Evaluation of microcrystalline chitosans for gastro-retentive drug delivery

In vivo absorption studies were carried out in human volunteers to evaluate whether microcrystalline chitosan (MCCh) granules would be gastro-retentive. Furosemide, which is site-specifically absorbed from the upper gastrointestinal tract, was used as model drug. The rate of release of furosemide in vitro could be prolonged by increasing the molecular weight (M-w) or amount of MCCh (150 to 240 kDa; 80 to 95%) in the granules, and also by addition of acidic excipients to the formulations. No marked changes in the in vivo absorption rate (t(max)) were noted, but the amounts of furosemide absorbed (AUCO(0-infinity) and C-max) decreased as the in vitro release rate decreased, although this was not statistically significant in the case of AUC. The highest AUC(0-infinity) (3050 mug l(-1) h) for furosemide (40 mg) was achieved with granules containing 80% MCCh of 150 kDa M-w. With MCCh of 240 kDa M-w AUC(0-infinity) was 1890 mug l(-1) h. This kind of pharmacokinetic profile of furosemide suggests that the gastric retention time of the granules is too short in relation to the release rate, and a large amount of the drug passes its "absorption window" before being released. The in vivo study produced no evidence that the chitosan formulations studied can be used as mucoadhesive gastro-retentive drug delivery systems. The results of in vitro mucoadhesion studies did not predict the results of in vivo studies. (C) 2003 Elsevier B.V. All rights reserved.