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

The objective of this study was to investigate the permeation-enhancing effect of thiolated polycarbophil (PCP) on peptide drugs. Mediated by a carbodiimide, increasing amounts of cysteine (Cys) were covalently bound to sodium neutralized PCP (NaPCP). The extent of covalently attached Cys was determined by quantifying the share of thiol groups on the resulting polymer-Cys conjugates via iodometric titration. The permeation-enhancing effect of polymer-Cys conjugates was evaluated in Ussing-type chambers using intestinal mucosa from guinea pigs. Whereas the transport enhancement ratio (P(app) polymer/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-FITC) led to ratios of 1.03 and 1.36 and in the case of insulin-fluorescein isothiocyanate (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 permeation-enhancing effect of PCP could not be improved by the addition of free unconjugated Cys. Because of their permeation-enhancing effect for the paracellular route of absorption, PCP-Cys conjugates probably represent a new tool for the peroral administration of peptide drugs. Copyright 2000 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1253-1261, 2000