Abstract
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.
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REFERENCES
R. Langer. Drug delivery and targeting. Nature 392:5-10 (1998).
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).
G. L. Amidon and H. J. Lee. Absorption of peptide and peptidomimetic drugs. Annu. Rev. Pharmacol. Toxicol. 34:321-341 (1995).
A. Fasano. Innovative strategies for the oral delivery of drugs and peptides. Trends Biotech. 16:152-157 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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.
T. Kararli. Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug Dispos. 16:351-380 (1995).
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).
P. Marbach, M. Neufeld, and J. Pless. Clinical applications of somatostatin analogs. Adv. Exp. Med. Biol. 188:339-353 (1985).
M. Gibaldi and D. Perrier. Pharmacokinetics. In J. Swarbrick (ed.), Drugs and the Pharmaceutical Science, Marcel Dekker, New York, 1975 pp. 409-424.
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).
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).
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).
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).
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.
G. Fricker, J. Drewe, J. Vonderscher, T. Kissel, and C. Beglinger. Enteral absorption of octreotide. Br. J. Pharmacol. 105:783-786 (1992).
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).
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).
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Thanou, M., Verhoef, J.C., Verheijden, J.H.M. et al. Intestinal Absorption of Octreotide Using Trimethyl Chitosan Chloride: Studies in Pigs. Pharm Res 18, 823–828 (2001). https://doi.org/10.1023/A:1011092613951
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DOI: https://doi.org/10.1023/A:1011092613951