title: Improved paracellular uptake by the combination of different types of permeation enhancers.
abstract: This study had the purpose to improve the paracellular uptake of drugs by combining the thiomer/reduced glutathione (GSH) permeation-enhancing system with a proteolytic enzyme. Due to the covalent binding of 2-iminothiolane to chitosan the thiomer chitosan-TBA (chitosan-4-thiobutylamidine) was obtained. Permeation studies were performed with freshly excised intestinal mucosa of guinea pigs mounted in Ussing-type chambers using on the one hand the low-molecular size marker flurescein (Na-Flu) and on the other hand the high-molecular size marker FITC-dextran. Apparent permeability coefficient (P(app)) as well as enhancement ratios (=P(app) permeation-enhancing system/P(app) control) were calculated. Trypsin, papain and bromelain displayed a permeation-enhancing effect for Na-Flu on the small intestinal mucosa. Enhancement ratios of 1.84, 1.63 and 1.78 were identified for 2% trypsin, 0.5% papain and 2% bromelain solutions, respectively. However, only bromelain could guarantee a significant permeation enhancement of FITC-dextran with a P(app) of 4.45+/-0.44 x 10(-6) cm/s representing an enhancement ratio of 1.57. A similar enhancement of FITC-dextran permeation was reached by the use of the chitosan-TBA (0.5%)/GSH (5%) system. Moreover, an additive permeation-enhancing effect of the chitosan-TBA/GSH system in combination with bromelain (2%) was observed, leading to a maximum P(app) of 5.91+/-0.51 x 10(-6) cm/s, which corresponds to an enhancement ratio of 2.1. According to these results, the combination of the thiomer/GSH system with bromelain might represent a new promising strategy in order to raise the in vivo efficacy of non-invasive administered hydrophilic macromolecular drugs.
authors.affiliation: Institute of Pharmaceutical Technology, Center of Pharmacy, University of Vienna, Althanstr 14, 1090 Vienna, Austria.
authors.forename: Davide
authors.initials: D
authors.lastname: Guggi
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology*; D004338:Drug Combinations; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D004364:Pharmaceutical Preparations