In vitro evaluation of the permeation-enhancing effect of thiolated polycarbophil

The objective of this study was to investigate the permeation-enhancing eff ect of thiolated polycarbophil (PCP) on peptide drugs. Mediated by a carbod iimide, increasing amounts of cysteine (Cys) were covalently bound to sodiu m neutralized PCP (NaPCP). The extent of covalently attached Cys was determ ined by quantifying the share of thiol groups on the resulting polymer-Cys conjugates via iodometric titration. The permeation-enhancing effect of pol ymer-Cys conjugates was evaluated in Ussing-type chambers using intestinal mucosa from guinea pigs. Whereas the transport enhancement ratio (P-app pol ymer/P-app control) for 0.5% (m/v) NaPCP was 1.14 using sodium fluorescein as model drug; it was 1.63 for 0.5% (m/v) PCP-Cys displaying a share of 2.2 % (m/m) Cys on the conjugate (PCP-Cys 2.2%). Moreover, the substitution of sodium fluorescein by bacitracin-fluorescein isothiocyanate (bacitracin-FIT C) led to ratios of 1.03 and 1.36 and in the case of insulin-fluorescein is othiocyanate (insulin-FITC) to ratios of 1.07 and 1.33, respectively (means ; n = 3). Additional permeation studies with 0.5% (m/v) PCP-Cys conjugates exhibiting a share of 1.8% up to 4.2% of cysteine showed enhancement ratios of 1.22 up to 1.47 for sodium fluorescein within 3 h. In contrast, the per meation-enhancing effect of PCP could not be improved by the addition of fr ee unconjugated Cys. Because of their permeation-enhancing effect for the p aracellular route of absorption, PCP-Cys conjugates probably represent a ne w tool for the peroral administration of peptide drugs. (C) 2000 Wiley-Liss , Inc. and the American Pharmaceutical Association.