title: An in-vitro exploration of permeation enhancement by novel polysulfonate thiomers.
abstract: The study was aimed to synthesize preactivated polysulfonate thiomers using poly(4-styrenesulfonic acid-co-maleic acid) (PSSA-MA) and to evaluate their permeation enhancing properties. PSSA-MA-cysteamine (PC) conjugates with 2-mercaptonicotinic acid (2MNA) having different degree of preactivation (PC1608-2MNA, PC2300-2MNA, PC3100-2MNA) were synthesized from the subsequent PSSA-MA-cysteamine thiomers (PC1608, PC2300 and PC3100). The permeation-enhancing features were evaluated by in-vitro models using low-molecular size marker sodium fluorescein (Na-Flu) and with high-molecular size marker fluorescein isothiocyanate-dextran (FD4). Associating the influence of degree of preactivation on permeation enhancement, following rank order PC3100-2MNA>PC3100>PC2300-2MNA>PC2300>PC1608-2MNA>PC1608>PSSA-MA>control was observed on Caco-2 cell monolayers and with little change in sequence on freshly excised rat intestine. The apparent permeability (Papp) was improved 3.16-fold for Na-Flu and 3.51-fold for FD4 on Caco-2 cell monolayers. Similarly, 4.17- and 3.60-fold improved Papp values were observed on freshly excised rat intestine for Na-Flu and FD4, respectively. More pronounced permeation effects on rat intestine compared to Caco-2 cell monolayer by the thiomer/preactivated conjugates indicated their mucus-interpenetration capability in addition to mucoadhesion. Thus relatively low molecular weight (LMW) preactivated polysulfonate thiomers could to a higher extent enhance permeation on membranes covered by mucus layer compared to high molecular weight thiomers/preactivated conjugates that usually exhibit higher permeation enhancing effects on Caco-2 cell monolayer.
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Arshad
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Sonja
authors.initials: S
authors.lastname: Bonengel
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Flavia
authors.initials: F
authors.lastname: Laffleur
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ijaz
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
authors.forename: Gintare
authors.initials: G
authors.lastname: Leonaviciute
authors.affiliation: Center for Chemistry and Biomedicine, Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: andreas.bernkop@uibk.ac.at.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003543:Cysteamine / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008298:Maleates / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010539:Permeability; D011137:Polystyrenes / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008298:Maleates; D011137:Polystyrenes; C518261:poly(4-styrenesulfonic acid-co-maleic acid); D003543:Cysteamine
keywords: Mucus interpenetration; Permeation enhancing; Poly(4-styrenesulfonic acid-co-maleic acid); Preactivated conjugate; Thiomer