(337a) Monodisperse Core-Shell Chitosan Microcapsules for pH-Responsive Burst Release of Hydrophobic Drugs

Microencapsulation
of drugs has attracted great attention because of its capability of masking
unpleasant drug tastes and odors, in controlled release of drugs and in
protecting drugs from undesirable degradation.^[1] Due to a large
interior space, core-shell microcapsules can enhance loading efficiency
compared with homogeneous microspheres. Stimuli-responsive microcapsules show
even greater advantages in controlling the release rate and targeting the
release site, because the release can be triggered by environmental
temperature, pH, ionic concentration and/or magnetic field.^[2] Among
those microcapsules, pH-responsive microcapsules have been paid much attention
because of large variations in physiological pH at different body sites in
normal as well as pathological conditions.^[3] For example, the pH value
of the gastric content can vary from a lower value of 1.2 in the fasted state
to a higher value of 5.0 under fed state.^[4] Gastric acid secretion
disorder can cause diseases such as gastroesophageal reflux disease and peptic
ulcer disease. Acid-suppression therapy has been adopted to treat those
diseases for decades. This treatment demands agents to reach its maximal
efficacy in a short time to alleviate patients' symptom as soon as possible.^[5]
Thus, the development of acid-triggered core-shell microcapsules for gastric
delivery with prompt onset and complete release characteristics in a
controllable manner is of both scientific and therapeutic interest.

Here, we report
on a novel strategy to fabricate core-shell chitosan microcapsules for
stomach-targeted rapid and complete drug release in a controllable manner by
designing an acid-triggered burst release mode for the capsules. The core-shell
chitosan microcapsule membrane is composed of terephthalaldehyde-crosslinked
chitosan hydrogel. In this study, our strategy for microcapsule preparation is
to use uniform-sized oil-in-water-in-oil (O/W/O) emulsions fabricated by
capillary microfluidic technique^[6] as templates and convert these emulsions
into core-shell microcapsules via interfacial crosslinking reaction. Inner oil
phase, middle water phase, and outer oil phase solutions were separately pumped
into the injection tube, the transition tube, and the collection tube through
polyethylene tubing attached to disposable syringes. Based on the coaxial
co-flow geometry, monodisperse O/W single emulsions were generated in the
transition tube and monodisperse O/W/O double emulsions were generated in the collection
tube. In our O/W/O double emulsion templates, the chitosan is in the middle water
layer and the inner oil phase contains oil-soluble terephthalaldehyde, which
acts as crosslinker in the subsequent interfacial crosslinking reaction. The
crosslinking reaction occurs at the inner O/W interface of the double emulsion
template as soon as the inner oil fluid contacts the middle water fluid in the transition
tube of the microfluidic device. The obtained O/W/O double emulsions were
collected in a container, and left to stand overnight to make sure the chitosan
in the water phase was completely crosslinked. The resultant microcapsules were
washed using a mixture of ethyl acetate and isopropanol (1©U5 v/v) to remove
the inner and outer oil solutions, and finally dispersed into water. Such
one-pot method presented here has competitive advantages for preparing
chitosan-based core-shell microcapsules with more controllable structure and
simpler procedure. Furthermore, lipophilic substances can be easily
encapsulated into the proposed chitosan microcapsules through the microfluidic
approach.

The microcapsules
have been found to display autofluorescent properties because of the formation
of Schiff's bases.^[7] The Fourier transform infrared (FTIR) analysis
also confirms the crosslinking reaction between chitosan and terephthalaldehyde

The average
outer diameters of the double emulsions and microcapsules are 292 µm and 224 µm,
respectively. The coefficient of variation (CV), which is defined as the
ratio of the standard deviation of the size distribution to its arithmetic
mean, is used to characterize the size monodispersity of particles. The CV
values for the double emulsions and the resultant microcapsules are 0.94% and
2.3% respectively, which indicate their narrow size distributions. The
throughput rate of the chitosan microcapsules prepared with a single
microfluidic device is 1.25 °Á10⁵ per hour.

In neutral
medium with pH 7.1, microcapsules shrink considerably during the initial period
of 24 h and afterwards the size of microcapsules shows nearly no change. Five
days later, the average outer diameter of microcapsules is reduced from 253 µm to
201 µm and the thickness of capsule membrane decreases by 23%. Although a
slight volume change is observed for the crosslinked chitosan microcapsules,
the microcapsules maintain good spherical shape and structural integrity in
neutral medium.

To estimate the
capability of acid-triggered burst release from microcapsules, the
decomposition processes of chitosan microcapsule membranes in the pH range of
1.5°«4.7
were studied systematically. Microcapsules were firstly immersed in deionized water.
Then, we introduced a sudden change to the pH value of their environmental
solution by quickly adding HCl or phosphate buffer solution with different pH
values.
All
the microcapsules swell first, and then gradually collapse and finally
decompose. The lower the environmental pH value, the faster the acid-triggered
swelling and the faster the decomposition of microcapsule membrane. When the environmental
pH value is 4.7, it takes 22 min for the microcapsules to completely decompose;
whereas, when the environmental pH value decreases to 1.5, the microcapsules
decompose rapidly in 39 s. This pH-dependent decomposition manner can be utilized
to develop smart gastric delivery systems, from which anti-acid agents can be
released at a rate that depends on the pH value of the gastric juice.

To demonstrate
the feasibility to encapsulate lipophilic drugs using our technique and the
acid-triggered burst release behavior of the prepared microcapsules, LR300, a
red fluorescent dye, is successfully encapsulated in the crosslinked chitosan
microcapsules as a lipophilic model drug (Fig. 1).

Fig. 1 The acid-triggered
burst release process of chitosan microcapsules.

The
burst and complete release pattern from the prepared chitosan microcapsules may
enable them to be promising stomach-specific drug carrier candidates for
quick-release.

References

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