Although beagle dogs have been widely used in bioavailability studies, it is well known that a variance in gastric pH can affect the bioavailability of certain compounds in the dog. To investigate the influence of gastric acidity on the bioavailability, we developed a method of monitoring gastric pH and a technique to control gastric pH in the beagle dog. Pharyngotomy was conducted on a beagle dog by using Leighton's method. A small pH electrode (ϕ=1.6 mm) was passed through the fistula from the lateral surface of the neck, down the esophagus, and into the stomach to allow continuous monitoring of gastric pH. Through treatment with sodium bicarbonate or pentagastrin, the gastric pH was maintained at a high level (pH 5.5-7.0) for 15-30 min or at a low level (pH ca. 1) for more than 40 min, respectively. The usefulness of this method to control gastric pH in a beagle dog was studied by using 7-[5-(4-m-trifluorophenylpiperazin-1-yl)-n-pentyl] theophylline (TFP), a weakly basic and slightly soluble compound used as a model compound. In a crossover study, 50 mg of powdered TFP was administered to beagle dogs with a high gastric pH, or a low pH, and to untreated beagle dogs. After dosing dogs with a low gastric pH, the plasma TFP concentrations attained a peak within 2 hr in all animals, and the interindividual variation was small. In the dogs with a high gastric pH and in untreated dogs, plasma concentration attained a peak at 0.5-6 hr, with a higher variability between the animals. However, the ACU (0-24 hr) did not differ markedly between the conditions. Thus, although the rate of absorption of TFP was affected by the gastric pH in beagle dogs, the extent of absorption was essentially unchanged. These results indicate that the technique to control gastric pH in dogs is useful for investigating the effect of gastric pH on oral bioavailability.

The compressibility estimation method of drugs, measuring with an infinitesimal quantity of sample, was studied by a static tableting experiment to improve the accuracy of preformulation study of tablets in the early drug development stage. Aspirin with plastic property and phenacetin with brittle property were used as model medicines, and compressibility was estimated by the stress displacement curves and the diametrical crushing strengths of the tablets. An examination concerning the effects of compression condition (particle size of sample, compression force, and sample quantity) on compressibility revealed that 1) the net work of aspirin performed by the upper punch is different from that of phenacetin, but the difference disagrees with the relationship between the compressibility of aspirin and that of phenacetin. On the other hand, 2) the difference of the total work performed by the upper punch agrees with the relationship between the compressibility of aspirin and that of phenacetin; 3) the diametrical crushing strength of an aspirin tablet does not change as particle size is increased, but that of phenacetin tablet decreases as the particle size increased; 4) the strengths of both the aspirin tablet and the phenacetin tablet increased as the compression force increased; and 5) the difference between the strength of the aspirin tablet and of the phenacetin tablet becomes clear as the sample quantity decreased. On the basis of these results, we defined the compressibility estimation method of drugs by using an infinitesimal quantity (40 mg) of sample per one measurement.

Adhesion by static electricity occurring in the dispensing of fine granules and granules causes variation of weight, weight loss, and consequently a variation of drug content. A countermeasure of static electricity is important for the assurance of the effect and safety of the medicine, and improvement is desired. We found that titanium oxide and rice starch were good for decreasing the adhesion by static electricity, which were dispersed to coating solutions and the fine granules were then coated with these solutions. In the fine granules coated with these materials, which could be a decreased occurrence of static electricity and improved dispensibility. It was found that the fine unevenness on the surfaces of coated granules formed by these materials was good for decreasing the adhesive force of granules occurring in contacting the vessel, apparatus, and granules and separating from them.

Organic pharmaceutical powders are highly adhesive and cause particle cohesion during the manufacturing process, preventing smooth automation. Furthermore, fine powders on the capsule cause contamination problems. Thus the removal of excess microparticles from the surface of the capsule is desirable in an automatic system. In this study, the adhesive force of fine particles on the surface of capsules was measured by the centrifugal force method. We used two types of capusules to measure the adhesive force of fine particles (HPMC capsule and gelatin capsule). Finededuster (FDD-104, Matsui MFG Co., Tokyo) was employed to remove fine particles from the capsule surface. A critical particle size of about 10 μm was found to exist, and larger particles were removed more efficiently. This situation is quite similar to that observed in other mechanical properties of powders such as angle of repose and flowability. We consider that the electical charge influenced the adhesive force of fine particles to the capsule surfaces.

