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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