Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 63, Issue 5
Displaying 1-12 of 12 articles from this issue
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Regular Articles
  • Physical Characterization of meso-Erythritol as a Crystalline Bulking Agent for Freeze-Dried Formulations
    Kahori Fujii, Ken-ichi Izutsu, Migiwa Kume, Takeshi Yoshino, Yasuo Yos ...
    2015 Volume 63 Issue 5 Pages 311-317
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c14-00692
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    The purpose of this study was to identify and characterize new crystalline bulking agents applicable to freeze-dried pharmaceuticals. Thermal analysis of heat-melt sugar and sugar alcohol solids as well as their frozen aqueous solutions showed high crystallization propensity of meso-erythritol and D-mannitol. Experimental freeze-drying of the aqueous meso-erythritol solutions after their cooling by two different methods (shelf-ramp cooling and immersion of vials into liquid nitrogen) resulted in cylindrical crystalline solids that varied in appearance and microscopic structure. Powder X-ray diffraction and thermal analysis indicated different crystallization processes of meso-erythritol depending on the extent of cooling. Cooling of the frozen meso-erythritol solutions at temperatures lower than their Tg′ (glass transition temperature of maximally freeze-concentrated phase, −59.7°C) induced a greater number of nuclei in the highly concentrated solute phase. Growth of multiple meso-erythritol anhydride crystals at around −40°C explains the powder-like fine surface texture of the solids dried after their immersion in liquid nitrogen. Contrarily, shelf-ramp cooling of the frozen solution down to −40°C induced an extensive growth of the solute crystal from a small number of nuclei, leading to scale-like patterns in the dried solids. An early transition of the freezing step into primary drying induced collapse of the non-crystalline region in the cakes. Appropriate process control should enable the use of meso-erythritol as an alternative crystalline bulking agent in freeze-dried formulations.
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  • Formation of the Ternary Inclusion Complex of Limaprost with α- and β-Cyclodextrins in Aqueous Solution
    Yasuo Inoue, Noboru Sekiya, Masanobu Yamamoto, Daisuke Iohara, Fumitos ...
    2015 Volume 63 Issue 5 Pages 318-325
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c14-00733
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    The inclusion mode of Limaprost in the presence of α- and β-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of β-CD in the solid state. The inclusion sites of α- and β-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and β-CDs, displacements in 13C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and β-CDs. In two-dimensional (2D) 1H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and β-CDs, suggesting that PGF2α interacts with α- and β-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ2-PGA1 (11-deoxy-Δ10) and 17S,20-dimethyl-trans-Δ2-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ10, while β-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and β-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/β-CD complex.
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  • Synthesis and Biological Evaluation of Piperic Acid Amides as Free Radical Scavengers and α-Glucosidase Inhibitors
    Koichi Takao, Takaki Miyashiro, Yoshiaki Sugita
    2015 Volume 63 Issue 5 Pages 326-333
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c14-00874
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    A series of piperic acid amides (4–24, 29, 30) were synthesized and their 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging and α-glucosidase inhibitory activities were evaluated. Among the synthesized compounds, the amides 11, 13 and 15, which contain o-methoxyphenol, catechol or 5-hydroxyindole moieties, showed potent DPPH free radical scavenging activity (11: EC50 140 µM; 13: EC50 28 µM; 15: EC50 20 µM). The amides 10, 18 and 23 showed higher inhibitory activity of α-glucosidase (10: IC50 21 µM; 18: IC50 21 µM; 23: IC50 12 µM). These data suggest that the hydrophobicity of the conjugated amines is an important determinant of α-glucosidase inhibitory activity. In addition, the amides 13 and 15 showed both potent DPPH free radical scavenging activity and α-glucosidase inhibitory activity (13: IC50 46 µM; 15: IC50 46 µM). This is the first report identifying the DPPH free radical scavenging and α-glucosidase inhibitory activities of piperic acid amides and suggests that these amides may serve as lead compounds for the development of novel α-glucosidase inhibitors with antioxidant activity.
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  • Glyceryl Monooleyl Ether-Based Liquid Crystalline Nanoparticles as a Transdermal Delivery System of Flurbiprofen: Characterization and in Vitro Transport
    Tomonobu Uchino, Akiko Murata, Yasunori Miyazaki, Toshihiko Oka, Yoshi ...
