Pharmaceutical Research

, Volume 18, Issue 6, pp 823–828

Intestinal Absorption of Octreotide Using Trimethyl Chitosan Chloride: Studies in Pigs

  • Maya Thanou
  • J. Coos Verhoef
  • Jos H. M. Verheijden
  • Hans E. Junginger


Purpose. To investigate the enhancing effect of trimethyl chitosan chloride (TMC) on the enteral absorption of octreotide and to delineate the required doses of both TMC and peptide in vivo in juvenile pigs.

Methods. Six female pigs (body weight, 25 kg) were operated to induce a stoma at the beginning of their jejunum and to insert an in-dwelling fistula for intrajejunal (IJ) administration of the formulations. A silicone cannula was inserted at the jugular vein for blood sampling. One week after surgery the pigs received IJ octreotide solution administrations with or without TMC at pH 7.4 or chitosan HCl at pH 5.5. For determining bioavailability (F) values, the pigs also received an octreotide solution intravenously (IV). Blood samples were taken from the cannulated jugular vein and subsequently analyzed by radioimmunoassay.

Results. Intrajejunal administration of 10 mg octreotide without any polymer (control solution) resulted in F values of 1.7 ± 1.1% (mean ± SE). Chitosan HCl 1.5% (w/v) at pH 5.5 led to a 3-fold increase in F compared to the control (non-polymer containing) formulations. Co-administration of octreotide with 5 and 10% (w/v) TMC at pH 7.4 resulted in 7.7- and 14.5-fold increase of octreotide absorption, respectively (F of 13.9 ± 1.3% and 24.8 ± 1.8%). IJ administration of 5 mg octreotide solutions resulted in low F values of 0.5 ± 0.6%, whereas co-administration with 5% (w/v) TMC increased the intestinal octreotide bioavailability to 8.2 ± 1.5%.

Conclusions. Cationic polymers of the chitosan type are able to enhance the intestinal absorption of the peptide drug octreotide in pigs. In this respect, TMC at neutral pH values of 7.4 appears to be more potent than chitosan HCl at a weak acidic pH of 5.5.

peroral delivery chitosan trimethyl chitosan (TMC) octreotide pigs intestinal absorption 


