Site-specific drug delivery and penetration enhancement in the gastrointestinal tract

Abstract

New types of biodegradable and pH-sensitive hydrogels were synthesized by the crosslinking of polymeric precursors. They contained both acidic comonomer and enzymatically degradable azoaromatic crosslinks. Such hydrogels are suitable for colon-specific drug delivery. In the low pH range of the stomach, the swelling of the gel is low and the drug is protected against digestion by enzymes. In the small intestine, the swelling increases. Upon arrival in the colon, a degree of swelling is reached that makes the crosslinks accessible to azoreductase activity. The gel is degraded and drug released. The hydrogels were characterized by the network structure (i.e., content of crosslinks, unreacted pendent groups, and cycles), the equilibrium and dynamic swelling as a function of pH, modulus of elasticity, and in vitro/in vivo degradation. The results indicated that the hydrogel network structure strongly depends on the reaction conditions such as polymer concentration, and the ratio of the reactive groups during the crosslinking reaction. The swelling and mechanical properties of hydrogels can be controlled by the modification of polymer backbone structure and/or the crosslinking density. Depending on the network structure, the degradation of hydrogels followed either a surface erosion or a bulk-degradation-like process. In vivo degradation rate of hydrogels was three to five times faster than that in vitro. The effect of a penetration enhancer, CapMul MCM (a medium chain glyceride), on physiological properties of rabbit intestinal epithelium was investigated in vitro using the Ussing chamber technique. It was shown that CapMul MCM affected tissue ion transport, permeability, and morphology in a concentration- and time-dependent manner. It was found that with minimal epithelial disruption and moderate change in ion transport in the colon, the increase in marker molecule permeabilities ranged between 7 and 25 times depending upon their molecular weight.