Biomedical Engineering Reference
In-Depth Information
Environmental stimuli contain physical stimuli such as temperature, electricity, mag-
netic field, and chemical stimuli such as pH, enzyme, ions, and specific molecular recog-
nition events. Depending on changes in the nature of the external environment,
responsive hydrogels undergo drastic alterations in their structure/behavior, which
facilitate drug payload release. Environmental stimuli can induce three types of hydro-
gel conformational changes: swelling, dissolution, or degradation [4]. Swelling of the
hydrogel opens the “pores” of the polymer network, which allows for faster diffusion of
entrapped molecules out of the hydrogel. Dissolution and degradation represent the
physical breakup of the hydrogel. When the cross-linkages between polymer chains
break, the hydrogel dissolves, subsequently allowing release of the drug. Degradation is
the destruction of the polymer chains themselves (i.e., by enzymes), causing drug release.
Each of these mechanisms can be executed with a number of different hydrogel pre-
paration strategies.
6.6.2.1 pH-Sensitive Release
The pH gradient in the human gastrointestinal (GI) tract ranges from 1 to 7.5 (saliva, 5-6;
stomach, 1-3; small intestine, 6.6-7.5; and colon, 6.4-7.0). When drugs are delivered via
oral administration, the most preferred route, they are expected to go through different
pH environments to reach the target site. The therapeutic efficiency may be affected due
to exposure to harsh environmental conditions, such as extreme acidic gastric juice.
Hence, pH is one of the important environmental parameters for DDSs. To achieve suc-
cessful oral delivery of drugs, pH-sensitive hydrogels are commonly used to protect med-
icine from invalidation in harsh environments or to guarantee effective drug release
within the GI tract selectively. These gels exhibit dramatic changes on pH, namely, swell-
ing and deswelling, thus controlling drug release behavior. All the pH-sensitive poly-
mers contain pendant acidic (e.g., carboxylic and sulfonic acids) or basic (e.g., ammonium
salts) groups that either accept or release protons in response to changes in environmental
pH [121].
Neutral or anionic polymers do not exhibit significant pH-sensitive behavior under
acidic conditions, while the cationic chitosan is responsive at low pH [4]. As mentioned
previously, chitosan exhibits pH-sensitive behavior as a weak polybase due to protona-
tion of amine groups at low pH and deprotonation at higher pH. Moreover, it is believed
that cationic hydrogels protonate and swell more when external pH is lower than the
p
K
a
of the ionizable groups (amino groups in chitosan have a p
K
a
value of ca. 6.5)
[122]. This characteristic leads to dissociation of H-bonding between chitosan chains,
together with chain repulsion and water inside the gel, facilitating drug release at
acidic medium. By cross-linking properly, chitosan hydrogels may serve as drug carriers
for the delivery of some chemical drugs into the stomach where pH is 1-3. However, for
the delivery of medicines to the intestine where pH is ca. 7.5, this property causes a limi-
tation. Modified chitosan is used to prepare chitosan-based hydrogels in order to deliver
certain drugs to the intestine. For example, thiolated chitosan was synthesized as a drug
delivery carrier to minimize drug release in acidic sites, such as in the stomach [123]. The
release amounts of indomethacin (IM) from thiolated chitosan beads were found to
increase with increase in pH of the dissolution medium. The release rate of IM at pH 7.4
was shown to be higher than that at pH 1.4 due to the ionization of thiol groups and high
solubility of IM in alkaline medium. The higher release rate in simulated intestinal fluid
enables drug delivery to take place preferentially in the intestine, avoiding then drug
leakage in the stomach.
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