Thiolated polymers: synthesis and in vitro evaluation of polymer-cysteamine conjugates

The purpose of the present study was to synthesize and characterize novel t hiolated polymers. Mediated by a carbodiimide cysteamine was covalently lin ked to sodium carboxymethylcellulose (CMC) and polycarbophil (PCP). The res ulting CMC-cysteamine conjugates displayed 77.9 +/- 6.7 and 365.1 +/- 8.7 p mol thiol groups per gram of polymer, whereas the PCP-cysteamine conjugates showed 26.3 +/- 1.9 and 122.7 +/- 3.8 mu mol thiol groups per gram of poly mer (mean +/- S.D.; n = 3). In aqueous solutions above pH 5.0 both modified polymers were capable of forming inter- and/or intra-molecular disulfide b onds. The reaction velocity of this oxidation process was accelerated with a decrease in the proton concentration. The oxidation proceeded more rapidl y within thiolated CMC than within thiolated PCP. Permeation studies carrie d out in Ussing-type chambers with freshly excised intestinal mucosa from g uinea pigs utilizing sodium fluorescein as model drug for the paracellular uptake revealed an enhancement ratio (R = P-app (conjugate)/P-app (control) ) of 1.15 and 1.41 (mean +/- S.D.; n = 3) for the higher thiolated CMC-cyst eamine (0.5%; m/v) and PCP-cysteamine conjugate (1.0%; m/v), respectively. The decrease in the transepithelial electrical resistance values was in goo d correlation with the enhancement ratios. Due to a high crosslinking tende ncy by the formation of disulfide bonds stabilizing drug carrier systems ba sed on thiolated polymers and a permeation enhancing effect, CMC- and PCP-c ysteamine conjugates represent promising excipients for the development of novel drug delivery systems. (C) 2001 Published by Elsevier Science B.V.