Preparation and characterization of chitosan microparticles intended for controlled drug delivery

https://doi.org/10.1016/S0378-5173(02)00487-8Get rights and content

Abstract

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic crosslinking. The particle sizes of TPP-chitosan microparticles were in range from 500 to 710 μm and encapsulation efficiencies of drug were more than 90%. The morphologies of TPP-chitosan microparticles were examined with scanning electron microscopy. As pH of TPP solution decreased and molecular weight (MW) of chitosan increased, microparticles had more spherical shape and smooth surface. Release behaviors of felodipine as a model drug were affected by various preparation processes. Chitosan microparticles prepared with lower pH or higher concentration of TPP solution resulted in slower felodipine release from microparticles. With decreasing MW and concentration of chitosan solution, release behavior was increased. The release of drug from TPP-chitosan microparticles decreased when cross-linking time increased. These results indicate that TPP-chitosan microparticles may become a potential delivery system to control the release of drug.

Introduction

Chitosan[poly(β-(1→4)-2-amino-2-deoxy-d-glucose)] is a natural cationic polysaccharide derived from chitin, which is copolymer, a glucosamine and an N-acetyl glucosamine units, combined together (Lee et al., 1997, Ravi Kumar, 2001). Chitosan has been extensively studied as carriers for drugs (Bayomi et al., 1998, Mi et al., 2001), protein carriers (Calvo et al., 1997) and gels for the entrapment of cells or antigens (Mi et al., 1999c) in the pharmaceutical industry. Moreover, chitosan has antacid and antiulcer characteristics, which prevents or weakens drug irritation in the stomach (Gupta and Ravi Kumar, 2000).

According to previous studies, drug release from chitosan microparticles could be controlled by crosslinking the matrix using chemical crosslinking agents such as glutaraldehyde (Jameela and Jayakrishnan, 1995, Genta et al., 1997, Genta et al., 1998, Blanco et al., 2000), NaOH (Chandy and Sharma, 1996, Lim et al., 1997, Vasudev et al., 1997) and ethylene glycol diglycidyl ether (Mi et al., 1999c). However, these chemical crosslinking agents have possibility of inducing undesirable effects. Chemically synthesized glutaraldehyde can cause irritation to mucosal membranes due to its toxicity (Lim et al., 1997, Mi et al., 2001, Shu et al., 2001).

To overcome this disadvantage of chemical cross-linking, ionic crosslinking interaction has been applied. For example, chitosan beads, micro or nanoparticles were produced by ionic cross-linking with tripolyphosphate (TPP) (Bodmeier et al., 1989, Shiraishi et al., 1993, Calvo et al., 1997). Shu and Zhu, 2000, Shu and Zhu, 2001 reported the chitosan bead, which was prepared with TPP, increased the drug loading efficiency as well as prolonging the drug release period, and they also showed that citrate cross-linked chitosan film possessed pH-sensitive swelling and drug controlled release properties. Mi et al. (2001) reported that the chitosan microspheres prepared with genipin, a naturally occurring crosslinking reagent, affected the release behavior of the drugs in microspheres.

TPP is nontoxic and multivalent anions. It can form gel by ionic interaction between positively charged amino groups of chitosan and negatively charged counterion of TPP (Aral and Akbuğa, 1998, Mi et al., 1999b, Shu and Zhu, 2000, Shu and Zhu, 2001). This interaction could be controlled by the charge density of TPP and chitosan, which is dependent on the pH of solution. The chitosan matrix could be depended on molecular weight (MW) of chitosan. Puttipipatkhachorn et al. (2001) reported that the higher the MW and degree of deacetylation of chitosan, the lower the release rate of chitosan film.

In this study, the chitosan microparticle was prepared with TPP and chitosan of various MW. The objective of this study was to evaluate the effect of the preparation process on the release behavior of chitosan microparticles, which was prepared by various conditions such as (1) concentration and MW of wall material (chitosan), (2) pH and concentration of cross-linker (TPP) solution and (3) curing time. Felodipine (C18H19C12NO4, MW 384.3), the treatment of hypertension, was used as a model drug.

Section snippets

Materials

Chitosan with different MW (2.5×106, 3.5×106, 6.5×106, the degree of deacetylation was 86.8, 86.4, 93.6%, respectively) were obtained from Biotech. Co. Ltd (Korea). Felodipine was obtained from Nivedita Chemical Pvt. Ltd (Mumbai, India). TPP and other reagents were all analytical reagents grade.

Preparation of TPP-chitosan microparticles

Various amounts of chitosan solutions were prepared by dissolving it in 1% acetic acid as shown in Table 1 and Tween 80 (2% v/v) was added into the solution as a surfactant. Core material, felodipine,

Properties of TPP-chitosan microparticles

TPP-chitosan microparticles were prepared by the ionic interaction between a positively charged amino group of chitosan and a negatively charged counterion of TPP. The ionization degree of TPP is dependent on the pH value of solution. In original TPP solution (pH 8.6), TPP is dissociated into OH and TPP ions (HP3O104− and P3O105−). However in low pH, only P3O105− anions are. Moreover, chitosan is a weak polybase, and as pH of the solution decreased, the ionization of amine group of chitosan

Conclusion

TPP-chitosan microparticles were modified by various factors to control the release of felodipine. The results shows that the pH and concentration of the crosslinking agent solution, MW and concentration of wall material and curing time play major roles on the TPP-chitosan matrix density: as the MW and concentration of chitosan solution and curing time increased, the release behaviors of felodipine decreased significantly. Also, lower pH and higher concentration of TPP solution resulted in

Acknowledgements

This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (HMP-00-PT-21700-0017).

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