Intestinal absorption of octreotide: N-trimethyl chitosan chloride (TMC) ameliorates the permeability and absorption properties of the somatostatin analogue in vitro and in vivo

Octreotide acetate is a somatostatin analogue used for the control of endoc rine tumors of the gastrointestinal (GI) tract and the treatment of acromeg aly. The oral absorption of octreotide is limited because of the limited pe rmeation across the intestinal epithelium. Both chitosan hydrochloride and N-trimethyl chitosan chloride (TMC), a quaternized chitosan derivative, are nonabsorbable and nontoxic polymers that have been proven to effectively i ncrease the permeation of hydrophilic macromolecules across mucosal epithel ia by opening the tight junctions. This study investigates the intestinal a bsorption of octreotide when it is coadministered with the polycationic abs orption enhancer TMC. Caco-2 cell monolayers were used as an in vitro intes tinal epithelium model, and male Wistar rats were used for in vivo studies. Octreotide with or without polymers (TMC; chitosan hydrochloride) was admi nistered intrajejunally in rats, and serum peptide levels were measured by radioimmunoassay. All applications and administrations were performed at ne utral pH values (i.e., pH = 7.4). In vitro transport studies with Caco-2 ce lls revealed an increased permeation of octreotide in the presence of TMC. Enhancement ratios ranged from 34 to 121 with increasing concentrations of the polymer (0.25-1.5%, w/v). In rats, 1.0% (w/v) TMC solution significantl y increased the absorption of the peptide analogue, resulting ina 5-fold in crease of octreotide bioavailability compared with the controls (octreotide alone). Coadministration of 1.0% (w/v) chitosan hydrochloride did not enha nce octreotide bioavailability. These results in combination with the nonto xic character of TMC suggest that this polymer is a promising excipient in the development of solid dosage forms for the peroral delivery and intestin al absorption of octreotide. (C) 2000 Wiley-Liss, Inc. and the American Pha rmaceutical Association.