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  1. 1.
    R. Langer. Drug delivery and targeting. Nature 392:5-10 (1998).Google Scholar
  2. 2.
    J. P. F. Bai, L.-L. Chang, and J.-H. Guo. Targeting of peptide and protein drugs to specific sites in the oral route. Crit. Rev. Ther. Drug Carrier Syst. 12:339-371 (1995).Google Scholar
  3. 3.
    G. L. Amidon and H. J. Lee. Absorption of peptide and peptidomimetic drugs. Annu. Rev. Pharmacol. Toxicol. 34:321-341 (1995).Google Scholar
  4. 4.
    A. Fasano. Innovative strategies for the oral delivery of drugs and peptides. Trends Biotech. 16:152-157 (1998).Google Scholar
  5. 5.
    A. Leone-Bay, N. Santiago, D. Achan, K. Chaudhary, F. De Morin, L. Falzarano, S. Haas, S. Kalbag, D. Kaplan, H. Leipold, C. Lercara, D. O'Toole, T. Rivera, C. Rosado, D. Sarubbi, E. Vuocolo, N. Wang, S. Milstein, and R. A. Baughman. N-acylated alpha-amino acids as novel oral delivery agents for proteins. J. Med. Chem. 38:4263-4269 (1995).Google Scholar
  6. 6.
    A. Leone-Bay, D. R. Paton, J. Freeman, C. Lercara, D. O'Toole, D. Gschneidner, E. Wang, E. Harris, C. Rosado, T. Rivera, A. De Vincent, M. Tai, F. Mercogliano, R. Agarwal, H. Leipold, and R. A. Baughman. Synthesis and evaluation of compounds that facilitate the gastrointestinal absorption of heparin. J. Med. Chem. 41:1163-1171 (1998).Google Scholar
  7. 7.
    S.-J. Wu and J. R. Robinson. Transport of human growth hormone across Caco-2 cells with novel delivery agents: Evidence for P-glycoprotein involvement. J. Control. Release 62:171-177 (1999).Google Scholar
  8. 8.
    H. E. Junginger and J. C. Verhoef. Macromolecules as safe penetration enhancers for hydrophilic drugs—A fiction? Pharm. Sci. Technol. Today 1:370-376 (1998).Google Scholar
  9. 9.
    M. M. Thanou, J. C. Verhoef, S. G. Romeijn, J. F. Nagelkerke, F. W. H. M. Merkus, and H. E. Junginger. Effects of N-trimethyl chitosan chloride, a novel absorption enhancer, on Caco-2 intestinal epithelia and the ciliary beat frequency of chicken embryo trachea. Int. J. Pharm. 185:73-82 (1999).Google Scholar
  10. 10.
    M. Thanou, B. I. Florea, M. W. E. Langemeÿer, J. C. Verhoef, and H. E. Junginger. N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats). Pharm. Res. 17:27-31 (2000).Google Scholar
  11. 11.
    M. Thanou, J. C. Verhoef, P. Marbach, and H. E. Junginger. Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo. J. Pharm. Sci. 89:951-957 (2000).Google Scholar
  12. 12.
    C. Tagesson and R. Sjodahl. Passage of molecules through the wall of the gastrointestinal tract. Intestinal permeability to polyethylene glycols in the 414 to 1,074-Dalton range. Eur. Surg. Res. 16:274-281 (1984).Google Scholar
  13. 13.
    W. Bauer, U. Briner, W. Doepfner, R. Haller, R. Huguenin, P. Marbach, T. J. Petcher, and J. Pless. SMS 201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 31:1133-1140 (1982).Google Scholar
  14. 14.
    P. Marbach, W. Bauer, D. Bodmer, U. Briner, C. Bruns, A. Kay, I. Lancranjan, J. Pless, F. Raulf, R. Robison, J. Sharkey, T. Soranno, B. Stolz, P. Vit, and G. Weckbecker. Discovery and development of somatostatin agonists. In R. T. Borchardt (ed.), Integration of Pharmaceutical Discovery and Development: Case Studies, Plenum Press, New York, 1998 pp. 183-209.Google Scholar
  15. 15.
    T. Kararli. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16:351-380 (1995).Google Scholar
  16. 16.
    A. B. Sieval, M. Thanou, A. F. Kotzé, J. E. Verhoef, J. Brussee, and H. E. Junginger. Preparation and NMR characterization of highly substituted N-trimethyl chitosan chloride. Carbohydr. Polymers 36:157-165 (1998).Google Scholar
  17. 17.
    P. Marbach, M. Neufeld, and J. Pless. Clinical applications of somatostatin analogs. Adv. Exp. Med. Biol. 188:339-353 (1985).Google Scholar
  18. 18.
    M. Gibaldi and D. Perrier. Pharmacokinetics. In J. Swarbrick (ed.), Drugs and the Pharmaceutical Science, Marcel Dekker, New York, 1975 pp. 409-424.Google Scholar
  19. 19.
    M. Lemaire, M. Azria, P. Dannecker, P. Marbach, A. Schweitzer, and G. Maurer. Disposition of Sandostatin, a new synthetic somatostatin analogue, in rats. Drug Metab. Dispos. 17:699-703 (1989).Google Scholar
  20. 20.
    P. Artursson, T. Lindmark, S. S. Davis, and L. Illum. Effect of chitosan on the permeability of monolayers of intestinal epithelial cells (Caco-2). Pharm. Res. 11:1358-1361 (1994).Google Scholar
  21. 21.
    L. Illum, N. F. Farraj, and S. S. Davis. Chitosan as a novel nasal delivery system for peptide drugs. Pharm. Res. 11:1186-1189 (1994).Google Scholar
  22. 22.
    H. L. Lueßen, B. J. De Leeuw, M. W. Langemeÿer, A. G. De Boer, J. C. Verhoef, and H. E. Junginger. Mucoadhesive polymers in peroral peptide drug delivery. VI. Carbomer and chitosan improve the intestinal absorption of the peptide drug buserelin in vivo. Pharm. Res. 13:1668-1672 (1996).Google Scholar
  23. 23.
    H. K. Holme, A. Hagen, and M. Dornish. Influence of chitosans with various molecular weights and degrees of deacetylation on the permeability of human intestinal epithelial cells (Caco-2). In R. A. A. Muzzarelli (ed.), Chitosan per os from Dietary Supplement to Drug Carrier, Atec, Grottamare, 2000 pp. 127-136.Google Scholar
  24. 24.
    G. Fricker, J. Drewe, J. Vonderscher, T. Kissel, and C. Beglinger. Enteral absorption of octreotide. Br. J. Pharmacol. 105:783-786 (1992).Google Scholar
  25. 25.
    J. Drewe, G. Fricker, J. Vonderscher, and C. Beglinger. Enteral absorption of octreotide: Absorption enhancement by polyoxyethylene-24-cholesterol ether. Br. J. Pharmacol. 108:298-303 (1993).Google Scholar
  26. 26.
    Y. H. Lee, B. A. Perry, J. P. Sutyak, W. Stern, and P. J. Sinko. Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin absorption in dogs. Pharm. Res. 17:284-289 (2000).Google Scholar

Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Maya Thanou
    • 1
  • J. Coos Verhoef
    • 1
  • Jos H. M. Verheijden
    • 1
    • 2
  • Hans E. Junginger
    • 1
  1. 1.Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical TechnologyLeiden UniversityLeidenThe Netherlands
  2. 2.Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands

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