Shusei Ito

Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate.

The dissolution behaviors of carbamazepine (CZP) polymorphs and pseudopolymorphs (form I, form III and dihydrate) and the bioavailabilities (BA) of each form in dogs after oral administration were investigated. Bioavailability tests were carried out at a dose of either 40 mg/body or 200 mg/body. The results of dissolution tests in JP13 first fluid (pH 1.2) at 37 degrees C indicated that the initial dissolution rate was in the order of form III>form I>dihydrate, while form III was transformed to dihydrate more rapidly than form I, resulting in decrease of the dissolution rate. The solubilities of both anhydrates (form I and form III), calculated from the initial dissolution rate of each anhydrate, were 1.5--1.6 times that of the dihydrate. At the dose of 40 mg/body, there were no significant differences in the area under the curve (AUC) between forms; their AUCs were nearly equal to that of CZP solution using polyethyleneglycol 400. These findings suggested that most crystalline powder of each form administered at the low dose was rapidly dissolved in gastrointestinal (GI) fluid. On the other hand, for the dose of 200 mg/body, significant differences in plasma concentration--time curves of CZP among polymorphic forms and dihydrate were observed. The order of AUC values was form I>form III>dihydrate. The inconsistency between the order of initial dissolution rates and that of AUC values at the high dose may have been due to rapid transformation from form III to dihydrate in GI fluids.

Nose-to-brain delivery of TS-002, prostaglandin D2 analogue

This study was conducted to investigate the possibility of performing nose-to-brain delivery of TS-002, which is an analog compound of prostaglandin D2 (PGD2) and thus would be a natural sleep inducer. The absolute bioavailability (BA) and sleep-inducing effect (SIE) following intranasal (IN) administration of TS-002 dry powder to cynomolgus monkeys were evaluated in comparison with intravenous (IV) administration. The SIE was evaluated as the accumulated time of sleeping-posture for 3 h. The brain distribution of TS-002 following IN administration of the dry powder was examined in rats. The absolute bioavailability (BA) in monkeys following IN administration of the dry powder (0.4–1.2 mg/body) was comparatively high (43.4–78.0%). The SIE following IN administration (0.05–0.4 mg/body) showed dose-dependency and its effect at 0.4 mg/body was twice as strong as that for IV administration (P < 0.05). The brain concentrations in rats following IN administration (0.1 mg/kg) were obviously higher than that for IV administration at the same dose. The highest content was observed in the olfactory bulb. These results demonstrated that TS-002 was directly transported from the olfactory region to brain, thereby showing that it may be possible to develop a novel sleep-inducing drug based on nose-to-brain delivery.

Characterization of polymorphs and hydrates of GK-128, a serotonin3 receptor antagonist

The polymorphic and pseudopolymorphic forms of GK-128, a newly developed benzothiochromenone derivative, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy, near-infrared spectrometry and hot-stage microscopy. The intrinsic dissolution rates at various temperatures were measured using the static disk method. GK-128 was found to have at least two hydrates (hemihydrate and monohydrate) and two anhydrates (anhydrate I and anhydrate II). When each form was stored at 25°C with a range of 0 to 97% relative humidity (RH), anhydrate I and anhydrate II were transformed to hemihydrate and monohydrate at above 90% RH and above 70% RH, respectively, while the crystalline forms of hydrates did not change after storage for 4 weeks. Intrinsic dissolution tests indicated that monohydrate was the most stable of these forms, since its dissolution rate was the slowest and no crystal transformation was observed during the dissolution tests. On the basis of the intrinsic dissolution rate of each form and the solubility of monohydrate, the solubilities of other metastable forms were calculated in order to estimate the transition temperature and the heats of dissolution. The transition temperature of hemihydrate and monohydrate was found to be 47°C, and the heats of dissolution of anhydrate I and anhydrate II were 16.5 and 14.7 kJ/mol, respectively.

Assessment of tableting properties using infinitesimal quantities of powdered medicine

In the early stage of new drug candidate development, the available quantity of drug substance is limited. In order to carry out preformulation studies of tablets in this stage, a static compression test was carried out with infinitesimal quantity of powder sample using the new Micro Powder Characterizer device. Aspirin, phenacetin, ascorbic acid and ethenzamide were used as model drugs. In this study, the possibility of use of the Micro Powder Characterizer as a device for estimating the tableting properties of each powder sample such as stress displacement curves, tablet tensile strength, stress relaxation rate, and ejection energy was evaluated. In addition, the differences between the Micro Powder Characterizer and the traditional large-scale compression testing machine were compared. It was found that tableting properties could be estimated by the Micro Powder Characterizer, and that the quantity required to estimate tableting properties was approximately 10 mg per measurement. The results were nearly equal to those obtained with the traditional large-scale compression testing machine. This technique thus appears to be useful for early-stage preformulation studies of new drug candidates.

Assessment of tableting properties using infinitesimal quantities of powder medicine II

Static compression tests were carried out using a new compression machine named the Micro Powder Characterizer. It requires infinitesimal quantities of samples in order to estimate the tableting properties (compressibility and tableting problems, e.g. capping, sticking and so on) of new drug candidates in the early stage of development. A total of six kinds of samples containing aspirin and ascorbic acid were used as model drugs. The estimation of compressibility was mainly performed by analysis of stress displacement curves and measurements of tensile strength. The tableting problems were predicted from maximum ejection stress and ejection energy. It was found from this study that it was possible to estimate the tableting property of the samples using the new compression machine. The Micro Powder Characterizer enables the tableting properties of pharmaceutical powders to be determined using approximately 10 mg per measurement, which indicates that appropriate tablet formulation studies of drug candidate might be promising in the early development stage.

Improvement of dissolution characteristics of 4-t-butyl-2′-car☐ymethoxy-4′-(3-methyl-2-butenyloxy)chalcone by β-cyclodextrin complexation

Abstract The inclusion complexation of 4-t-butyl-2′-car☐ymethoxy-4′-(3-methyl-2-butenyloxy)chalcone (SU-740), a newly developed antiulcer agent, with β-cyclodextrin (β-CyD) in water and in solid state was investigated for the purpose of improving the low aqueous solubility and oral bioavailability. SU-740 formed 1:1 and 1:2 (guest:host) inclusion complexes in water and in the solid state and the 1:1 stability constant was much higher than the 1:2 stability constant. The dissolution rate of SU-740 was significantly improved by the complexation with β-CyD, suggesting the enhanced bioavailability.