Abstract
The cationic thiomer chitosan-thioglycolic acid (TGA) shows excellent mucoadhesive features. In order to deepen the knowledge concerning this new excipient the optimization of its synthesis and a detailed characterization of its properties was the objective of this study Mediated by increasing quantities of a carbodiimide, thioglycolic acid was covalently attached to chitosan forming amide bonds with the primary amino groups of the polymer Determined with Ellman's reagent, 38 ± 3, 104 ± 2, 685 ± 43, and 885 ± 7 pmol thiol groups (n=3; ± SD) were bound per gram polymer at carbodiimide concentrations of 50, 75, 100, and 125 mM, respectively. The immobilized thiol groups displayed a comparatively higher reactivity to form disulfide bonds than the thiol groups in a corresponding mixture of chitosan and free unconjugated TGA. In an aqueous 0.5% (rnlv) chitosan-TGA gel 59 ± 5% of the thiol groups formed disulfide bonds within 6 hours at pH 6.0, whereas merely 5 ± 3% were oxidized in the corresponding physical mixture of chitosan and TGA. Diffusion studies showed that the modified polymer was capable of binding cysteine and cysteine methyl ester. The result supports the theory that the improved mucoadhesive properties of thiolated chitosan are based on the formation of disulfide bonds with cysteine moieties of mucus glycoproteins. Because of its availability via an efficient synthetic pathway and its mucoadhesive properties based on the capability to bind cysteine subunits, chitosan-TGA seems to be a promising new excipient for various drug delivery systems.
Highlights
IntroductionThe binding capability for cysteine and a derivative thereof will be evaluated within this study, as the covalent binding of thiomers to mucus glycoproteins seems to take place via cysteine moieties within the mucin amino acid sequence
Within the last years a promising new type of mucoadhesive hydrophilic polymers has been introduced into the pharmaceutical literature Because of the immobilization of thiol moieties on well established hydrophilic polymers such as poly(acry1ates) and cellulose derivatives theirA
The result supports the theory that the improved mucoadhesive properties of thiolated chitosan are based on the formation of disulfide bonds with cysteine moieties of mucus glycoproteins
Summary
The binding capability for cysteine and a derivative thereof will be evaluated within this study, as the covalent binding of thiomers to mucus glycoproteins seems to take place via cysteine moieties within the mucin amino acid sequence. Apart from the formation of disulfide bonds between thiomers and cysteine groups of mucus glycoproteins, the formation of inter- and/or intra-chain disulfide bonds within chitosan-TGA itself seems to be another important capability of this novel excipient Because of this cross-linking process the cohesive properties of chitosan can be improved rendering it useful e.g. as tablet binder or for the manufacture of particulate delivery systems which are stabilized by disulfide bonds within the polymeric network. A detailed evaluation of the influence of the covalent attachment of TGA on the reactivity of thiol groups being responsible for this crosslinking process was the objective of this study
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