Behavior of mucoadhesive nanoparticles having hydrophilic polymeric chains in the intestine.

The behavior of nanoparticles having surface hydrophilic poly(N-isopropylacrylamide), poly(N-vinylacetamide), poly(vinylamine) or poly(methacrylic acid) chains in the intestine was examined. The permeability of salmon calcitonin (sCT) from the mucosal to serosal side of the everted jejunum was enhanced in the presence of nanoparticles. This enhancement, which correlated with the amount of sCT incorporated in nanoparticles, disappeared completely after removal of the mucous layer. When fluorescein isothiocyanate-dextran (FD-4) was used instead of sCT, its permeability through the everted jejunum with and without mucous layer was not enhanced by any nanoparticles, because FD-4 was not incorporated in nanoparticles at all. These findings indicated that the accumulation of nanoparticles incorporating sCT in the mucous layer resulted in the enhancement of sCT permeability. Nanoparticles with poly(N-isopropylacrylamide) or poly(vinylamine) on their surfaces did not cause any damage to the intestinal mucosa. Also, none of the nanoparticles opened the tight junction of the intestinal membrane. It was concluded that mucoadhesion of nanoparticles incorporating sCT to the gastrointestinal mucosa contributed to the absorption enhancement of sCT.

Optimized chemical structure of nanoparticles as carriers for oral delivery of salmon calcitonin.

Nanoparticles having two kinds of surface hydrophilic polymeric chains were prepared by the free radical copolymerization between styrene and hydrophilic macromonomers terminating in vinylbenzyl groups. Their potential as carriers for oral peptide delivery was investigated using salmon calcitonin (sCT) in rats. After oral administration of mixtures of sCT and nanoparticles, the ionized calcium concentration in blood was measured. The absorption of sCT was significantly enhanced by nanoparticles having poly-N-isopropylacrylamide (PNIPAAm) chains on their surfaces. This enhancement effect was considerably increased by introducing cationic poly-vinylamine (PVAm) groups to the surface of PNIPAAm nanoparticles. The absorption enhancement depended on the ratio of NIPAAm and VAm macromonomers to styrene in the nanoparticle preparation. In contrast, the introduction of nonionic poly-vinylacetamide (PNVA) groups eliminated completely the absorption-enhancing function of PNIPAAm nanoparticles. It was suggested that this disappearance was due to the shielding of PNIPAAm groups by PNVA groups. The enhancement effect of sCT absorption by nanoparticles was greatly dominated by their chemical structure that was closely related to surface characteristics. Optimization of the chemical structure on the basis of the mechanism of the absorption enhancement resulted in the further improvement of sCT absorption.