Chitosan-dibasic orthophosphate hydrogel: A potential drug delivery system
Introduction
In a variety of therapeutic contexts, it is necessary to administer therapeutic agents to patients parentally, and in a manner that allows for sustained local delivery of the active agent. For example, local release of therapeutic agents may be desirable in the case where an agent has a narrow therapeutic index, as a means of maintaining efficacy at the organ or tissue where an effective dose is required, while avoiding systemic toxicity and unwanted side-effects. One of the most efficient methods of parental delivery of macromolecules is via thermo-sensitive in-situ gels (Ruel-Gariepy et al., 2000). These gels avoid the need for encapsulation of the active compound in organic solvents or heat treatment which often reduces drug activity (Martini and Lauria, 2003). As well, they have a lower cost and associated risk compared to surgical implantation of drug delivery devices in the body. Recently, much attention has been paid towards the application of chitosan in such drug delivery systems due to its many desirable properties.
Chitosan is derived from chitin, a naturally occurring amino polysaccharide found in various organisms including the cell walls of fungi and exoskeletons of arthropods such as crabs, shrimps and insects (Kumar, 2000, Chenite et al., 2001). Chitosan is a polymer composed of β-(1–4)-linked glucosamine residues and it is cationic, nontoxic, biocompatible and biodegradable (Dhanikula and Panchagnula, 2004, Kashyap et al., 2007, Weska, 2007). In addition, chitosan is mucoadhesive, susceptible to enzymatic degradation and has antibacterial activity and intrinsic wound healing properties (He et al., 1998, Helander et al., 2001, Ueno et al., 2001). Due to these characteristics and the fact that chitosan is abundant and economical to produce (Peter, 1995, Kumar, 2000), it has attracted a wide range of medical and pharmaceutical applications (Oungbho and Muller, 1997, Dodane and Vilivalam, 1998, Bernkop-Schnurch, 2000, Borchard, 2001, Shu et al., 2001, Okamoto, 2002, Shu and Zhu, 2002, Khor and Lim, 2003).
At pH below its pKa (pH 6.2), chitosan is water-soluble and positively charged due to protonation of amine groups present on the polymeric chains (Cho et al., 2005). This results in electrostatic repulsion between the polymeric chains and hence chitosan is retained in its solution form. When the pH exceeds 6.2, a gel-like precipitate forms from chitosan aqueous solutions due to the neutralization of chitosan amine groups, leading to the removal of repulsive interchain electrostatic forces, allowing for hydrogen bonding and hydrophobic interactions between chains. Chenite et al. (2001) have reported the neutralization of chitosan solution by a organic polyol counterionic monohead salt, β-glycerophosphate (βGP), leading to the gelation of this polymer system.
The purpose of this study was to evaluate the feasibility of developing a thermo-activated in-situ gelling chitosan delivery system using an inorganic salt present in the body fluid such as potassium phosphate as the gelling agent. Parameters affecting the gelation properties and the release characteristics were investigated. The evaluation on the cytotoxicity of these hydrogels is also reported.
Section snippets
Materials
Low molecular weight (MW) chitosan was obtained from Fluka BioChemika (Switzerland). Analytical grade potassium dihydrogen phosphate (KH2PO4), dipotassium hydrogen orthophosphate (K2HPO4) and tripotassium phosphate (K3PO4) were acquired from GPR (BDH, England). Acetic acid (CH3COOH) was purchased from Ajax Finechem (Australia). FITC-dextran, β-lactoglobulin and bovine serum albumin (BSA) were obtained from Sigma–Aldrich (Australia). Micro BCA Protein assay kit was purchased from Pierce,
Effect of basic degree of orthophosphate salt on gelation
It was found that samples containing KH2PO4 at molar ratios tested could not gel at any of the evaluated temperature settings. The pH of these solutions was between 5.0 and 5.2. In contrast, upon heating, chitosan/K2HPO4 solutions became more viscous and gelation occurred with gel strength observed to be proportional to temperature (data not shown). The pH range of these solutions was found to be between 7.0 and 7.6. For samples containing K3PO4, a strong basic salt, local precipitation of
Discussion
Chitosan is a pH-dependent cationic, non-toxic, antibacterial, easily bioabsorbable, biodegradable, biocompatible (Chandy and Sharma, 1990, Hirano et al., 1990) and mucoadhesive biopolymer (Henriksen et al., 1996, He et al., 1998). It was ranked as GRAS (generally recognised as safe) by FDA (Food and Drug Administration). Therefore, chitosan can be widely used in pharmaceutical preparations and food products without concern for patient or consumer safety. Chitosan remains dissolved in aqueous
Conclusion
The ability of DHO to induce the thermo-activated gelation of chitosan solutions was demonstrated. Gelation temperature and gelation time of Chi/DHO systems are adjustable and can be controlled for use in a particular utility. The in vitro cytotoxicity study indicates that neutral Chi/DHO hydrogels are non-toxic toward SaOS-2 cells. The potential of Chi/DHO as a prolonged drug delivery vehicle was demonstrated using FITC-dextran, β-lactoglobulin and BSA. The release of these macromolecules
Acknowledgements
This project was supported by the University of Melbourne. We would like to thank Dr Simon Crawford (School of Botany, University of Melbourne) for his assistance with SEM imaging.
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