Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
62 巻, 11 号
選択された号の論文の14件中1~14を表示しています
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  • Yoshihiro Hayashi, Saori Otoguro, Takahiro Miura, Yoshinori Onuki, Yas ...
    2014 年 62 巻 11 号 p. 1062-1072
    発行日: 2014/11/01
    公開日: 2014/11/01
    [早期公開] 公開日: 2014/08/09
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    A multivariate statistical technique was applied to clarify the causal correlation between variables in the manufacturing process and the residual stress distribution of tablets. Theophylline tablets were prepared according to a Box–Behnken design using the wet granulation method. Water amounts (X1), kneading time (X2), lubricant-mixing time (X3), and compression force (X4) were selected as design variables. The Drucker–Prager cap (DPC) model was selected as the method for modeling the mechanical behavior of pharmaceutical powders. Simulation parameters, such as Young’s modulus, Poisson rate, internal friction angle, plastic deformation parameters, and initial density of the powder, were measured. Multiple regression analysis demonstrated that the simulation parameters were significantly affected by process variables. The constructed DPC models were fed into the analysis using the finite element method (FEM), and the mechanical behavior of pharmaceutical powders during the tableting process was analyzed using the FEM. The results of this analysis revealed that the residual stress distribution of tablets increased with increasing X4. Moreover, an interaction between X2 and X3 also had an effect on shear and the x-axial residual stress of tablets. Bayesian network analysis revealed causal relationships between the process variables, simulation parameters, residual stress distribution, and pharmaceutical responses of tablets. These results demonstrated the potential of the FEM as a tool to help improve our understanding of the residual stress of tablets and to optimize process variables, which not only affect tablet characteristics, but also are risks of causing tableting problems.
  • Takao Komasaka, Hisako Fujimura, Toshiaki Tagawa, Akio Sugiyama, Yasun ...
    2014 年 62 巻 11 号 p. 1073-1082
    発行日: 2014/11/01
    公開日: 2014/11/01
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    The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)–0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher Cmax and 4.4 and 1.6 times higher area under the concentration–time curve from 0–24 h (AUC0–24 h) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.
  • Zizhen Liu, Rui Jiang, Meng Xie, Guanling Xu, Weirui Liu, Xiaohong Wan ...
    2014 年 62 巻 11 号 p. 1083-1091
    発行日: 2014/11/01
    公開日: 2014/11/01
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    Dianbaizhu, a folk medicine from Gaultheria leucocarpa BLUME var. yunnanensis (FRANCH.) T. Z. HSU & R. C. FANG (Ericaceae) used as an antirheumatic, has multiple plant origins and officinal parts. A rapid high-performance liquid chromatography with diode array detector (HPLC-DAD) method was established for the simultaneous determination of the characteristic ingredient methyl benzoate-2-O-β-D-glucopyranosyl(1→2) [O-β-D-xylopyranosyl(1→6)]-O-β-D-glucopyranoside and seven bioactive constituents in eight Gaultheria species. This chromatographic method is precise, accurate, and stable. Kruskal–Wallis analysis, hierarchical cluster analysis, and factor analysis were used to analyze the content of reference compounds in different Gaultheria species and officinal parts. The analyses showed significant differences (p<0.05) in Gaultheria species but few differences (p>0.05) in their medicinal parts. G. leucocarpa var. yunnanensis appeared to the best among the Gaultheria species tested for the treatment of rheumatic diseases. Taken together, the results show that this simultaneous quantification of multiple active constituents using HPLC-DAD combined with chemometrics can be reliably applied to evaluate the quality of Dianbaizhu.
  • Yoshinori Saito, Tomomi Mukai, Yuko Iwamoto, Makiko Baba, Koji Takiguc ...
    2014 年 62 巻 11 号 p. 1092-1099
    発行日: 2014/11/01
    公開日: 2014/11/01
    [早期公開] 公開日: 2014/09/10
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    Eight new hydroperoxides and a new enone of germacrane-type sesquiterpenoids were isolated from the aerial parts of eight different samples of Eupatorium heterophyllum DC. (Asteraceae) collected in P. R. China. The structures were determined based on spectroscopic analyses. Seven of the eight samples produced hiyodorilactone A as a major constituent, while one afforded neither hiyodorilactone nor hydroperoxide. The results indicated the presence of diversity within this species.
