Effect of Absorption Behavior of Solubilizers on Drug Dissolution in the Gastrointestinal Tract: Evaluation Based on In Vivo Luminal Concentration-Time Profile of Cilostazol, a Poorly Soluble Drug, and Solubilizers.

The purpose of this study was to evaluate the effect of absorption behavior of solubilizers on drug dissolution in the gastrointestinal tract. After oral administration of FITC-dextran (FD-10), a nonabsorbable marker, and cilostazol (CZ), a low-solubility drug, with or without solubilizers (dimethyl sulfoxide [DMSO], and d-α-tocopherol polyethylene glycol 1000 succinate [TPGS]), the in vivo rat luminal concentrations of these compounds were determined by direct sampling of residual water in each segment of the gastrointestinal tract. DMSO was rapidly absorbed and not detected in the middle small intestine. Conversely, the TPGS concentration increased by 1.5- and 2-fold relative to the initial dose concentration in the middle and lower small intestine, respectively, owing to condensation. Then, normalized area under the luminal concentration-time curve of solid CZ was calculated from the luminal concentration-time profiles of FD-10 and solid CZ to evaluate in vivo dissolution behavior of CZ. The dissolution of CZ was marked when administered with TPGS compared with that when administered with DMSO, especially in the lower small intestine. This clearly indicates that absorbability of solubilizers is one of the important factors in determining the solubilizing effect. These findings may be beneficial to development of oral lipophilic drugs.

Prediction of oral absorption of low-solubility drugs by using rat simulated gastrointestinal fluids: the importance of regional differences in membrane permeability and solubility.

PURPOSE: This study aimed to develop a novel approach for predicting the oral absorption of low-solubility drugs by considering regional differences in solubility and permeability within the gastrointestinal (GI) tract. METHODS: Simulated GI fluids were prepared to reflect rat in vivo bile acid and phospholipid concentrations in the upper and lower small intestine. The saturated solubility and permeability of griseofulvin (GF) and albendazole (AZ), a drug with low aqueous solubility, were measured using these simulated fluids, and fraction absorbed (Fa) at time t after oral administration was calculated. RESULTS: The saturated solubility of GF and AZ, a drug with low aqueous solubility, differed considerably between the simulated GI fluids. Large regional differences in drugs concentration were also observed following oral administration in vivo. The predicted Fa values using solubility and permeability data of the simulated GI fluid were found to correspond closely to the in vivo data. CONCLUSION: These results indicated the importance of evaluating regional differences in drug solubility and permeability in order to predict oral absorption of low-solubility drugs accurately. The new methodology developed in the present study could be useful for new oral drug development.

Species differences in the dissolution and absorption of griseofulvin and albendazole, biopharmaceutics classification system class II drugs, in the gastrointestinal tract.

It is well known that large differences exist in the bioavailability of orally administered drugs between species. Dissolution is the first step in the oral absorption of solid drugs. In this study, we measured the in vivo luminal concentrations of griseofulvin (GF) and albendazole (AZ), Biopharmaceutics Classification System (BCS) class II drugs, and the GF fraction absorbed (Fa) in rats. Then, we compared the GF Fa in rat with that in other species reported previously to evaluate differences in drug dissolution and oral absorption. The Fa of GF has been reported to decrease from 80% to 40% with an increase in the oral dose in dogs and humans, because the rate-limiting step for absorption shifts from dissolution to solubility. However, such non-linearity was not observed in rats that were administered doses in the same ranges as those in humans, and the Fa values in rats were higher than those in dogs or humans. The in vivo luminal concentration of GF after oral administration in rats was much higher than the saturated solubility of GF in fasted-state simulated dog (FaSSIF(dog)) or human intestinal fluid (FaSSIF(human)). Furthermore, oral administration of AZ showed similar tendencies of interspecies differences in dissolution and oral absorption.

[Evaluation of dissolution of osmotic-controlled release paliperidone tablets using the reciprocating cylinder method].

