N-trimethylated chitosan chloride (TMC) improves the intestinal permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in vivo (rats).
OBJECTIVE
To evaluate N-trimethyl chitosan chloride (TMC) of high degrees of substitution as intestinal permeation enhancers for the peptide drug buserelin in vitro using Caco-2 cell monolayers, and to investigate TMCs as enhancers of the intestinal absorption of buserelin in vivo, in rats.


METHODS
TMCs were tested on Caco-2 cells for their efficiency to increase the paracellular permeability of the peptide buserelin. For the in vivo studies male Wistar rats were used and buserelin was administered with or without the polymers intraduodenally. Both types of experiments were performed at pH 7.2.


RESULTS
Transport studies with Caco-2 cell monolayers confirmed that the increase in buserelin permeation is dependent on the degree of trimethylation of TMC. In agreement with the in vitro results, in vivo data revealed highly increased bioavailability of buserelin following intraduodenal co-administration with 1.0% (w/v) TMCs. Intraduodenally applied buserelin resulted in 0.8% absolute bioavailability, whereas co-administrations with TMCs resulted in mean bioavailability values between 6 and 13 %. Chitosan HCl (1.0%; pH = 7.2) did not significantly increase the intestinal absorption of buserelin.


CONCLUSIONS
Both the in vitro and in vivo results indicate that TMCs are potent mucosal permeation enhancers of the peptide drug buserelin at neutral pH values.
Thanou
M
M
Division of Pharmaceutical Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Florea
B I
BI
Langemeÿer
M W
MW
Verhoef
J C
JC
Junginger
H E
HE
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002064:Buserelin / Q000493:pharmacokinetics*; D018938:Caco-2 Cells; D002686:Chitin / Q000031:analogs & derivatives* / Q000494:pharmacology; D048271:Chitosan; D004337:Drug Carriers; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D004337:Drug Carriers; C118071:N-trimethyl chitosan chloride; D002686:Chitin; D048271:Chitosan; D002064:Buserelin