Intestinal absorption of octreotide using trimethyl chitosan chloride: Studies in pigs

Purpose. To investigate the enhancing effect of trimethyl chitosan chloride (TMC) on the enteral absorption of octreotide and to delineate the require d doses of both TMC and peptide in vivo in juvenile pigs. Methods. Six female pigs (body weight, 25 kg) were operated to induce a sto ma at the beginning of their jejunum and to insert an in-dwelling fistula f or intrajejunal (IJ) administration of the formulations. A silicone cannula was inserted at the jugular vein for blood sampling. One week after surger y 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 polyme r (control solution) resulted in F values of 1.7 +/- 1.1% (mean +/- SE). Ch itosan HCl 1.5% (w/v) at pH 5.5 led to a 3-fold increase in F compared to t he control (non-polymer containing) formulations. Go-administration of octr eotide with 5 and 10% (w/v) TMC at pH 7.4 resulted in 7.7- and 14.5-fold in crease 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 increa sed 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 resp ect, TMC at neutral pH values of 7.4 appears to be more potent than chitosa n HCl at a weak acidic pH of 5.5.