Mono-N-carboxymethyl chitosan (MCC), a polyampholytic chitosan derivative, enhances the intestinal absorption of low molecular weight heparin across intestinal epithelia in vitro and in vivo.
The synthesis and evaluation of mono-N-carboxymethyl chitosan (MCC) as an intestinal permeation enhancer for macromolecular therapeutics is presented. MCCs were synthesized from two different viscosity grade chitosans to yield both high and low viscosity grade products. These MCCs were tested on Caco-2 cells for their efficiency to decrease the transepithelial electrical resistance (TEER) and to increase the paracellular permeability of the anionic macromolecular anticoagulant low molecular weight heparin (LMWH). For in vivo studies, LMWH was administered intraduodenally with or without MCC to rats. Both types of experiments were performed at pH 7.4. Results show that both viscosity grade MCCs managed to significantly decrease the TEER of Caco-2 cell monolayers when they were applied apically at concentrations of 3-5% (w/v). Transport studies with Caco-2 cells revealed substantial increases of LMWH permeation in the presence of both viscosity grade MCCs compared with controls. In rats, 3% (w/v) low viscosity MCC significantly increased the intestinal absorption of LMWH, reaching the therapeutic anticoagulant blood levels of LMWH. Both in vitro and in vivo results indicate that the polyampholytic chitosan modification MCC is a suitable and functional polymer for the delivery and intestinal absorption of anionic macromolecular therapeutics like LMWH.
Thanou
M
M
Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, P.O. Box 9502, 2300RA Leiden, The Netherlands.
Nihot
M T
MT
Jansen
M
M
Verhoef
J C
JC
Junginger
H E
HE
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002686:Chitin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048271:Chitosan; D004347:Drug Interactions; D017097:Electric Impedance; D006495:Heparin, Low-Molecular-Weight / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011108:Polymers / Q000494:pharmacology; D011419:Propidium / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D006495:Heparin, Low-Molecular-Weight; D011108:Polymers; C426873:mono-N-carboxymethylchitosan; D002686:Chitin; D011419:Propidium; D048271:Chitosan