This study was performed to determine the exclusion criteria that differentiate poorly absorbed drugs from good drug candidates, and to accelerate drug development by exclusion of unnecessary assessment. The molecular and pharmacokinetic properties of 222 commercially available oral drugs were tabulated and their correlations were analyzed. The exclusion criteria obtained were 1) a molecular weight of more than 500, and 2) a ClogP value of more than 5. Exceptions to molecular weight criteria were compounds with a sugar moiety, high atomic weight, and large cyclic structure. It was also suggested that being a substrate for MDR1 (P-glycoprotein) does not always result in poor bioavailability, and that drug development by chemical modification of a seed or lead compound with quantitative structure activity relationship analysis can result in lower bioavailability, higher bound fraction and lower urinary excretion, which would hamper later development processes and might result in considerable drug-drug interaction. The criteria should be adjusted according to the pharmacological profiles of the agents in question and depending on the estimated profit, but ignoring these criteria may result in a significant waste of time and money during drug development.
-Purpose. The bile acids, phospholipids, inorganic ions, and pH in luminal fluid are important factors for the dissolution and oral absorption of solid drugs. In this study, we evaluated the regional differences in these factors in the rat gastrointestinal (GI) tract. The solubility of griseofulvin, a poorly water-soluble drug, in the luminal fluid in each segment was also measured. In addition, the data from rats were compared with those from other species published previously to evaluate the species differences in the composition of luminal fluid. Methods. Rat abdomen was opened and residual water was sampled from each region of GI tract to measure the various components concentrations. Results. The total bile acid concentration was about 2 times higher in the lower than upper jejunum, and phospholipids were much higher in the upper and lower jejunum. The solubility of griseofulvin in the lower jejunal fluid (153-260 g/mL) was about 1.5-2 times higher than those in the upper jejunal fluid (99-146 g/mL). The regional differences in inorganic ions and pH were also observed. As for species differences, the total bile acid and phospholipid concentration in rats GI tract were much higher than those of dogs and humans. Conclusion. The regional and species differences of the components in the GI fluid should be useful to predict dissolution and oral absorption of solid drugs.
To improve the dissolution and oral absorption properties of probucol, a novel wet-milling process using the ULTRA APEX MILL was investigated. The particle size of bulk probucol powder was 17.1 µm. However, after wet-milling with dispersing agents such as Gelucire 44/14, Gelucire 50/13, vitamin E-TPGS, and Pluronic F-108, the probucol particle sizes decreased to about 77-176 nm. Scanning electron microscopy (SEM) analysis also suggested that the probucol particles were successfully milled into the nanometer range. An in vitro dissolution study showed that the dissolution rates of all nanopowders were several folds higher than those of the corresponding mixed powders. When orally administered to rats, the AUC values of probucol nanopowders treated with Gelucire 44/14 and 50/13, and vitamin E-TPGS were about 3.06-3.54-folds greater than that of the bulk powder. Therefore, through this study, we have developed a new pharmaceutical technique to improve the dissolution rate and oral absorption of probucol using the ULTRA APEX MILL by wet-milling with various dispersing agents.
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