Shigeharu Yokohama

Influence of water soluble fillers in hydroxypropylmethylcellulose matrices on in vitro and in vivo drug release.

The purpose of this study was to investigate the effect of fillers in gel-forming matrix on in vivo drug release after oral dosing. A further purpose was to predict the in vivo performance from in vitro dissolution test. Three controlled-release acetaminophen tablets containing hydroxypropylmethylcellulose (HPMC) with or without highly water soluble fillers, lactose or polyethylene glycol 6000 (PEG6000), were prepared. Water penetration into the matrix was enhanced by addition of fillers in the matrices, but the three tablets showed similar in vitro dissolution profiles, indicating that fillers in the HPMC matrices little affected the in vitro drug release. In contrast, the fillers in HPMC matrices did affect the in vivo performance in dogs. The absorption profile of HPMC matrix with PEG6000 was the fastest, followed by that with lactose and without water soluble filler, in that order. As the matrix with PEG6000 had a large amount of water and gelated a large portion of the matrix when in contact with water, the gel layer would be disintegrated by the gastrointestinal motility. It was found that dissolution of gel-forming HPMC matrices under mechanical stress by glass beads well correlated with the in vivo performance of the matrix, with little correlation by the conventional paddle method.

Common solubilizers to estimate the Caco-2 transport of poorly water-soluble drugs

Solubilizers are often used to enhance the bioavailability of drugs with poor aqueous solubility. This study focuses on the use of the Caco-2 system containing solubilizers to predict the absorption of poorly water-soluble drugs in humans. First, the effects of propylene glycol (PG), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), polyethylene glycol 400 (PEG 400), and Tween 80 on the viability (transepithelial electrical resistance, TEER) of 3-day cultured Caco-2 monolayers were evaluated. These solubilizers, even at the low concentration, reduce the viability of Caco-2 monolayers; these results indicate the impossibility for 3-day cultured Caco-2 monolayers to be used for this test. Next, the effects of PG, Tween 80, PEG 400, HP-beta-CD, Pluronic F-68 (Pluronic), HCO-40, sodium lauryl sulfate (SLS), Gelucire 44/14, Transcutol P, and extract gall powder on the viability of 21-day cultured Caco-2 monolayers and the apparent permeability (P(app)) of propranolol (PPL), Nadolol (NDL), and FITC-dextran 4000 (FD-4) were investigated. Five different solubilizing methods (20% PG, 5% Tween 80, 5% PEG 400, 5% HP-beta-CD, and 5% Tween 80+5% PEG 400) did not affect the viability of 21-day cultured Caco-2 monolayers. Furthermore, the P(app) values of the three compounds containing these solubilizers did not differ from the values for control formulations (without solubilizers). These results clearly suggest that the use of PG, Tween 80, PEG 400, or HP-beta-CD as solubilizing excipients and the testing of these formulations on 21-day cultured Caco-2 monolayers can predict intestinal absorption of poorly water-soluble drugs in humans.

A new index, the core erosion ratio, of compression-coated timed-release tablets predicts the bioavailability of acetaminophen

Although compression-coated tablets are a commonly used timed-release drug delivery technology, their utility is often limited by poor bioavailability. To try to improve the bioavailability of these tablets, the effect of their core composition of compression-coated tablet on in vivo pharmacokinetics was investigated. First, the extent of mass reduction of cores in different compression-coated tablet core formulations was used to establish a new index, the core erosion ratio. The data show that adding excipients with high water solubility to the core results in a greater core erosion ratio. Next, to elucidate the effect of core erosion ratio on in vivo acetaminophen (AAP) release, three compression-coated tablet formulations with similar in vitro AAP release profiles but different core erosion ratios were administered to four fasted dogs. The time for first appearance (TFA) of AAP in plasma did not differ significantly among formulations, indicating that the in vivo lag time was the same for all formulations. In separate experiments, necroscopy revealed that 3h after oral administration, the tablets were located in the ileum and colon and that all three formulations had identical GI transit times. However, the area under the AAP plasma concentration-time curve was greater in dogs given formulations with larger core erosion ratios. These results suggest that a formulation with a large core erosion ratio can significantly increase in vivo drug release from compression-coated tablets, leading to increased drug absorption from the lower GI tract.

Failure of stability prediction for minodronic acid injectable by accelerated stability testing.

