chitosan, alginate, pectin, hylauronic acid, and dextran have
received much attention. Protein-based polymers such as albumin, casein, and gelatin have also
been investigated for oral peptide delivery.
Among such materials, chitosan-based systems are of utmost importance. Chitosan ((1-4)-2-
amino-2-deoxy-β-d-glucan), which is the deacetylated form of chitin, is of great interest as a func-
tional material of high potential in various fi elds such as the biomedical fi eld [104,105]. Chitosans
have found application as biomaterials in tissue engineering and in controlled drug-release systems
for various routes of delivery. Being cationic in nature chitosan possesses mucoadhesive properties.
It has unique ability to control the release of active agents, avoids use of organic solvents for the fab-
rication, and has free amino groups available for cross-linking [106]. Excellent review articles out-
lining the major fi ndings on the pharmaceutical applications of chitosan-based nano/microparticles
have been published in the last few years [107,108]. However, it was Illum who fi rst reported that
chitosan can promote the transmucosal absorption of small polar molecules as well as peptide and
protein drugs system [109]. Chitosan attracted the attention of pharmaceutical scientists as a muco-
adhesive polymer that could be useful for peptide-drug delivery.
When protonated (pH 6.5), chitosan is able to increase the paracellular permeability of peptide
drugs across mucosal epithelia. Chitosan in its protonated form is able to interact with the epithelial
tight junctions and to provoke their opening allowing for paracellular permeation of hydrophilic
macromolecular drugs [110]. Chitosan can bind tightly to the intestinal epithelium, inducing redis-
tribution of F-actin and the tight junction protein ZO-1 [111]. Chitosan nanoparticles were able to
demonstrate reduction in TER value in caco-2 experiments [112,113]. However, the major drawback
with chitosan is their limited solubility at pH above 6.5. At neutral pH, chitosan exist in nonproton-
ated form and was found ineffective in improving the permeability of intestinal epithelium [111].
Thanou et al. proposed that the problem of chitosan's ineffectiveness at neutral pH values could be
tackled by derivatization at the amine group. Trimethyl chitosan chloride (TMC) was proved to
increase substantially the intestinal absorption and bioavailability of peptide drugs. The mechanism
by which TMC enhances intestinal permeability is similar to that of protonated chitosan. It revers-
ibly interacts with the components of the tight junctions, leading to the widening of the paracellular
routes [114,115].
Chitosan nanocapsules were prepared by the solvent displacement technique using high (450 kDa)
and medium (160 kDa) molecular weight chitosan glutamate as well as high-molecular weight chitosan
hydrochloride (270 kDa). The nanocapsules were used for the oral delivery of salmon calcitonin [116].
The results of the
in vivo
studies, following oral administration to rats, indicated that chitosan nano-
capsules were able to reduce the serum calcium levels signifi cantly and to prolong this reduction for
at least 24 h. Bioadhesive polysaccharide chitosan nanoparticles (CS-NP) were prepared by ionotropic
gelation of chitosan with tripolyphosphate anions [117]. The ability of CS-NP to enhance intestinal
absorption of insulin and increase the relative pharmacological bioavailability of insulin was investi-
gated by monitoring the plasma glucose level of alloxan-induced diabetic rats after oral administration
of various doses of insulin-loaded CS-NPs. CS-NP enhanced the intestinal absorption of insulin to a
greater extent than the aqueous solution of chitosan
in vivo
. Above all, after administration of 21 IU/kg
insulin in the CS-NP, the hypoglycemia was prolonged over 15 h, and the average pharmacological
bioavailability relative to subcutaneous (SC) injection of insulin solution was up to 14.9%. Chitosan
capsules were also exploited for colon-specifi c delivery of insulin [118]. Hydroxypropyl methyl cel-
lulose phthalate was used to coat chitosan capsules to achieve colon-specifi c delivery. Capsules were
administrated orally to Wistar rats (20 IU). Hypoglycemic effect started after 6 h and lasted for 24 h.
The bioavailability of insulin from the chitosan capsules was 5.3% compared with the intravenous one.
Recently application of chitosan-based particles toward developing oral vaccine-delivery systems was
demonstrated [119].
In vivo
uptake of chitosan microparticles prepared by precipitation or coacervation
