In vitro and in vivo analysis of pulsatile biodegradation of mucoadhesive hydrogels

Targeting mucosal tissues in the gastrointestinal tract by particulate drug delivery systems requires a supportive platform to avoid uncontrolled dispersion. It is expected that such a platform will erode at a rapid, predetermined rate, coupled with mucoadhesive properties, all aimed at creating a critical mass of drug-loaded particles at the injured epithelium. This strategy was challenged by exploiting two types of micro-matrices (beads): calcium alginate (CaAlg) and chitosan oxalate (CtOx). The beads were loaded with different types of dyes (cationic anionic and hydrophobic) or with the BCS Class II NSAID indomethacin (Ind). Their collapse kinetics in the presence of ionic de-cross-linkers (oxalic acid in the case of CaAlg and CaCH in the case of CtOx) was measured in vitro (mechanical tests and dye release kinetics) and in vivo (pharmacokinetic analysis of degradation-driven cecal release of Ind in the cecum of rats). It was found that ionic de-cross-linking caused a concentration-dependent disassembly of the CaAlg and CtOx beads, leading to a burst release of the dye probes. This observation was repeated in the cecum of anesthetized rats after local concomitant administration of both types oflnd-loaded beads and ionic de-cross-linker solutions. The concomitant administration caused an enhanced absorption of similar Ind doses. It is concluded that a prototype of a partially "smart" (non-reversible) supportive carrier, with the capability of responding to an external stimulus in a controlled manner has been demonstrated. Tailoring the de-cross-linker concentration to each polysaccharide composition would yield an optimal pulsatile effect at the desired mucosal region.