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17184870

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pubmed-article:17184870pubmed:abstractTextChitosan has been shown to act on the mucosal epithelial barriers mainly when protonated at acidic pH values in which it is soluble. Soluble chitosan is able to improve the permeation and absorption of neutral to cationic macromolecules only, as it forms polyelectrolyte complexes with anionic macromolecules. LMWH (Low Molecular Weight Heparin) is an anionic polysaccharide finding clinical application as an improved antithrombotic agent compared to Unfractionated Heparin (UFH). In this study we have employed N-sulfonato-N,O-carboxymethylchitosan (SNOCC) as a potential intestinal absorption enhancer of LMWH, Reviparin. SNOCC was prepared at 3 different viscosity grades 20, 40 and 60 cps and identified as SNOCC-20, SNOCC-40 and SNOCC-60, respectively. SNOCC materials were tested in vitro for their ability to decrease the Trans Epithelial Electrical Resistance (TEER) of Caco-2 cell monolayers. They were further tested as transport enhancers of hydrophilic compounds such as (14)C-mannitol, FITC-Dextran (MW 4400 Da) and Reviparin (LMWH). Solutions of Reviparin, with or without SNOCC, were administered intraduodenally in vivo in rats and the absorption of the drug was assessed by measuring the Anti-Xa levels in rat plasma. In vitro studies showed that SNOCC materials were able to induce a concentration dependent decrease in the TEER of the Caco-2 monolayers. SNOCC-40 and -60 were shown to decrease resistance more readily compared to the low viscosity SNOCC-20. (14)C-mannitol permeation data across intestinal epithelia were in agreement with the observed decrease in TEER; the higher viscosity SNOCC-60 was the most effective demonstrating a 51-fold enhancement of the permeation of the radiolabeled marker. Studies with both FITC-Dextran and Reviparin demonstrated significantly increased permeation across Caco-2 cell monolayers when they were co-incubated at the apical side of the monolayer. Intestinal absorption of Reviparin in rats was increased when it was co-administered with SNOCC-40 and -60, in agreement with in vitro data. Anti-Xa levels were elevated to and above the antithrombotic levels and were sustained for at least 6 h, giving an 18.5-fold increase in the AUC of LMWH in rats. In conclusion, SNOCC-40 and -60 have been shown to enhance both permeation and absorption of Reviparin across intestinal epithelia proving their potential as polymeric absorption enhancers.lld:pubmed
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pubmed-article:17184870pubmed:articleTitleN-sulfonato-N,O-carboxymethylchitosan: a novel polymeric absorption enhancer for the oral delivery of macromolecules.lld:pubmed
pubmed-article:17184870pubmed:affiliationGenetic Therapies Centre, Chemistry, Imperial College London, SW72AZ, London, UK. maya.thanou@imperial.ac.uklld:pubmed
pubmed-article:17184870pubmed:publicationTypeJournal Articlelld:pubmed