Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure

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Abstract

By adopting a novel chitosan cross-linked method, i.e. chitosan/gelatin droplet coagulated at low temperature and then cross-linked by anions (sulfate, citrate and tripolyphosphate (TPP)), the chitosan beads were prepared. Scanning electron microscopy (SEM) observation showed that sulfate/chitosan and citrate/chitosan beads usually had a spherical shape, smooth surface morphology and integral inside structure. Cross-sectional analysis indicated that the cross-linking process of sulfate and citrate to chitosan was much faster than that of TPP due to their smaller molecular size. But, once completely cross-linked, TPP/chitosan beads possessed much better mechanical strength and the force to break the beads was approximately ten times higher than that of sulfate/chitosan or citrate/chitosan beads. Release media pH and ionic strength seriously influenced the controlled drug release properties of the beads, which related to the strength of electrostatic interaction between anions and chitosan. Sulfate and citrate cross-linked chitosan beads swelled and even dissociated in simulated gastric fluid (SGF) and hence, model drug (riboflavin) released completely in 5 h; while in simulated intestinal fluid (SIF), beads remained in a shrinkage state and drug released slowly (release % usually <70% in 24 h). However, swelling and drug release of TPP/chitosan bead was usually insensitive to media pH. Chitosan beads, cross-linked by a combination of TPP and citrate (or sulfate) together, not only had a good shape, but also improved pH-responsive drug release properties. Salt weakened the interaction of citrate, especially sulfate with chitosan and accelerated beads swelling and hence drug release rate, but it was insensitive to that of TPP/chitosan. These results indicate that ionically cross-linked chitosan beads may be useful in stomach specific drug delivery.

Introduction

Chitosan, with excellent biodegradable and biocompatible characteristics, is a naturally occurring polysaccharide. Due to its unique polymeric cationic character and its gel and film forming properties, chitosan has been extensively examined in the pharmaceutical industry for its potential in the development of drug delivery systems (Chandy and Sharma, 1992, Chandy and Sharma, 1993, Yao et al., 1996, Patel and Amiji, 1996, Felt et al., 1998, Illum, 1998, Giunchedi et al., 1998, Gupta and Kumar, 2000).

Recently, the use of complexation between oppositely charged macromolecules to prepare chitosan beads (or microspheres) as controlled drug release formulation, especially for peptide and protein drug delivery, has attracted much attention because this process is very simple and mild (Huguet et al., 1994, Polk et al., 1994, Liu et al., 1997, Dumitriu and Chornet, 1998). In addition, reversible physical cross-linking by electrostatic interaction instead of chemical cross-linking is applied to avoid possible toxicity of reagents and other undesirable effects.

Compared to polyanions, the preparation of cross-linking chitosan matrices using anions was found to be simpler and milder. For example, tripolyphosphate (TPP) cross-linked chitosan beads can be prepared simply by dropping chitosan droplets into TPP solution and this procedure was found to be useful in the pharmaceutical industry (Kawashima et al., 1985a, Kawashima et al., 1985b, Bodmeier et al., 1989, Shirashi et al., 1993, Sezer and Akbuga, 1995, Aydin and Akbuga, 1996, Calvo et al., 1997, Aral and Akbuga, 1998). Unfortunately, up to now, only a few ionic cross-linked chitosan beads have been reported.

TPP/chitosan bead usually had poor mechanical strength, which limited its usage in drug delivery. In our previous studies, a novel approach was developed to improve the mechanical strength of TPP/chitosan beads by more than ten times (Shu and Zhu, 2000). Furthermore, other anions (sulfate and citrate etc.) were also found to interact with chitosan by electrostatic force (Shu and Zhu, 2001, Shu et al., 2001), therefore sulfate and citrate cross-linked chitosan films were prepared and their controlled drug release properties were investigated (Shu and Zhu, 2001, Shu et al., 2001).

In this paper, we aimed to prepare sulfate and citrate cross-linked chitosan beads and investigate the model drug controlled release performances (especially pH and ionic strength responsive properties) of sulfate, citrate and TPP cross-linked chitosan beads, which was discussed in view of the difference in molecular structure of the anions.

Section snippets

Materials

Chitosan was obtained from Tianbao Chitosan Co. Ltd. (Ningbao, People's Republic of China) and refined twice by dissolving in dilute HAc solution and precipitating from dilute ammonia, the degree of deacetylation was 86%, Mv was 460,000. Gelatin (type B, ≈225 Bloom) was obtained from Sigma (St. Louis, MO). Riboflavin (Mw 376.37) was purchased from Aldrich (Milwaukee). Sodium sulfate, sodium citrate, sodium tripolyphosphate (TPP) and other reagents were all commercially available and used as

Morphology observation

Sulfate, citrate and TPP carry a maximum of two, three and five negative charges, respectively (Scheme 1). The electrostatic interaction between TPP and chitosan had been reported and exploited in the pharmaceutical industry to prepare TPP cross-linked chitosan beads, for long time (Kawashima et al., 1985a, Kawashima et al., 1985b, Bodmeier et al., 1989, Shirashi et al., 1993, Sezer and Akbuga, 1995, Aydin and Akbuga, 1996, Calvo et al., 1997, Aral and Akbuga, 1998). Our recent results revealed

Conclusions

Sulfate, citrate and TPP cross-linked chitosan beads were prepared by our recently developed method. Due to their smaller molecular size, the cross-linking process of sulfate and citrate to chitosan was much faster than that of TPP; but once completely cross-linked, TPP/chitosan beads possessed much better mechanical strength than sulfate/chitosan and citrate/chitosan beads, due to its strongest interaction with chitosan. Release media pH and ionic strength seriously influenced the controlled

Acknowledgements

The authors wish to thank the National Natural Science Foundation of China for financial support.

References (26)

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