Intestinal absorption of octreotide using trimethyl chitosan chloride: studies in pigs.
OBJECTIVE
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.
Thanou
M
M
Leiden/Amsterdam Center for Drug Research, Division of Pharmaceutical Technology, Leiden University, The Netherlands.
Verhoef
J C
JC
Verheijden
J H
JH
Junginger
H E
HE
D000818:Animals; D002686:Chitin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D048271:Chitosan; D004337:Drug Carriers / Q000493:pharmacokinetics*; D005260:Female; D006728:Hormones / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000502:physiology*; D007583:Jejunum / Q000378:metabolism; D015282:Octreotide / Q000097:blood / Q000493:pharmacokinetics*; D013552:Swine
D004337:Drug Carriers; D006728:Hormones; C118071:N-trimethyl chitosan chloride; D002686:Chitin; D048271:Chitosan; D015282:Octreotide