Chitosan-Based Gels for the Drug Delivery System - Chitosan Based Hydrogels: Functions and Applications - page 290

[138]. The drug release behavior was strongly influenced by the applied voltage and the
concentration of MMT, which affected the cross-linking density of the nanohydrogels.
And the release mechanism changed from a diffusion-controlled mode to a swelling-con-
trolled mode under electrostimulation. This new class of nanohydrogels was reported to
provide an interesting alternative as a long-standing electrically induced DDS with reli-
able drug release performance.
6.6.2.4 Enzyme-Sensitive Release
To achieve more specific release of drugs, responsiveness to enzymes that are localized to
different areas of the body could be the best choice. Enzyme-controlled DDSs have been
developed for colon-specific therapeutic delivery [139-141]. In an enzyme-controlled sys-
tem, local enzymes produced from microflora in the human colon such as amylase, pecti-
nase, and β-d-glucosidase break down a prodrug or a formulation containing biodegradable
polymers such as pectin, guar gum, and chitosan to release the drug. Glycosidic linkages
on chitosan are susceptible to glycosidic hydrolysis by microbial enzymes in the colon.
Therefore, chitosan can be used as a colon-specific drug delivery vehicle.
Zhang et al. [139] prepared a multiparticulate system of chitosan hydrogel beads for
colon-specific delivery of macromolecules using fluorescein isothiocyanate-labeled BSA as
the model protein. The hydrogel bead was formed by polyelectrolyte complexation of chi-
tosan with TPP. Drug release indicated that rat cecal and colonic enzymes can attack chi-
tosan even after it has been cross-linked and its solubility reduced, resulting in a greater
protein release under conditions pertaining to the colon.
In terms of chitosan-based hydrogels, an enzyme-sensitive system may, at the same time,
be in response to some other stimuli, such as pH of the environment [140,141]. Nunthanid
et al. [141] recently developed a colonic DDS based on a combination of time-, pH-, and
enzyme-controlled systems. A combination of chitosan acetate (CSA) and hydroxypropyl
methylcellulose was used as compression-coats for 5-aminosalicylic acid tablets. These
chitosan-based coats were capable of retarding the release of aminosalicylic acid until the
dosage forms reach the colon and there the drug was released. The delay release mecha-
nisms during the lag time were time- and pH-controlled by the swelling gel erosion of
both polymers in the acidic medium and the less solubility at high pH of CSA, respectively.
The solubility of CSA at low pH facilitates drug release, while the degradation of CSA
by the enzyme in the colon plays an important role in the release of the drug and helps
accelerate drug release in the colon.
6.6.2.5 Glucose-Sensitive Release
In addition to the commonly used stimuli described above, other stimuli have also been
used for making environment-sensitive hydrogels in order to deliver certain kinds of
drugs. For example, an insulin delivery system usually requires a glucose-sensing ability
to trigger the release of necessary amounts of insulin. A glucose-sensitive in situ gelling
system based on chitosan for pulsatile delivery of insulin was developed by Kashyap et al.
[142]. Glucose oxidase, an enzyme that can specifically interact with glucose and sense its
levels, together with insulin, was added into a chitosan-GP solution that can form hydro-
gels at body temperature. These gels were found to release the entrapped insulin in a
pulsatile manner in response to changes in physiological glucose concentrations. The
release mechanism of this glucose-sensitive system may be as follows: Glucose oxidase
immobilized in pH-sensitive chitosan hydrogels can sense glucose levels and convert