    2015 Volume 63 Issue 5 Pages 334-340
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00029
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    Liquid crystalline nanoparticles (LCNs) were prepared using glyceryl monooleyl ether (GME) by the modified film rehydration method. Hydrogenated lecithin (HL), 1,3-butylene glycol (1,3-BG), and Poloxamer 407 were used as additives. The prepared LCN formulations were evaluated based on particle size, small-angle X-ray diffraction (SAXS) analysis, 1H- and 19F-NMR spectra, and in vitro skin permeation across Yucatan micropig skin. The composition (weight percent) of the LCN formulations were GME–HL–1,3-BG (4 : 1 : 15), 4% GME-based LCN and GME–HL–1,3-BG (8 : 1 : 15), 8% GME-based LCN and their mean particle sizes were 130–175 nm. Flurbiprofen 5 and 10 mg was loaded into 4% GME-based LCN and 8% GME-based LCN systems, respectively. The results of SAXS and NMR suggested that both flurbiprofen-loaded formulations consist of particles with reverse type hexagonal phase (formation of hexosome) and flurbiprofen molecules were localized in the lipid domain through interaction of flurbiprofen with the lipid components. Flurbiprofen transport from the LCN systems across the Yucatan micropig skin was increased compared to flurbiprofen in citric buffer (pH=3.0). The 8% GME-based LCN systems was superior to the 4% GME-based LCN for flurbiprofen transport. Since the internal hexagonal phase in the 8% GME-based LCN systems had a higher degree of order compared to the 4% GME-based LCN in SAXS patterns, the 8% GME-based LCN system had a larger surface area, which might influence flurbiprofen permeation. These results indicated that the GME-based LCN system is effective in improving the skin permeation of flurbiprofen across the skin.
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  • Synthesis and Evaluation of 1H-Pyrrolo[2,3-b]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3
    Yutaka Nakajima, Takashi Tojo, Masataka Morita, Keiko Hatanaka, Shohei ...
    2015 Volume 63 Issue 5 Pages 341-353
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    Advance online publication: March 14, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00036
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    Janus kinases (JAKs) have been known to play crucial roles in modulating a number of inflammatory and immune mediators. Here, we describe a series of 1H-pyrrolo[2,3-b]pyridine derivatives as novel immunomodulators targeting JAK3 for use in treating immune diseases such as organ transplantation. In the chemical modification of compound 6, the introduction of a carbamoyl group to the C5-position and substitution of a cyclohexylamino group at the C4-position of the 1H-pyrrolo[2,3-b]pyridine ring led to a large increase in JAK3 inhibitory activity. Compound 14c was identified as a potent, moderately selective JAK3 inhibitor, and the immunomodulating effect of 14c on interleukin-2-stimulated T cell proliferation was shown. Docking calculations and WaterMap analysis of the 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives were conducted to confirm the substituent effects on JAK3 inhibitory activity.
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  • Development of Gummi Drugs of Aripiprazole as Hospital Formulations
    Shinya Uchida, Shogo Hiraoka, Noriyuki Namiki
    2015 Volume 63 Issue 5 Pages 354-360
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00038
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    About half of patients with schizophrenia have poor adherence to taking medication, so many have recurrence, therefore, providing formulations that enable patients to continue their medication without interruption is important. We aimed to develop a gummi drug that contains aripiprazole (which can reduce schizophrenia and manic symptoms in bipolar disorder). We were able to develop gummi drugs (OD-G, PW-G and OS-G) using three commercially available aripiprazole products (Abilify® orally disintegrating tablets, powder formulation, and oral solutions, respectively) as hospital formulations. Furthermore, we developed improved OD-G (iOD-G), which contained high aripiprazole content. Pharmaceutical characteristics of iOD-G were demonstrated to be suitable for hospital formulations, and iOD-G could be stored for ≤1 month. No significant differences in the dissolution and pharmacokinetics of divided portions of iOD-G were observed when compared with commercially available aripiprazole products. This study confirmed that new dosage forms of aripiprazole in gummi drugs can be developed as hospital formulations, which will contribute to improve medication adherence of patients.
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  • Ginsenoside Rg3 Bile Salt-Phosphatidylcholine-Based Mixed Micelles: Design, Characterization, and Evaluation
    Xiu Yu, Huan Xu, Meina Hu, Xiaojiao Luan, Kaiqian Wang, Yuanshan Fu, D ...