  • Hai-Bo Wang, Wen Qi, Lin Zhang, Dan Yuan
    2014 年 62 巻 11 号 p. 1100-1109
    発行日: 2014/11/01
    公開日: 2014/11/01
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    An ultra performance liquid chromatography (UPLC) coupled with quadrupole time-of-flight mass spectrometry (Q-TOF/MS) method has been optimized and established for the rapid analysis of the alkaloids in 22 samples originating from five Uncaria (U.) species. The accurate mass measurement of all the protonated molecules and subsequent fragment ions offers higher quality structural information for the interpretation of fragmentation pathways of the various groups of alkaloids. A total of 19 oxindole alkaloids, 16 indole alkaloids and 1 flavone were identified by co-chromatography of the sample extract with authentic standards, comparison of the retention time, characteristic molecular ions and fragment ions, or were tentatively identified by MS/MS determination. Moreover, the method was validated for the simultaneous quantification of the 24 components within 10.5 min. The potential chemical markers were identified for classification of the U. species samples by principal component analysis (PCA) and orthogonal partial least squared discriminant analysis (OPLS-DA). The results demonstrate the similarity and differences in alkaloids among the five U. species, which is helpful for the standardization and quality control of the medical materials of the U. Ramulus Cum Unics (URCU). Furthermore, with multivariate statistical analysis, the determined markers are more definite and useful for chemotaxonomy of the U. genus.
  • Xiaoda Song, Yushun Yang, Jing Zhao, Yangjian Chen
    2014 年 62 巻 11 号 p. 1110-1118
    発行日: 2014/11/01
    公開日: 2014/11/01
    [早期公開] 公開日: 2014/09/05
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    Fatty acid biosynthesis is essential for bacterial survival. β-Ketoacyl–acyl carrier protein (ACP) synthase III (FabH), is a particularly attractive antibacterial target, since it is central to the initiation of fatty acid biosynthesis. Three series of 21 cinnamaldehyde acylhydrazone derivatives, A39, B39, and C39, were synthesized and evaluated for FabH-inhibitory activity. Compound B6 showed the most potent biological activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis (minimum inhibitory concentrations (MICs) values: 1.56–3.13 µg/mL) and was comparable with the positive control. Docking simulation by positioning compound B6 in the FabH structure active site was performed to explore the possible binding model.
  • Chung-Kyu Ryu, Sun Young Oh, Soo Jung Choi, Da Young Kang
    2014 年 62 巻 11 号 p. 1119-1124
    発行日: 2014/11/01
    公開日: 2014/11/01
    [早期公開] 公開日: 2014/09/05
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    2H-[1,2,3]Triazolo[4,5-g]isoquinoline-4,9-diones and 2H-[1,2,3]triazolo[4,5-g]quinoline-4,9-diones were synthesized and tested for in vitro antifungal activity against pathogenic fungi. Many of those synthesized showed potent antifungal activity. Compounds 3a, 3b, 3g, and 3h completely inhibited the growth of all fungal species tested at the MIC level of 0.8–12.5 µg/mL. The results suggest that 2H-[1,2,3]triazolo[4,5-g]isoquinoline-4,9-diones could be antifungal agents.
Notes
  • Yutaka Inoue, Sayuri Sato, Chisa Yamamoto, Mikio Yamasaki, Ikuo Kanamo ...
    2014 年 62 巻 11 号 p. 1125-1130
    発行日: 2014/11/01
    公開日: 2014/11/01
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    The aim of this study, we evaluated a complex between thiourea (TU) and carbamazepine (CBZ) of a poorly soluble drug by using powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR) spectroscopy, X-ray crystallography and the solubility test. PXRD of TU/CBZ=2/1, 1/1, and 1/2 prepared by solvent evaporation (EVP) revealed characteristic diffraction peaks at 2θ=6.7°, 8.8°, 13.5°, and 20.4°, therefore molecular interaction between TU and CBZ presumably occurred. Results of the FT-IR spectroscopy, asymmetric and symmetric NH stretching vibration of TU were shifted to high region by TU/CBZ=2/1, 1/1, and 1/2 EVP. TU/CBZ=2/1 and 1/1 EVP had absorption derived from TU. It was considered that complex were formed by TU/CBZ=1/2. X-Ray crystallography of TU and CBZ revealed a crystal structure with one TU molecule arranged near two CBZ molecules. Molecules of the same type overlap in this layer. When doing a solubility test by using CBZ and samples of EVP, physical mixture and crystals in TU/CBZ=1/2 to confirm the solubility in water of TU/CBZ complex, there is no difference with the CBZ. It considered that the structure of a complex differs from the tunnel structure of inclusion complexes that has been previously reported contribute to result it.
  • Masahiro Sakai, Satoshi Kaneko, Mikio Nakamura, Yasuoki Murakami, Hide ...
