Skip to main content
SpringerLink
Log in

Chitosans as Absorption Enhancers for Poorly Absorbable Drugs. 1: Influence of Molecular Weight and Degree of Acetylation on Drug Transport Across Human Intestinal Epithelial (Caco-2) Cells

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Chitosan has recently been demonstrated to effectively enhance the absorption of hydrophilic drugs such as peptides and proteins across nasal and intestinal epithelia (1–3). In this study, the effect of the chemical composition and molecular weight of chitosans on epithelial permeability and toxicity was investigated using monolayers of human intestinal epithelial Caco-2 cells as a model epithelium.

Methods. Eight chitosans varying in degree of acetylation (DA) and molecular weight were studied. The incompletely absorbed hydrophilic marker molecule 14C-mannitol was used as a model drug to assess absorption enhancement. Changes in intracellular dehydrogenase activity and cellular morphology were used to assess toxicity.

Results. Chitosans with a low DA (1 and 15%) were active as absorption enhancers at low and high molecular weights. However, these chitosans displayed a clear dose-dependent toxicity. Chitosans with DAs of 35 and 49% enhanced the transport of 14C-mannitol at high molecular weights only, with low toxicity. One chitosan (DA = 35%; MW = 170kD) was found to have especially advantageous properties such as an early onset of action, very low toxicity, and a flat dose-absorption enhancement response relationship.

Conclusions. The structural features of chitosans determining absorption enhancement are not correlated with those determining toxicity, which makes it possible to select chitosans with maximal effect on absorption and minimal toxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. L. Illum, N. F. Farraj, and S. S. Davis. Pharm. Res. 11:1186–1189 (1994).

    Google Scholar 

  2. C. O. Rentel, C. M. Lehr, J. A. Bouwstra, H. L. Luessen, and H. E. Junginger. Proceed. Intern. symp. control. Rel. Bioact. Mater. 20:446–447 (1993).

    Google Scholar 

  3. P. Artursson, T. Lindmark, S. S. Davis, and L. Illum. Pharm. Res. 11:1358–1361 (1994).

    Google Scholar 

  4. M. J. Jackson. In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract. Second edition, Raven Press, New York, 1987, pp. 1597–1621.

    Google Scholar 

  5. J. L. Madara and J. S. Trier. In L. R. Johnson (ed.), Physiology of the Gastrointestinal Tract. Second edition, Raven Press, New York, 1987, pp. 1251–1266.

    Google Scholar 

  6. P. L. Smith, D. A. Wall, C. H. Gochoco, and G. Wilson. Adv. Drug Del. Rev. 8:253–290 (1992).

    Google Scholar 

  7. E. S. Swenson and W. J. Curatolo. Adv. Drug Del. Rev. 8:39–92 (1992).

    Google Scholar 

  8. J. H. Hochman and P. Artursson. J. Control. Rel. 29:253–267 (1994).

    Google Scholar 

  9. K. M. Vårum, M. W. Anthonsen, H. Grasdalen, and O. Smidsrød. Carbohydr. Res. 211:17–23 (1991).

    Google Scholar 

  10. K. M. Vårum, M. W. Anthonsen, H. Grasdalen, and O. Smidsrød. Carbohydr. Res. 217:19–27 (1991).

    Google Scholar 

  11. M. W. Anthonsen, K. M. Vårum, and O. Smidsrød. Carbohydr. Polymers 22:193–201 (1993).

    Google Scholar 

  12. R. J. Nordtveit, K. M. Vårum, and O. Smidsrød. Carbohydr. Polymers 23:253–260 (1994).

    Google Scholar 

  13. A. Domard. Int. J. Biol. Macromol. 9:98–104 (1987).

    Google Scholar 

  14. M. W. Anthonsen and O. Smidsrød. Carbohydr. Polymers 26:303–305 (1995).

    Google Scholar 

  15. C. J. Brine, P. A. Sandford, and J. P. Zikakis. Advances in Chitin and Chitosan, Elsevier Applied Science, London, 1992.

    Google Scholar 

  16. S. W. Chang, J. Y. Westscott, J. E. Henson, and N. V. Voelkel. J. Appl. Physiol. 62:1932–1943 (1987).

    Google Scholar 

  17. H. M. Ekrami and W. C. Shen. J. Drug Target. 2:469–475 (1995).

    Google Scholar 

  18. C. M. Lehr, J. A. Bouwstra, E. H. Schacht, and H. E. Junginger. Int. J. Pharm. 78:43–48 (1992).

    Google Scholar 

  19. K. M. Vårum, M. W. Anthonsen, M. H. Ottøy, H. Grasdalen, and O. Smidsrød. In: C. J. Brine, P. A. Sandford, and J. P. Zikakis (eds.), Advances in Chitin and chitosan, Elsevier Applied Science, London, 1992, pp. 127–136.

    Google Scholar 

  20. P. Artursson. J. Pharm. Sci. 79:476–482 (1990).

    Google Scholar 

  21. K. Lappalainen, I. Jääskeläinen, K. Syrjänen, A. Urtti, and S. Syrjänen. Pharm. Res. 11:1127–1131 (1994).

    Google Scholar 

  22. E. K. Anderberg, C. Nyström, and P. Artursson. J. Pharm. Sci. 81:879–887 (1992).

    Google Scholar 

  23. A. G. DeBoer and D. D. Breimer. In A. G. DeBoer (ed.), Drug Absorption Enhancement: Concepts, Possibilities, Limitations and Trends, Harwood Academic Publishers, Chur, 1994, pp. 155–175.

    Google Scholar 

  24. E. S. Swenson, W. B. Milisen, and W. Curatolo. Pharm. Res. 11:1132–1142 (1994).

    Google Scholar 

  25. E. K. Anderberg and P. Artursson. J. Pharm. Sci. 82:392–398 (1993).

    Google Scholar 

  26. A. Santana, S. Hyslop, E. Antunes, M. Mariano, Y. S. Bakhle, and G. DeNucci. Agents Actions 39:104–110 (1993).

    Google Scholar 

  27. I. Westergren and B. B. Johansson. Acta Physiol. Scand. 149:99–104 (1993).

    Google Scholar 

  28. G. T. A. McEwan, M. A. Jepson, B. H. Hirst, and N. L. Simmons. Biochim. Biophys. Acta 1148:51–60 (1993).

    Google Scholar 

  29. C. J. Bentzel, M. Fromm, C. E. Palant, and U. Hegel. J. Membr. Biol. 95:9–20 (1987).

    Google Scholar 

  30. C. J. Tzan, J. R. Berg, and S. A. Lewis. Am. J. Physiol. 265 (Cell Physiol. 34):C1637–1647 (1993).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmaceutics, Uppsala University, Biomedical Center, P.O. Box 580, S-75123, Uppsala, Sweden. To whom correspondence should be addressed

    Nicolaas G. M. Schipper & Per Artursson

  2. Norwegian Biopolymer Laboratory (NOBIPOL), Dept. of Biotechnology, The Norwegian Institute of Technology (NTH), University of Trondheim, 7034, Trondheim, Norway

    Kjell M. Vårum

Authors
  1. Nicolaas G. M. Schipper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kjell M. Vårum
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Per Artursson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schipper, N.G.M., Vårum, K.M. & Artursson, P. Chitosans as Absorption Enhancers for Poorly Absorbable Drugs. 1: Influence of Molecular Weight and Degree of Acetylation on Drug Transport Across Human Intestinal Epithelial (Caco-2) Cells. Pharm Res 13, 1686–1692 (1996). https://doi.org/10.1023/A:1016444808000

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1016444808000

Search

Navigation