Hydrogels for colon-specific peptide drug delivery

Novel hydrogels based on hydrophilic N-substituted (meth)acrylamides, N-tert-butylacrylamide and acrylic acid crosslinked with azoaromatic compounds of varying length and electron density of the azo bond were synthesized. These gels are suitable for colon-specific peptide drug delivery. The crosslinks are degradable by microbial azoreductases present predominantly in the colon. In the low pH range of the stomach, the gel has a low degree of swelling and the peptide drug is protected against digestion by enzymes. The degree of swelling increases as the gel passes down the gastrointestinal tract due to the increase in pH. Upon arrival in colon the gel has reached a degree of swelling that makes the crosslinks accessible to azoreductases and mediators. The gel is then degraded and the peptide drug released. The hydrogels were characterized by equilibrium degree of swelling, modulus of elasticity in compression, acido-basic properties and permeability of insulin as a function of pH. It was found that the structure of the polymer backbone influenced the degree of swelling and pH-sensitivity of the gel. In all cases, the degree of swelling was lower at pH 2 than at pH 7.4. Modulus of elasticity and permeability correlated with the degree of swelling. As degree of swelling increased, the modulus of elasticity decreased and permeability of insulin increased. The degree of dissociation was found to increase correlating with the degree of swelling as pH increased. The degradability in vitro and in vivo was found to be related to the degree of swelling of the gel. The higher the degree of swelling, the higher the degradability. However, structural and electronic factors were also shown to influence reduction azo bonds. Colonic absorption of peptide drugs was demonstrated using insulin as a model drug. Coadministered with an absorption enhancer, sodium taurocholate, significant blood levels of insulin were detected in rats. The feasibility of the gels studied for site-specific peptide drug delivery to the colon has been shown. To optimize a drug delivery system based on these gels, the results presented must be related to physiological factors, such as transit time and pH variations of the gastrointestinal tract.