A liquid formulation containing 0.5 mg/ml minodronic acid, 40 mM, pH 4.5, citrate, and sodium chloride added to adjust the osmolarity of the final formulation was stored in flint glass ampoules at 25, 40, 50, and 60 degrees C. At specified times, the drug potency and pH, and the tendency to generate particulate matter, were measured. Test samples stored at 40 degrees C for 6 months or at 50 and 60 degrees C for 3 months were stable with no potency loss and no particulate increase. However, despite the satisfactory stability at high temperatures, the amount of particulate matter increased when the formulation was stored at 25 degrees C. Scanning electron microscopy-energy dispersive X-ray analysis of the particulate matter revealed that it contains aluminum and phosphorus, the latter thought to be derived from minodronic acid. In contrast, the number of the particulate matter did not increase, when the formulation was stored in either plastic containers or in SiO(2)-treated glass ampoules(.) The spike of minodronic acid solution with aluminum ions led to the particulate generation. These results demonstrate that the particulate matter is a complex of minodronic acid molecules and aluminum ions, which apparently leached from the glass of regular ampoules. Since the particulate generation could not be observed at higher temperatures, it was suggested that the complex formation was exothermic and accelerated testing did not predict the stability in terms of particulate generation.

Small Intestinal Absorption of Bropirimine in Rats and Effect of Bile Salt on the Absorption

The intestinal absorption characteristics of a poorly water‐soluble drug, bropirimine, were investigated by the in‐situ small intestinal loop method using male Sprague‐Dawley rats.

Potential Use of Cyclodextrins to Enhance the Solubility of YM466 in Aqueous Solution

Abstract Various solubilizing agents for YM466, a new Factor Xa inhibitor, were investigated to begin designing the aqueous formulation for subcutaneous administration. The tentative target concentration was 5 mg/mL. First, three kinds of buffer solutions (glycine–HCl, citrate, and lactate) were examined for their solubilizing effects. The dissolution rate of YM466 in lactate buffer was the fastest, as determined by visual examination at room temperature. The dissolution rate of YM466 in lactate buffer was enhanced, without degradation, by heating at 40°C, and YM466 solution at a concentration of 1 mg/mL became transparent 10 min after the start of heating. The solubility of YM466 increased along with lactate concentrations ranging from 50 mM to 200 mM and reached a high of 1.3 mg/mL after increasing lactate concentration to 200 mM at 5°C. The addition of cyclodextrins β-cyclodextrin (β-CD), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), and γ-cyclodextrin (γ-CD), but not α-cyclodextrin (α-CD), had remarkable impact on its solubility, and 7–8 mg/mL of YM466 was dissolved by the addition of HP-β-CD or γ-CD. These results demonstrated that YM466 was included in cyclodextrins and that the inclusion formations required a cavity size larger than α-CD. Based on the calculation from the linear portion of the phase solubility diagrams, apparent stability constants of α-CD, β-CD, HP-β-CD, and γ-CD at 5°C were estimated to be 2 M−1, 206 M−1, 143 M−1, and 276 M−1, respectively. Therefore, we found that γ-CD has the largest inclusion capacity.

Bioavailability of Bropirimine 250 mg Tablet in Dogs: Effect of Food

The postprandial effect on the bioavailability of bropirimine in dogs after oral administration of bropirimine tablets (Bropirimine 250 mg Tablet) was investigated.

Stabilization of minodronic acid in aqueous solution for parenteral formulation.

The composition, concentration, and buffer pH of potential minodronic acid formulations were evaluated for their drug stability and for their tendency to generate particles after storage for up to 4 weeks at 60 degrees C. The results indicate that citrate and tartrate buffers maintain drug stability and inhibit the formation of particles. The stability of minodronic acid in these solutions increased slightly as the buffer concentration increased, exhibiting less particle formation than in other buffers. Since citrate buffer was considered the most promising stabilizer for minodronic acid, the pH-stability relationship in 100 mM citrate with pH ranging from 3 to 7 was evaluated during storage for 4 weeks at 60 degrees C. The results demonstrate that solution pH of 3-5 result in optimal stability of minodronic acid with no formation of precipitates. A white precipitate was observed in citrate-containing sample solutions with pH of 6 and 7. Analysis of the isolated precipitate provided support for the hypothesis that the precipitate is a complex between minodronic acid and aluminum ions apparently leached from the glass of the ampoules.

Characteristics of intestinal absorption of adinazolam and in vivo evaluation of oral sustained release tablets of adinazolam in beagle dogs

Abstract The characteristics of intestinal absorption of adinazolam in rats were investigated using an in situ intestinal loop method on the upper, middle and lower parts of the small intestine, and colon. The disappearance of the drug from the intestinal lumen was measured to estimate the absorption. Adinazolam was readily absorbed from various sites of the small intestine and colon indicating no absorption site specificity. Absorption followed first-order kinetics with a disappearance half-life of less than 15 min. Dose dependency or saturation of the absorption were not observed in the experimental concentration range of 5–1000 μg/ml. In one of the experiments to investigate the effect of postprandial administration, the intestinal absorption of adinazolam decreased somewhat when the administered solution contained either 5% bile powder or 5% polysorbate 80. In the biopharmaceutic study, the sustained release (SR) tablet significantly prolonged the plasma adinazolam concentration in beagle dogs in comparison to that of the rapidly disintegrating conventional tablets (conventional tablet) of adinazolam. The mean residence time (MRT) of adinazolam from the SR tablets was about 5-times greater than that of the conventional tablets.