Application Mechanism and Safety Aspects

Chitosan (poly[|3-(1-4)-2-amino-2-deoxy-D-glucopyranose]) is a cationic poly-saccharide comprising copolymers of glucosamine and N-acetylglucosamine (Fig. 6.3c). Nowadays chitosan is available in different molecular weight (polymers 500,000-50,000 Da, oligomers 2,000 Da), viscosity grades, and degree of deacetylation (40-98%). It is next to cellulose the most abundant polysaccharide in nature. Chitosan is insoluble at neutral and alkaline pH values, whereas it forms salts with inorganic and organic acids such as glutamic acid, hydrochloric acid, lactic acid, and acetic acid. Chitosan is generally regarded as biocompatible, slowly biodegradable natural origin polymer (Hirano and Noishiki, 1985; Chandy and Sharma, 1990). It is widely used in the food industry as a food additive and as a weight loss product. Chitosans have found a number of applications as biomaterials in tissue engineering and in controlled drug release systems for various routes of delivery (Dodane and Vilivalam, 1998; Illum, 1998; Suh and Matthew, 2000). Chitosan polymers are also used as a safe excipient for a number of pharmaceutical applications (e.g., excipient in granules and tablets, gels and microspheres) (Baldrick, 2000). Chitosan has been included in the European Pharmacopoeia since 2002.

The bioadhesive properties were first described by Lehr et al. (1992d) demonstrating that chitosan in the swollen state is an excellent mucoadhesive at porcine intestinal mucosa and is also suitable for repeated adhesion. The authors also reported that chitosan underwent minimal swelling in artificial intestinal fluids due to its poor aqueous solubility at neutral pH values, proposing that substitution of the free-NH2 groups with short alkyl chains would change the solubility and hence the mucoadhesion profile. The strong mucoadhesive properties of chi-tosan are due to the formation of hydrogen and ionic bonds between the positively charged amino groups of chitosan and the negatively charged sialic acid residues of mucin glycoproteins (Rossi et al., 2000).

Illum et al. (1994) described that chitosan solutions at 0.5% (w/v) concentrations are highly effective at increasing the absorption of insulin across nasal mucosa in rats and sheep. The mechanism of action of chitosan was suggested to be a combination of bioadhesion and a transient widening of the tight junctions in the membrane. The influence of chitosan's degree of deacetylation and MW was also investigated on the permeability of Caco-2 cell intestinal monolayers. Schipper and coworkers (1996) studied the effect of chitosan solutions at pH 5.5 on the permeability of the nonabsorbable paracellular marker [14C]mannitol and intracellular dehydrogenase activity. It was found that chitosans with a high degree of deacetylation were effective as absorption enhancers at low and high molecular weight, and also showed clear dose-dependent toxicity, whereas chitosans of low degree of deacetylation were effective at only high molecular weight and showed low toxicity. The effects of chitosans of both low and high molecular weight and degree of deacetylation were further investigated by the same authors with respect to their ability to bind at epithelial Caco-2 cell monolayers. Both chitosans appeared to bind tightly to the epithelium, inducing a redistribution of F-actin (change from a filamentous to a globular structure) and the tight junction's zonula occludens-1 protein. No intracellular uptake of chitosan could be observed. It was also shown that these effects were mediated by chitosan's cationic charges, since addition of the highly anionic heparin to the test solution inhibited the absorption enhancing effect (Schipper et al., 1997).

Kerec and coworkers (2005) just recently investigated the role of Ca2+ on the permeability effect of chitosan on the isolated pig urinary bladder. Their results show that when calcium ions were applied together with chitosan to the lumi-nal surface of the urinary bladder, they decrease the permeability of the model drug moxifloxacin in a concentration dependent way. These experiments show that Ca2+ ions are of no benefit to absorption enhancement when simultaneously given to both chitosans and polyacrylates (LueBen et al., 1996a).

Whereas for most absorption enhancers studied the cytotoxicity profile was evident, chitosan gave contradictory results regarding safety (Carreno-Gomez and Duncan, 1997). Dodane et al. (1999) investigated the effect of chitosan (degree of deacetylation 80%) solutions at pH 6.0-6.5 on the structure and function of Caco-2 cell monolayers. Using a series of microscopic techniques, the authors were able to show that chitosan had a transient effect on the tight junction's permeability and that viability of the cells was not affected. However, chitosan treatment slightly perturbed the plasma membrane, but this effect was reversible.

In a preliminary study, Chae and coworkers (2005) investigated the molecular weight (MW) dependent Caco-2 cell layer transport phenomena (in vitro) and the intestinal absorption patterns after oral administration (in rats in vivo) of water soluble chitosans. The absorption of chitosans was significantly influenced by its MW. As the MW increases, the absorption decreases. The absorption both in vitro and in vivo of a chitosan with a MW of 3.8 kDa was about 25 times higher in comparison to a high MW chitosan (230 kDa). On the other side, the chitosans showed concentration- and MW-dependent cytotoxic effects: the chi-tosan oligosaccharides (MW < 10 kDa) showed negligible cytotoxic effects on the Caco-2 cells whereas the high MW chitosans were more toxic in this experimental setting. However, the abundant use of chitosans in the food industry and the use of chitosan as excipient for peroral drug delivery systems prove that also chitosan with a high molecular weight can be regarded as safe.

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