To clarify the thermodynamic stability of chloramphenicol palmitate polymorphic forms (form A, form B, and form C), differential scanning calorimetry and powder X-ray diffractometry at elevated temperatures were performed, and solubilities in 35% t-butanol/water mixture at various temperatures were determined. Furthermore, the effects of polymorphic forms on the plasma levels of chloramphenicol in dogs were evaluated, and the dissolution rate in the presence of sodium cholate and enzymatic hydrolysis rate in the presence of lipase were then determined to confirm the relationship between thermodynamic stability and absorption of chloramphenicol from chloramphenicol palmitate polymorphic forms. The van't Hoff plots of solubility data of the three forms indicated that thermodynamic stability was in the order form A>form B>form C. The order of thermodynamic stability of the polymorphic forms agreed well with the results of thermal analysis and powder X-ray diffraction at elevated temperatures, but was inconsistent with that previously reported by Aguiar and Zelmer. When each form was administered orally as arabic gum suspensions, the areas under the curve (AUCs) of form C and form B were respectively 2.2 times and 1.6 times those of form A. The order of AUCs of the forms corresponded well with the order of thermodynamic stability. The differences in chloramphenicol level in plasma among the polymorphic forms were due to the differences in dissolution rate, which affected the apparent enzymatic hydrolysis rate.

We have previously shown that cis-unsaturated fatty acids dissolved in propylene glycol (PG) directly alter the lipid structure of the stratum corneum, subsequently enhancing the transfer of PG into the dermis. In turn, PG disorders the protein structure of the dermis by using fourier infrared transform/attenuated total reflection (FT-IR/ATR) analysis. The present study evaluates the skin permeability of indomethacin (IM) and PG enhanced by petroselinic and oleic acids in vitro and in vivo in rat. Petroselinic acid enhanced the permeability of IM and PG more than oleic acid did. This was consistent with the degree of skin structure alternation caused by petroselinic acid and oleic acid. To differentiate petroselinic acid from oleic acid as the skin penetration enhancer, we examined the stability of cis-unsaturated fatty acids in constituents of the stratum corneum by calculating the interaction energy, using molecular mechanics analysis. Palmitic acid and stearic acid were chosen as model compounds, since these fatty acids contributed to the increased lipid fluidity of the stratum corneum as the constituents. The results of calculations when using a molecular model with an optimized structure indicated that the energy difference, ΔE, between cis-unsaturated and saturated fatty acids was negative in each of the combinations and that petroselinic acid was more potent than oleic acid in interacting with saturated fatty acids. These data suggest that the ability of petroselinic and oleic acids to evaluate skin permeability depend on the affinity for the constituents of the stratum corneum.

We have developed a deglutition aid jelly that will allow almost all solid preparations to be barrier-free dosage form preparations. During development, an evaluation test for application was performed in a healthy care facility for the elderly, and a survey on properties, color, taste and container, which are required for the jelly, was conducted. Based on results of the survey, a jelly like wafer was obtained under the following conditions. An agar was chosen as a main ingredient. Six percent of erythritol and sorbitol was employed for a good filling performance and to retain 10-30 g/cm² of jelly intension and about 5% of the loss of water content. Other gelatinizers and flavors are also combined, each at a lower additional level. Since this product has no interaction with medicines, no bafflement for disintegration or dissolubility of the existing tablets, facility of taking it even for children and people with difficulty in swallowing, no risk of taking it by mistake, and securement for safety, this product therefore could contribute to the improvement of QOL for people who feel burdened by taking medicines.

The effects of uniformity of binder distribution of granules and granule hardness on the compressibility of granules manufactured with different methods of binder addition (solution addition method and powder addition method) on various wet granulation methods were investigated. As a result, the uniformity of binder distribution of granules was found to be the main factor in controlling the compressibility of granules for tablets on wet granulation compared with granule hardness. It was suggested that uniform binder distribution of granules on wet granulation is important for the excellent compressibility of granules for tablets.

