Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 288

Graft copolymers of chitosan can also be used as pH-sensitive drug release systems.
Hydrogels for colon-specific drug delivery were synthesized by graft copolymerization of
chitosan and acrylic acid using N , N ′-methylene-bis-(acrylamide) as a cross-linker [124].
These hydrogels have good pH sensitivity due to the charge balance of the amine groups
of chitosan and the carboxyl groups of acrylic acid in the graft copolymer network. The
content of chitosan and the degree of cross-linking were reported to be key factors influ-
encing the swelling kinetics. By tailoring these factors, a very low equilibrium swelling
degree of the hydrogel in the range of pH 2.2-4.0 and the largest degree of swelling at pH
7.4 were observed. Moreover, a decrease of swelling degree was observed on increasing
the pH to beyond 7.4. Therefore, no drug release in the stomach together with a little
amount of release in the small intestine can be achieved, which enables this hydrogel to be
a potential candidate for application in oral colon-specific DDSs.
An IPN or PEC of chitosan and another polymer or polyelectrolyte is also used to release
drugs through the pH-sensitive mechanism [125-128]. Swelling in IPN hydrogels is mod-
erated by the amount of hydrophobic/hydrophilic groups and the cross-linking density
[125], while swelling of the PEC complexes is due to a change in the charge balance inside
the hydrogel [128]. If the charge density of either polymer or polyelectrolyte is no longer
sufficiently high enough to ensure complexation, then the polyelectrolyte “glue” can no
longer hold the polymer chains together, leading to swelling or dissolution. By selecting
polymers or polyelectrolytes based on their isoelectric points, PEC swelling and dissolu-
tion can be tailored for drug release at varying pH values [4].
6.6.2.2 pH and Temperature Dual-Sensitive Release
Chitosan hydrogels are a type of hydrogel exhibiting pH-sensitive property. Sometimes
temperature-sensitive polymers are introduced into the chitosan system to obtain a pH/
temperature dual-sensitive DDS. One of the most attractive features of temperature-
responsive hydrogels as drug carriers is their intelligent property or autoadjustable
function to external temperature changes. The combination of pH- and temperature-
sensitiveness is quite useful in protecting drugs from degradation, to avoid drugs causing
unwanted adverse effects, when they pass through different organs and tissues, and to
deliver drugs to specific tissues [129]. For example, chitosan-coated alginate beads contain-
ing PNIPAAm are used as a controlled pH- and temperature-sensitive DDS with improved
encapsulation efficiency and delayed release rate [130]. The author proposed that the LCST
of the systems could be adjusted to around 37°C or even higher temperatures in future
work. Such systems could be physiologically relevant, for instance, for targeted drug
release of solid tumors in the intestinal tract [130]: (1) the drug administered orally can
bypass the acidity of gastric fluids without liberating substantial amounts of drug and go
into the intestinal fluids; (2) the tumor is subjected to local hyperthermia (typically between
37°C and 42°C), which triggers drug release.
Ma et al. [131] prepared pH- and temperature-sensitive carboxymethyl chitosan-graft-
poly( N , N -diethylacrylamide) (CMCTS-g-PDEA) hydrogels as carriers of VB 2 at different
pH values. It was found that VB 2 released only 10% in pH 1.2 buffer solutions and as much
as 26% in pH 7.4 buffer solutions within the same time. This pH-sensitiveness was due to
the formation of a large number of hydrogen bonds between the -COOH and -OH groups
in CMCTS and/or the -CONR 2 groups in PDEA in acidic solution. Thus, from a more prac-
tical point of view, these hydrogel systems can bypass the acidity of gastric fluid without
liberating substantial amounts of the loaded drug and accomplish purpose in specific
drug-controlled release in the intestine. On the other hand, this hydrogel was also found