Evaluation of factors affecting gastrointestinal absorption of a novel anticoagulant FX-93 for development of oral formulation.

To find out factors causing the low bioavailability of FX-93, a novel anticoagulant, its solubility, membrane permeability, and the effect of bile salt on the absorption of FX-93 were investigated. The solubility of FX-93 under physiological conditions ranged from 0.3 to 18.3 mg/mL and the dose number was calculated to be 0.02-0.27, suggesting that the intrinsic solubility of FX-93 should not be a limiting factor for oral absorption. Apparent permeability of FX-93 across Caco-2 cell monolayer suggested that its fraction of dose absorbed would range between 30% and 40% in humans. Furthermore, FX-93 was substantially absorbed from each segment of rat intestine. However, the decrease in the gastrointestinal transit rate significantly decreased maximum plasma concentration and area under the plasma concentration-time curve of FX-93 after oral dosing in dogs, suggesting that FX-93 absorption would be suppressed by some components in the small intestinal lumen. An in situ rat administration study indicated that bile significantly decreased the intestinal absorption of FX-93 by two-thirds, which could be attributed to the decrease in FX-93 solubility by the interaction with bile or bile acid. Nuclear magnetic resonance spectroscopy analysis suggested that FX-93 would interact with bile salt between the naphthalene ring of FX-93 and steroidal backbone of bile salt.

Studies on lactulose formulations for colon-specific drug delivery.

A novel, colon-targeted delivery system (CODES), which uses lactulose, was investigated in this study. Lactulose is not absorbed in the upper GI tract, but degraded to organic acids by enterobacteria in the lower gastrointestinal tract, especially the colon. A CODES consists of three components: a core containing lactulose and the drug, an inner acid-soluble material layer, and an outer layer of an enterosoluble material. When a CODES containing a pigment was introduced into the rat cecum directly after shaking in JP 2nd fluid for 3 h, pigment release was observed 1 h after introduction. A CODES containing 5-aminosalicylic acid (5-ASA) was orally administered to fasting and fed dogs to evaluate its pharmacokinetic profiles. 5-ASA was first detected in plasma after 3 h, which is the reported colon arrival time for indigestible solids, after dosing to fasting dogs. The T(max) in fed dogs was delayed by 9 h when compared to fasting dogs. This corresponds to the gastric emptying time. However, the C(max) and AUC under fed conditions were almost as same as those under fasting conditions. The results of this study show that lactulose can act as a trigger for drug release in the colon, utilizing the action of enterobacteria.