Solid dispersions of nifedipine (NP) with three types of poloxamers (PXMs), namely, PXM 188, PXM 288 and PXM 407, were prepared by melting, solvent and kneading methods to improve the NP dissolution characteristics. The melting method gave the highest enhancing effect to the dissolution rate (p<0.05), followed by the solvent and kneading methods. The highest dissolution rate was obtained from PXM 188 prepared by the melting method at the 1:10 drug:carrier mixing ratio. The possible mechanisms for dissolution improvement obtained from the X-ray diffraction and differential scanning calorimetric studies were discussed. The amorphization of the drug at the higher mixing ratio, the improvement of the wettability and the solubility seemed to participate in the fast release mechanisms of NP. Moreover, the infrared spectra showed the presence of intermolecular hydrogen bonding between drug molecules and poloxamers.

The purpose of the present study is to investigate the effect of loads applied to agitating powder beds on the particle size distribution. Lactose (JP) was used as a test powder bed and was processed under loads ranging from 6.24 to 41.9 g/cm² by a newly developed powder stress mixer. Particle size distribution and flowability of the processed powder was determined. Particle size distribution was determined by an image analysis system that involves optical microscopy. The internal friction coefficient was measured by a direct shear tester. It was found that at the light load (6.24 g/cm²), particles smaller than 74 μm increased and internal friction coefficient slightly increased with an increase of mixing time. At the heavy loads (29.2 g/cm² and 41.9 g/cm²), particles initially smaller than 74 μm became predominant, but further mix processing reduced them. Internal friction coefficient increased initially, but decreased with an increase of mixing time. Under the heavy loads, this is probably due to a quick increase of fine particles and their subsequent agglomeration to form larger particles. Furthermore, it was assumed that there was a critical fine particle size and critical quantity under which the physical properties of the powder bed change significantly.

We studied the effects of salicylic acid ointment by using the occlusive dressing technique (ODT) on keratinized human heel skin. The amount of sweat induced by ODT increased in comparison with that by a simple application method (control). Moreover, we observed that the morphological changes in the softening of keratinized heel skin by ODT were faster than those by the control method. The present results clearly indicated that ODT of salicylic acid ointment induced the softening of keratinized heel skin.

The bioavailability (BA) of E3810, an unstable compound in acid, was studeid by controlling gastric pH in beagle dogs. The BAs, after the administration of E3810 solution orally to dogs with a low or a high gastric pH, were 3.16 ± 1.28% and 76.4 ± 13.8%, respectively. These results suggested that E3810 decomposes rapidly in the presence of gastric acid, but its BA is high if the decomposition of E3810 is avoided in the gastrointestinal tract. To establish a dosage form of E3810 for toxicity testing in the dog, E3810 enteric-coated tablets (ϕ=6.5 mm) and E3810 solution were administered. The t_max after the administration of E3810 enteric-coated tablets was prolonged (t_max=5.42 hr), suggesting a slow gastric emptying, or a delay in the release of E3810. In contrast, when the tablets were asministered orally to fasted beagle dogs, t_max was obtained within 1 hr, suggesting rapid release once the tablet left the stomach. After administration of E3810 solution to beagle dogs with a high gastric pH, the BA was high, with the lowest variability. In the preliminary toxicity test, E3810 solution was administered to dogs with a high gastric pH once a day for seven days. The plasma concentrations of E3810 on day 1 and day 7 increased dose-dependently, and there is no difference in pharmacokinetics between day 1 and day 7. These results indicate that the method to control gastric pH in dogs is useful for the dosing of a compound that is unstable in gastric acid.

The chromatographic broadening method was used for the determination of diffusion coefficients (D) of parabens in water. The D values were obtained with precision, and coefficients of variation were below 0.05. The concentration of methylparaben in the injected solution did not affect D values in the range examined (100 μg/ml-0.5 μg/ml). The D values of parabens decreased with M. W., and that of methylparaben (8.25×10^-6cm²/s, at 25°C, 1.0 μg/ml) was 1.45 times higher than that of n-amylparaben (5.70×10^-6cm²/s, at 25°C, 1.0 μg/ml). The D values increased with temperature, and the activation energy for the diffusion of methylparaben and n-amylparaben were 18.8 kJ/mol and 20.0 kJ/mol, respectively. The increase of D with temperature could be due mainly to a decrease of viscosity of water.