Fee, Monica
(2006)
Evaluation of chitosan stability in aqueous systems.
PhD thesis, University of Nottingham.
Abstract
This study considers the molecular weight, conformation, stability and nanoparticle formation of the polysaccharide chitosan in relation to its pharmaceutical applications in the drug delivery. Chitosan has bioadhesive and absorption enhancing properties that augment its use in the delivery of therapeutic proteins and peptides across mucosal membranes.
The molecular weights of a range of chitosans, with degree of acetylation (DA) ranging form 7 to 30%, were studied using the hydrodynamic techniques of SEC-MALLS (size exclusion chromatography coupled with multi-angle laser light scattering) and analytical ultracentrifugation. It was found that there was reasonable agreement between the two techniques with molecular weights obtained ranging between 42000 and 200000 kDa. These results indicated that the use of SEC-MALLS as a measure of degradation during storage studies would be valid and this technique would be more convenient due to the much shorter time required for each sample.
Conformational studies indicated that in 0.2M acetate buffer, pH 4.3, the chitosan samples studied appeared to have an extended conformation which is in agreement with studies performed by other researchers (e.g. Anthonsen, M. W., K. M. Vårum and O. Smidsrød (1993) Carbohydrate Polymers 11: 193-201 and Dyer, A. M., M. Hinchcliffe, P. Watts, J. Castile, I. Jabbal-Gill, R. Nankervis, A. Smith and L. Illum (2002) Pharmaceutical Research 19(7): 998-1008), non-withstanding complications in interpretation through possible solvent draining effects (Berth, G., Colfen, H., Dautzenberg H (2002) Prog. Coil. Int. Sci. 119, 50-57).
Degradation studies were performed using viscosity measurements and SECMALLS to measure molecular weight. The effect of solution parameters such as pH and ionic strength were examined as well as structural parameters, e.g. molecular weight and DA. Degradation was found to increase as the pH of the solution decreased indicating that acid hydrolysis was occurring. The range of ionic strength studied (0.1 - 0.3M) did not have any significant effect on degradation rate. For the samples studied, molecular weight appeared to have little effect on degradation, however, the more deacetylated the polysaccharide, the slower the rate of degradation due to increased charged residues along the chain.
Finally chitosan nanoparticles were then prepared using ionotropic gelation with tripolyphosphate pentasodium. This technique produced nanoparticles in the size range 320 - 380 run with an insulin loading capacity of 30-50%. Insulin-loaded nanoparticles were prepared and resuspended in acetate buffer at various pHs. The molecular weight and insulin loading was tested at 2-week intervals and results indicated that chitosan degradation was reduced by 30% compared to a control chitosan solution, and the total amount of insulin incorporated remained constant over the storage period.
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