PHEA-graft-polymethacrylate supramolecular aggregates for protein oral delivery

Abstract

Salmon calcitonin (sCT) is characterized by a poor oral availability. A new copolymer, β-poly(N-2-hydroxyethyl)-graft-{N-2-ethylene[2-poly(methacrylic acid sodium salt)isobutyrate]}-d,l-aspartamide (PHEA-IB-p(MANa+)), was designed for the oral administration of sCT through the formation of supramolecular aggregates (SAs) based on electrostatic interactions. Several sCT/PHEA-IB-p(MANa+) weight ratios were characterized by turbidimetry, DLS, zeta potential, and microscopy analysis. After the incubation of sCT/PHEA-IB-p(MANa+) complex with digestive enzymes, 10% (w/w) of loaded sCT was released in the native form. In vitro investigation was carried out to determine the copolymer effect on the permeability of sCT in Caco-2 cell monolayers. sCT pharmacokinetic profile and the pharmacodynamic effect on calcium plasma level were determined following an oral administration of the lead sCT/PHEA-IB-p(MANa+) SA (1/5 ratio) in rats. The SA yielded a marked prolongation of the sCT lowering calcium ...