CHITOSANS AS ABSORPTION ENHANCERS FOR POORLY ABSORBABLE DRUGS .1. INFLUENCE OF MOLECULAR-WEIGHT AND DEGREE OF ACETYLATION ON DRUG TRANSPORTACROSS HUMAN INTESTINAL EPITHELIAL (CACO-2) CELLS

Purpose. Chitosan has recently been demonstrated to effectively enhanc e the absorption of hydrophilic drugs such as peptides and proteins ac ross nasal and intestinal epithelia (1-3). In this study, the effect o f the chemical composition and molecular weight of chitosans on epithe lial permeability and toxicity was investigated using monolayers of hu man intestinal epithelial Caco-2 cells as a model epithelium. Methods. Eight chitosans varying in degree of acetylation (DA) and molecular w eight were studied. The incompletely absorbed hydrophilic marker molec ule C-14-mannitol was used as a model drug to assess absorption enhanc ement. Changes in intracellular dehydrogenase activity and cellular mo rphology were used to assess toxicity. Results. Chitosans with a low D A (1 and 15%) were active as absorption enhancers at low and high mole cular weights. However, these chitosans displayed a clear dose-depende nt toxicity. Chitosans with DAs of 35 and 49% enhanced the transport o f C-14-mannitol at high molecular weights only, with low toxicity. One chitosan (DA = 35%; MW = 170kD) was found to have especially advantag eous properties such as an early onset of action, very low toxicity, a nd a flat dose-absorption enhancement response relationship. Conclusio ns. The structural features of chitosans determining absorption enhanc ement are not correlated with those determining toxicity, which makes it possible to select chitosans with maximal effect on absorption and minimal toxicity.