    2015 Volume 63 Issue 5 Pages 361-368
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00045
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    20(R)-Ginsenoside Rg3 (G-Rg3) has good inhibition of tumor angiogenesis and anti-tumor effect. However, its poor aqueous solubility and liposolubility are not ideal for clinical applications. In this study, a G-Rg3 bile salt-phosphatidylcholine-based mixed micelle system (BS-PC-MMS) was prepared. The optimization of G-Rg3 BS-PC-MMS was carried out using response surface methodology based on a central composite design. The encapsulation efficiency (EE) and light transmission (LT) of the optimized formulation were 90.69±2.54% and 99.10±3.12%, respectively. The average particle size of micelles was 20 nm. To increase the stability of G-Rg3 BS-PC-MMS, the lyophilized formulation of micelles was prepared. The G-Rg3 BS-PC-MMS did not produce hemolysis of erythrocytes within a certain concentration range and exhibited a good inhibition of tumor cells. The chick embryo chorioallantoic membrane assay results showed that the G-Rg3 BS-PC-MMS significantly inhibited angiogenesis. The G-Rg3 BS-PC-MMS is thus shown to be a safe, stable, and promising drug delivery system.
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  • Synthesis and Anticancer Evaluation of 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles, 1,2,4-Triazoles and Mannich Bases
    Nadia Youssef Megally Abdo, Mona Monir Kamel
    2015 Volume 63 Issue 5 Pages 369-376
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00059
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    A series of 5-(pyridin-4-yl)-N-substituted-1,3,4-oxadiazol-2-amines (3a–d), 5-(pyridin-4-yl)-N-substituted-1,3,4-thiadiazol-2-amines (4a–d) and 5-(pyridin-4-yl)-4-substituted-1,2,4-triazole-3-thiones (5a–d) were obtained by the cyclization of hydrazinecarbothioamide derivatives 2a–d derived from isonicotinic acid hydrazide. Aminoalkylation of compounds 5a–d with formaldehyde and various secondary amines furnished the Mannich bases 6a–p. The structures of the newly synthesized compounds were confirmed on the basis of their spectral data and elemental analyses. All the compounds were screened for their in vitro anticancer activity against six human cancer cell lines and normal fibroblast cells. Sixteen of the tested compounds exhibited significant cytotoxicity against most cell lines. Among these derivatives, the Mannich bases 6j, 6m and 6p were found to exhibit the most potent activity. The Mannich base 6m showed more potent cytotoxic activity against gastric cancer NUGC (IC50=0.021 µM) than the standard CHS 828 (IC50=0.025 µM). Normal fibroblast cells WI38 were affected to a much lesser extent (IC50>10 µM).
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  • Magnetic Resonance Imaging of the Phase Separation in Mixed Preparations of Moisturizing Cream and Steroid Ointment after Centrifugation
    Yoshinori Onuki, Chiaki Funatani, Takashi Yokawa, Yoshihisa Yamamoto, ...
    2015 Volume 63 Issue 5 Pages 377-383
    Published: May 01, 2015
    Released on J-STAGE: May 01, 2015
    DOIhttps://doi.org/10.1248/cpb.c15-00088
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    A mixed preparation consisting of a water-in-oil emulsion-type moisturizing cream and a steroid ointment is frequently prescribed for the treatment of atopic dermatitis. We have investigated the compatibility of moisturizing creams and ointments because there are concerns regarding the physical stability of these mixed preparations. The key technology used in this study was magnetic resonance imaging (MRI). A commercial moisturizing cream and white petrolatum or clobetasone butyrate (CLB) ointment samples were mixed in a weight ratio of 1 : 1. A centrifugation test protocol (20000×g for 3 min) was implemented to accelerate the destabilization processes in the samples. After centrifugation, the mixed preparations separated into three distinct layers (upper, middle, and lower), while no phase separation was observed using moisturizing cream alone. The phase separation was monitored using chemical shift selective images of water and oil and quantitative T2 maps. In addition, MR and near-infrared spectroscopy were employed for component analysis of each phase-separated layer. Collectively, it was confirmed that the lower layer contained water, oils, and organic solvent, while the upper and middle layers were composed solely of oils. Furthermore, this study investigated the distribution of CLB in the phase-separated samples and showed that a heterogeneous distribution existed. From our results, it was confirmed that the mixed preparation became unstable because of the incompatibility of the moisturizing cream and ointment.
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