Mono-carboxymethyl chitosan

A usual approach to increase chitosan s solubility at neutral pH values is the substitution of the primary amine. Whereas N-substitution with alkyl groups (i.e. -CH3 groups) can increase the aqueous solubility without affecting its cationic character, substitution with moieties bearing carboxyl groups can yield polymers with polyampholytic properties (Muzzarelli et al. 1982). Mono-carboxymethylated chitosan (MCC) was synthesized and further... 

Thanou, M., Nihot, M.T., Jansen, M., Verhoef, J.C. and Junginger, H.E. (2001d) Mono— A-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo. J. Pharm. Sci. 90 38-46. 

Chitosan-based nano- and microparticles are widely used for fabrication of controlled dmg release systems. Numerous studies have demonstrated that chitosan and its derivatives (A-trimethyl chitosan, mono-A-carboxymethyl chitosan, etc.) are effective and safe for absorption enhance to improve mucosal (nasal, peroral) delivery of hydrophylic macromolecules, such as peptide and protein dmgs as well as heparins [37,38]. This absorption enhancing effect of chitosan is caused by the opening of intercellular tight junctions, thereby favoring the paracellular transport of macro-molecular dmgs. Recently, a series of successful model chitosan-based polymer systems for mucosal dmg delivery have been reported. Thus, Lim et al. [39] have proposed novel polymer microparticles based on combination of hyaluronic acid and chitosan hydroglutamate... 

FIGURE 25.1 Chemical structures of chitin and chitosan derivatives which have been utilized as immuno-adjuvants (A) chitin (B) chitosan (C) triuiethyl chitosan (D) mono-A-carboxymethyl chitosan. 

Sayin, B., S. Somavarapu, X. W. Li, M. Thanou, D. Sesardic, H. O. Alpar, and S. enel. 2008. Mono-lV-carboxymethyl chitosan (MCC) and A-trimethyl chitosan (TMC) nanoparticles for non-invasive vaccine delivery. International Journal of Pharmaceutics 363 (1-2) 139-148. 

Saym B, Somavarapu S, Li XW, Sesardic D, enel S, Alpar OH. TMC-MCC (N-trimethyl chitosan-mono-N-carboxymethyl chitosan) nanocomplexes for mucosal delivery of vaccine. Eur J Pharm Sci. 2009 38(4) 362-9. 

To overcome these limitations, chitosan has turned out to be a promising candidate as it sufficiently encapsulates the biomacromolecules and helps in their paracel-lular transport across the biological surface. Chitosan and some of its water-soluble derivatives such as N-trimethyl chitosan and mono-N-carboxymethyl chitosan have been used for improving the nasal and peroral absorption of various proteins, peptides and heparins via paracellular transport across the mucosa by opening the intercellular junctions [144-146]. 

As previously mentioned, the amino groups are target moieties for the modification of the backbone in order to gain certain additional advantageous properties. For instance, various chitosan derivatives such as chitosan-EDTA conjugates [15], A -trimethylated chitosan [16], mono-A-carboxymethyl chitosan [17] and A-sulfo-chitosan [18] have been introduced in the pharmaceutical field in the last decade. A further modification of chitosan is based on the immobilization of thiol groups, leading to so-called thiolated chitosans (Fig. 1). 

Besides the above amine reactions for chitosan, alkylation can take place as well. However, this reaction is able to occur at both the C2 amino group and the C6 primary hydroxyl group of chitosan. Zhu et al. synthesized O-carbojymethyl chitosan (OCMCS) via the reaction of chitosan and mono-chloroacetic acid, where major carboxymethyl substitutions were located at the C6 position. The resulting materials showed better water solubility and ampholytic behavior. Beyond a critical aggregation concentration, the... 

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