The dissolution profiles of paliperidone from INVEGA(®) 3-mg tablets, osmotic-controlled release tablets, were evaluated by using the reciprocating cylinder method (RC method). We used 4 different compositions of the dissolution fluids, by considering the environment of the tablet in the gastrointestinal tract. After a lag time of 2 to 4 h, paliperidone was approximately dissolved to 24 h by zero-order release. The dissolution characteristics of paliperidone were not affected by the kind of the test medium, pH, and surfactant. In addition, the dissolution of the tablets was evaluated using the paddle method in distilled water, Japanese Pharmacopeia (JP) 1st test fluid, and JP 2nd test fluid. The dissolution profiles of paliperidone obtained using the RC method and the paddle method were very similar. Further, the dispersion of the percentage of the dissolved paliperidone obtained using the RC method and the paddle method was small.

Regional differences in the components of luminal water from rat gastrointestinal tract and comparison with other species.

PURPOSE: The bile acids, phospholipids, inorganic ions, and pH in luminal fluid are very 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 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 and phospholipid concentrations were much higher in the lower jejunum and upper jejunum, respectively, than in the other regions. The solubilities of griseofulvin in the lower jejunal fluid (153-260 ug/mL) were about 1.5-2 times higher than those in the upper jejunal fluid (99-146 ug/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: These informations about the regional differences and species differences of the components in the GI fluid should be very useful to consider dissolution and oral absorption of solid drugs.

Nanoparticulation of probucol, a poorly water-soluble drug, using a novel wet-milling process to improve in vitro dissolution and in vivo oral absorption.

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.

Nanoparticulation of poorly water soluble drugs using a wet-mill process and physicochemical properties of the nanopowders.

In order to improve the dissolution and oral absorption properties of poorly water soluble drugs such as omeprazole, albendazole and danazol, various dispersing agents were added to prepare nanopowder formulations using an ULTRA APEX MILL, which is a wet-mill instrument, and their physicochemical properties were evaluated. Using Pluronic F-108 or F-68 as dispersing agents, slurries containing drug particles having nanometer size were obtained for all model drugs tested. Omeprazole, a heat labile drug, was not degraded by wet-milling and the omeprazole nanoparticles in a milled slurry did not aggregate for 24 h after wet-milling. After lyophilization of these milled slurries containing drug nanoparticles, fine solid white nanopowders were obtained. Scanning electron microscopy (SEM) suggested that the model drugs were milled into nanometer size. X-ray powder diffraction (XRPD) patterns and Differential Scanning Calorimetry (DSC) curves confirmed that all milled drug nanopowders were crystalline, although milling of albendazole nanopowder transformed it to another crystal form. Wet-milling using an ULTRA APEX MILL offers a highly effective approach to produce stable drug nanopowders and is a very useful tool for bioavailability enhancement of poorly water soluble and heat labile drugs.

MDR1 up-regulated by apoptotic stimuli suppresses apoptotic signaling.

PURPOSE: Recently, MDR1 (P-glycoprotein) and related transporters have been suggested to play a fundamental role in regulating apoptosis, but little information is available concerning the role of MDR1. Here, the effect of apoptotic stimuli on the MDR1 mRNA and apoptotic signaling was examined in MDR1-overexpressing cells. METHODS: The expression levels of mRNA for MDR1, MRP1, MRP2, p53, p21, Bax, and Bcl-2 were measured by real time quantitative polymerase chain reaction in HeLa and its MDR1-overexpressing sublines. The effects of apoptotic stimuli by cisplatin (CDDP) on their levels were also assessed as well as on caspase 3, 8, and 9 activities. RESULTS: MDR1 was rapidly upregulated when the cells were exposed to apoptotic stimuli by CDDP. The increase in Bax mRNA to Bcl-2 mRNA ratio after treatment with CDDP was suppressed in MDR1-overexpressing cells. The increases in caspase 3 and 9 activities after treatment with CDDP were suppressed in MDR1-overexpression cells. CONCLUSION: MDR1 is upregulated by apoptotic stimuli suppressed apoptotic signaling presumably via the mitochondrial pathway.