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Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2)

Kotzé, Awie F, Thanou, Maya M, Lueßen, Henrik L, de Boer, (A)Bert G, Verhoef, J.Coos, Junginger, Hans E·1999·European Journal of Pharmaceutics and Biopharmaceutics
DOI 10.1016/s0939-6411(99)00006-5
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Abstract

N-trimethyl chitosan chloride (TMC), a partially quaternized derivative of chitosan with superior water solubility, was synthesized with different degrees of quaternization [12.6% quaternized (TMC-L) and 19.9% quaternized (TMC-H)] and the effects of these novel polymers on the permeability of intestinal epithelial cells were investigated in Caco-2 cell monolayers. Transepithelial electrical resistance (TEER) measurements showed that both polymers in 1.5-2.5% w/v concentrations caused a pronounced, concentration dependent lowering in TEER values, but that TMC-H was more effective than TMC-L at similar concentrations (36 +/- 3% reduction with TMC-L and 53 +/- 6% reduction with TMC-H at 2.0% concentrations). Similar results were obtained in transport studies with the hydrophilic radioactive markers [14C]mannitol (MW 182.2) and [14C]polyethylene glycol 4000 ([14C]PEG 4000, MW 4000). The transport of [14C]mannitol was increased 51-fold (TMC-L) and 97-fold (TMC-H) at 2.5% concentrations. No deleterious effects to the cells could be demonstrated with trypan blue exclusion studies. The results show that TMC is able to open the tight junctions of intestinal epithelial cells to allow for paracellular transport of hydrophilic molecules. It is concluded that the charge density of TMC, as determined by the degree of quaternization, is an important factor determining its potential use as an absorption enhancer across intestinal epithelia.

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Research works printed but not linked: 14

  1. Borchard, 1996, The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III. Effects of chitosan glutamate and carbomer on epithelial tight junctions in vitro, J. Control. Rel., 39, 131, 10.1016/0168-3659(95)00146-8 · DOI
  2. Kotzé, 1998, Comparison of the effect of chitosan salts and N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells, J. Control. Rel., 51, 35, 10.1016/S0168-3659(97)00154-5 · DOI · Paper page
  3. Artursson, 1994, Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2), Pharm. Res., 11, 1358, 10.1023/A:1018967116988 · DOI
  4. Lueßen, 1996, Mucoadhesive polymers in peroral drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug Buserelin in vivo, Pharm. Res., 13, 1666, 10.1023/A:1016488623022 · DOI
  5. Illum, 1994, Chitosan as a novel nasal delivery system for peptide drugs, Pharm. Res., 11, 1186, 10.1023/A:1018901302450 · DOI
  6. Schipper, 1997, Chitosans as absorption enhancers for poorly absorbable drugs 2: mechanism of absorption enhancement, Pharm. Res., 14, 923, 10.1023/A:1012160102740 · DOI
  7. Madara, 1987, Intestinal absorptive cell tight junctions are linked to cytoskeleton, Am. J. Physiol., 253, C171, 10.1152/ajpcell.1987.253.1.C171 · DOI
  8. Kotzé, 1997, N-trimethyl chitosan chloride as a potential absorption enhancers across mucosal surfaces: in vitro evaluation in intestinal epithelial cells, Pharm. Res., 14, 1197, 10.1023/A:1012106907708 · DOI
  9. Kotzé, 1997, Chitosans for enhanced delivery of therapeutic peptides across intestinal epithelia: in vitro evaluation in Caco-2 cell monolayers, Int. J. Pharm., 159, 243, 10.1016/S0378-5173(97)00287-1 · DOI
  10. Domard, 1986, New method for the quaternization of chitosan, Int. J. Macromol., 8, 105, 10.1016/0141-8130(86)90007-3 · DOI
  11. Sieval, 1998, Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride, Carbohydrate Polymers, 36, 157, 10.1016/S0144-8617(98)00009-5 · DOI
  12. Noach, 1993, Cell-polarity dependent effect of chelation on the paracellular permeability of confluent Caco-2 cell monolayers, Int. J. Pharm., 90, 229, 10.1016/0378-5173(93)90195-L · DOI
  13. Hurni, 1993, Permeability enhancement in Caco-2 cell monolayers by sodium salicylate and sodium taurodihydrofusidate: assessment of effect reversibility and imaging of transepithelial transport routes by confocal laser scanning microscopy, J. Pharmacol. Exp. Ther., 267, 942
  14. M. Thanou, A.F. Kotzé, T. Scharringhausen, H.L. Lueßen, A.G. de Boer, J.C. Verhoef, H.E. Junginger, Effect of the degree of quaternization of N-trimethyl chitosan chloride for enhanced transport of hydrophilic compounds across intestinal Caco-2 cell monolayers, J. Control. Rel. (Special issue) (1999) in press. · DOI

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Metadata

Authors
Kotzé, A. F., Thanou, M. M., Lueßen, H. L., de Boer, (. G., Verhoef, J. C., & Junginger, H. E.
Venue
European Journal of Pharmaceutics and Biopharmaceutics
Publisher
Elsevier BV
Published
1999-05
Volume
47
Issue
3
Pages
269-274
ISSN
0939-6411
DOI
10.1016/s0939-6411(99)00006-5
Cited by
90
References
0
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)

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CoChat. (2026). Citation check: Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). https://app.cochat.ai/papers/10.1016/s0939-6411(99)00006-5
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Kotzé, A. F., Thanou, M. M., Lueßen, H. L., de Boer, (. G., Verhoef, J. C., & Junginger, H. E. (1999). Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). European Journal of Pharmaceutics and Biopharmaceutics. https://doi.org/10.1016/s0939-6411(99)00006-5