Chitosans as absorption enhancers of poorly absorbable drugs 3: Influence of mucus on absorption enhancement

Chitosans are potent nontoxic absorption enhancers after nasal administrati on but their effects on the intestinal epithelium in vivo has not been stud ied in detail. In this study, the effects of chitosans with varying molecul ar weights and degrees of acetylation on the absorption of a poorly absorbe d model drug (atenolol) were studied in intestinal epithelial cell layers w ith or without a mucus layer and in an in situ perfusion model of rat ileum . The effects of the chitosans on epithelial morphology and release of lact ate dehydrogenase (LDH) into the perfusate were investigated in the in situ model. The chitosans had pronounced effects on the permeability of mucus-f ree Caco-2 layers and enhanced the permeation of atenolol 10- to 15-fold, w ith different absorption kinetics for different chitosans, in accordance wi th previous results. In contrast, enhancement of atenolol absorption throug h rat ileum was modest. LDH release from the tissues perfused with chitosan s did not increase, indicating that the chitosans were used at nontoxic con centrations. Morphological examination of the perfused ileal tissues reveal ed more mucus discharge from the tissues exposed to chitosans than from con trols, which suggested that the discharged mucus may inhibit the binding of chitosan to the epithelial surface and hence decrease the absorption-enhan cing effect. This hypothesis was supported by studies with intestinal epith elial HT29-H goblet cells covered with a mucus layer. The binding of chitos an to the epithelial cell surface and subsequent absorption-enhancing effec ts were significantly reduced in mucus-covered HT29-H cultures. When the mu cus layer was removed prior to the addition of chitosan, the cell surface b inding and absorption-enhancing effects of the chitosans were increased. We conclude that the modest absorption-enhancing effects of unformulated chit osan solutions in the perfused rat ileum are a result of the mucus barrier in this tissue. This effect may be overcome by increasing the local concent rations of both chitosan and drug, i.e,. through formulation of the chitosa n into a particulate dosage form. (C) 1999 Published by Elsevier Science B. V. All rights reserved.