Conjugation of poorly absorptive drugs with mucoadhesive polymers for the improvement of oral absorption of drugs.

Mucoadhesive poly(vinylamine) conjugates for improving oral absorption of alendronic acid were designed and prepared. Alendronic acid was conjugated via spacers containing brush border peptidase-susceptible amino acid residues. Alanylalendronic acid and alanylprolylalendronic acid were synthesized as expected substrates against brush border aminopeptidase N and dipeptidyl peptidase IV, respectively. In vitro release profiles of alendronic acid from them during incubation with luminal contents and brush border membrane vehicles of the rat's intestine were examined. The studies indicated that alanylproline was a useful peptide spacer for local release of alendronic acid in brush border membranes. We subsequently designed and prepared poly(vinylamine)-alendronic acid conjugates with succinoylglycylglycylphenylalanylalanylproline spacers, in consideration of steric hindrance of polymer chains on cleavability of the spacers and the substrate specificity of dipeptidyl peptidase IV. Oral absorption of alendronic acid after administration of the conjugates was compared with that of free alendronic acid in rats. Conjugation successfully resulted in a 2.5-fold increase in the oral absorption with statistical significance. This novel approach has a potential to improve oral absorption of drugs with poorly absorptive properties caused by low membrane permeability.