    2014 年 62 巻 11 号 p. 1131-1135
    発行日: 2014/11/01
    公開日: 2014/11/01
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    The interaction of mycophenolate mofetil (MMF) with ferrous ions (Fe2+) in the solid state, in water, and in polar organic solvents was investigated using 1H-NMR, 13C-NMR, IR, and UV-visible (Vis) spectroscopies. A red-purple colored substance was formed after grinding solid MMF and FeSO4·7H2O in a mortar. The IR spectrum of taken as a KBr tablet of the colored substance showed a new absorption band at 1651 cm−1. Although the color disappeared when the sample was dissolved in water, it persisted in organic solvents such as MeOH or dimethyl sulfoxide (DMSO). The UV-Vis spectrum of a 0.25 mM MeOH solution of MMF showed a new absorption maximum at 507 nm in the presence of Fe2+ ions, while an aqueous solution of the same mixture showed no significant change from the MMF solution. All the signals in the 13C-NMR spectrum in DMSO-d6 solution were unambiguously assigned. Upon the addition of 0.5 eq. of Fe2+ ions, all the carbon signals except those of the 2-morpholinoethyl group almost disappeared, which clearly indicated that the Fe2+ ions were located far away from the 2-morpholinoethyl groups in the MMF molecules. On the basis of these results, we have concluded that the MMF–Fe2+ complex is actually formed in the solid state as well as in polar organic solvents such as MeOH or DMSO.
  • Ki Hyun Kim, Eunjung Moon, Sang Keun Ha, Won Se Suh, Ho Kyung Kim, Sun ...
    2014 年 62 巻 11 号 p. 1136-1140
    発行日: 2014/11/01
    公開日: 2014/11/01
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    A bioassay-guided fractionation and chemical investigation of the MeOH extract from the twigs of Lindera glauca (SIEB. et ZUCC.) BLUME resulted in the isolation and identification of six lignans (16) including three new lignan derivatives, named linderuca A (1), B (2), and C (3). The structures of the new compounds (13) were determined on the basis of spectroscopic analyses, including two dimensional NMR and circular dichroism (CD) spectroscopy studies. The cytotoxic activities of the isolates (16) were evaluated by determining their inhibitory effects on human tumor cell lines. Compounds 15 showed antiproliferative activities against A549, SK-OV-3, SK-MEL-2, and HCT-15 cell lines with IC50 values of 7.79–29.42 µM. Based on the understanding that inflammation is a crucial cause of tumor progression, we also investigated the anti-inflammatory activities of the isolates (16) in the lipopolysaccharide-stimulated murine microglia BV-2 cell line by measuring nitric oxide (NO) levels. The new lignans (13) significantly inhibited NO production with IC50 values of 12.10, 9.48, and 9.87 µM, respectively, without cytotoxicity.
  • Toshihiro Nohara, Yukio Fujiwara, Rino Kudo, Koki Yamaguchi, Tsuyoshi ...
    2014 年 62 巻 11 号 p. 1141-1145
    発行日: 2014/11/01
    公開日: 2014/11/01
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    In this study, the new stable sulfur-containing compounds onionins A2 (1) and A3 (2) were isolated from the acetone extracts of the bulbs of Allium cepa L. and identified as the stereoisomers of onionin A1 discovered in our previous study. Their chemical structures, 3,4-dimethyl-5-(1E-propenyl)-tetrahydrothiophene-2-sulfenic acid-S-oxides, were characterized using various spectroscopic techniques. In addition, 1 and 2 together with onionin A1 were successfully isolated from the leaves of the Welsh onion, Allium fistulosum L. The onion-extracted fractions showed good potential to inhibit the polarization of M2 activated macrophages, indicating their possible ability to inhibit tumor cell proliferation.
  • Munetaka Kunishima, Daiki Kato, Shuichi Nakanishi, Masanori Kitamura, ...
    2014 年 62 巻 11 号 p. 1146-1150
    発行日: 2014/11/01
    公開日: 2014/11/01
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    We studied the specific labeling of streptavidin using the modular method for affinity labeling (MoAL) that we developed based on a catalytic amide-forming reaction using 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and a tertiary amine catalyst. The primary structures of avidin and streptavidin are significantly different from each other, and streptavidin does not possess an acidic amino acid equivalent to Asp108 of avidin, which is the target acidic amino acid that was labeled using MoAL. However, using biotinylated modular ligand catalysts (MLC) originally designed for labeling avidin, the labeling of streptavidin was found to successfully proceed at Glu51, which is located in a different region. The present study indicates that MoAL is readily applicable to protein labeling without a precise design for MLC. The most important factor for the design of MLC is to ensure that the linker is of sufficient length to connect the ligands to a catalytic site.
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