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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 CaCl2 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 of Ind-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.

The purpose of this study was to develop a biodegradable drug platform composed of chitosan and guar gum and to explore the possibility of using it for local adjuvant or neoadjuvant therapy of colorectal cancer. Celecoxib (Cx), a chemopreventative drug for familial adenomatous polyposis (FAP) and under trial for reducing post surgical colorectal malignancies, was selected as a model drug for this topical system because of the contraindications that are associated with its systemic administration. Films made of chitosan (Ct) and guar gum (GG) were prepared, characterized for equilibrium swelling, mucoadhesion, in vitro and in vivo degradation and loaded with Cx. Short term dosing studies in vitro were performed in the HT-29 colon carcinoma cell line that was incubated with Cx using the MTT test to assess IC50. The impact of a single high dose was evaluated and compared with a repeating low-dose regimen. In vivo dosing experiments with Cx were performed in the perfused intestine of the anaesthetized rat. Measuring tissue LDH assessed epithelium injury. Mechanical, mucoadhesion and in vitro degradation of the polysaccharide films were dictated by manipulating the ratios of Ct and GG. The addition of rat cecal contents to the dissolution medium increased the total Cx released from those films containing high amounts of GG. MTT reduction, a measure of cell proliferation, diminished as a function of increasing drug concentration and exposure time in the HT-29 cell line studies. Local high concentrations of Cx were shown to impede the proliferation of cancer cells directly, while chemoprevention has been demonstrated with low Cx doses. Healthy cells were shown to be sensitive to high Cx doses. Maximum therapeutic efficiency in the context of minimal healthy tissue exposure would thus be predicted utilizing a local delivery system such as the proposed adhesive, biodegradable polysaccharide composites.

The in vitro release of physostigmine salicylate (PS) from a submicron emulsion and an aqueous solution was studied using the dialysis bag method. These formulations were then perfused to various locations along the rat small intestine (proximal, mid, and distal jejunum), and two lengths (10 and 55 cm). The disappearance of PS from the luminal compartment and its appearance in the blood compartment was monitored. In the in vitro drug release from emulsion experiments, a biphasic appearance of PS in the sink solution was observed, suggesting a possible sustained release from the emulsion. However, absorption data from perfusion studies did not correlate with this in vitro observation. No significant difference was found in absorption from emulsion versus solution in the mid jejunum where PS absorption was maximal. The difference between the two liquid formulations was observed only in those intestinal segments where the absorption was relatively low [absorption rate values of 4.6 +/- 0.86 and 9.98 +/- 2.04 (log%/min) x 10(-3) in the proximal and distal parts of the small intestine, respectively, as compared with 14.0 +/- 1.2-14.8 +/- 1.1 (log%/min) x 10(-3) in the mid jejunum]. In the distal part of the rat small intestine, PS was absorbed significantly better from solution than from the submicron emulsion. Cholinesterase activity in blood samples collected after intestinal perfusion with emulsion or solution revealed lower enzyme activity following emulsion administration.