Thiolated Polymers of Polyacrylates and Cellulose Derivatives

Thiolated polymers are synthesized by immobilizing thiol groups on polyacry-lates or cellulose derivatives (Fig. 6.3d) by the group of Bernkop-Schniirch (Bernkop-Schniirch and Steiniger, 2000; Bernkop-Schnurch et al., 2000; Leitner et al., 2003a; Clausen and and Bernkop-Schnurch, 2000). The main purpose of introducing free thiol groups into polymers, which already have mucoadhesive properties, is to further strongly increase the strength of their mucoadhesiveness due to the chemical reaction of the thiol groups of the mucins and the thiol groups of the thiolated polymers by forming stable covalent disulfide bridges. With this elegant approach the mucoadhesiveness of such polymers and additionally their cohesiveness could be strongly increased. However, because of the turnover time of mucus, which has been estimated in the isolated intestinal loop of the rat by Lehr et al. (1991) to be in the order of 47-270 min, the residence time of these thiolated polymers and the delivery systems made of such thiolated polymer will be restricted to this time interval. A reasonable assumption is that the polymers will stick to the mucus at the time of 3 h after peroral application.

Bernkop-Schnurch and coworkers (2000; Bernkop-Schnurch et al.2000) linked L-cysteine covalently to PCP (Fig. 6.3d) mediated by a carbodiimide. The resulting thiolated polymers displayed 100 ± 8 and 1, 280 ± 84 |imol thiol groups per gram, respectively. in aqueous solutions these modified polymers were capable of forming inter and/or intramolecular disulfide bonds. Due to the formation of disulfide bonds within the thiol-containing polymers, the stability of matrix tablets could be strongly improved. Whereas tablets based on the corresponding unmodified polymer disintegrated within 2 h, the swollen carrier matrices of thiolated NaCMC and PCP remained stable for 6.2 h and for more than 48 h, respectively. With the model drug rifampicin controlled release characteristics of these thiolated matrix tablets could be demonstrated. Tensile studies carried out with the unmodified and thio-lated polymers at pH 3, 5, and 7, respectively, revealed that only if the polymer displays a pH value of 5, the total work of adhesion could be improved significantly due to the covalent attachment of thiol groups. The permeation enhancing effect of thiolated polycarbophil on intestinal mucosa from guinea pigs showed weak enhancement ratios (1.1-1.5) in comparison to control tests.

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