Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
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Volume 49, Issue 10
Displaying 1-33 of 33 articles from this issue
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Regular Articles
  • Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitor
    Hidemitsu NISHIDA, Yutaka MiYAZAKI, Yoshihiro KITAMURA, Masayuki OHASH ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1237-1244
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1237
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    Intravascular clot formation is an important factor in a number of cardiovascular diseases. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), which is a key enzyme in coagulation cascade responsible for the generation of thrombin by limited proteolysis of its zymogen, prothrombin. We have investigated 1-arylsulfonyl-3-piperazinone derivatives, containing a 4-(piperidino)pyridine group in place of guanidino and/or amidino groups, and discovered compound M55113 (30a: 4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-pyridinyl)-4-piperidinyl]-methyl]piperazinone), as a potent inhibitor of FXa (IC50=0.06 μM) with high selectivity for FXa over trypsin and thrombin.
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  • Thermal Behaviour of Diclofenac Sodium: Decomposition and Melting Characteristics
    Petar TUDJA, M. Zahirul I. KHAN, Ernest MEŠTROVIC, Michaela HOR ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1245-1250
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1245
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    The thermal behaviour and melting characteristics of diclofenac sodium were investigated using various instrumental techniques—differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier-transform infrared (FT-IR) spectroscopy and thin layer chromatography (TLC). DSC analysis of diclofenac sodium performed under dynamic flow of either synthetic air or helium or nitrogen did not produce any sharp endothermic peak characteristic of melting peak of a pure substance. Both the rate of scanning of the sample and the environmental atmospheric condition significantly affected the thermographic profile of diclofenac sodium. An exothermic peak prior to an endothermic peak corresponding to melting of the substance appeared when heated under dynamic flow of synthetic air suggesting oxidation (decomposition) of diclofenac sodium before reaching its melting point. In fact, at a scanning rate of 1 °C/min only the exothermic peak appeared in the thermogram, suggesting complete decomposition prior to melting under the dynamic flow of synthetic air. DSC, FT-IR and TLC data obtained from samples heated under the dynamic flow of either helium or nitrogen revealed formation of a related compound, 1-(2,6-dichlorophenyl)-indolin-2-one, an indol-cyclic amide, as a result of an intramolecular cyclization reaction during the heating process. TGA data demonstrated a loss of 11.4—20.2% of the mass of diclofenac sodium when heated under various environmental conditions, and also supported the oxidative nature of degraded product(s) when the thermal process occurred slowly under a dynamic flow of synthetic air.
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  • Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: β-Cyclodextrin and Tolbutamide: Hydroxypropyl-β-Cyclodextrin Complexes
    Francisco José Baptista VEIGA, Catarina Marques FERNANDES, Rui ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1251-1256
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1251
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    A structural study of the inclusion compound of tolbutamide (TBM) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) was attempted by means of 1H-nuclear magnetic resonance (1H-NMR) experiments and computer molecular modelling. To establish the stoichiometry and stability constant of the β-CD:TBM complex, the continuous variation method was used. The presence of true inclusion complexes between TBM and β-CD or HP-β-CD in solution was clearly evidenced by the 1H-NMR technique. Changes in chemical shifts of H-3 and H-5 protons, located inside the CD cavity, associated with variations in the chemical shifts of TBM aromatic protons provided clear evidence of inclusion complexation, suggesting that the phenyl moiety of the drug molecule was included in the hydrophobic cavity of CDs. This view was further supported by the observation of intermolecular NOEs between TBM and β-CD and by the aid of a molecular modelling program, which established the most probable structure of the complex. The molecular graphic computation confirmed that the minimum energy, positioning TBM relative to β-CD, occurs when the aromatic ring of TBM is included within the β-CD cavity by its wider side, leaving the aliphatic chain externally, which is in good agreement with the results of 1H-NMR studies.
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  • Cathodic Adsorptive Stripping Square-Wave Voltammetry of the Anti-inflammatory Drug Meloxicam
    Abd-Elgawad RADI, Mohamed GHONEIM, Amr BELTAGI
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1257-1260
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1257
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    The adsorptive behavior of the anti-inflammatory drug meloxicam was studied by cyclic, differentia-pulse and square-wave voltammetry on a hanging mercury drop electrode (HMDE). The drug was accumulated at HMDE and a well-defined stripping peak current was obtained at −1.42 V vs. Ag/AgCl (saturated KCl) electrode in acetate buffer solution (pH 5.0). A voltammetric procedure was developed for the determination of meloxicam using square-wave cathodic adsorptive stripping voltammetry (SW-CASV). The optimum working conditions for the determination of the drug were established. The analysis of meloxicam in human plasma was carried out satisfactorily.
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  • Preparation and Characterization of Insulin-Loaded Acrylic Hydrogels Containing Absorption Enhancers
    Takahiro UCHIDA, Yuka TOIDA, Sadako SAKAKIBARA, Yohko MIYANAGA, Hiromi ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1261-1266
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1261
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    The objectives of this study were to prepare insulin-loaded acrylic hydrogel formulations containing various absorption enhancers, to perform in vitro and in vivo characterization of these formulations, and to evaluate the factors which affecting insulin availability on rectal delivery of insulin using this hydrogel system. The acrylic block copolymer of methacrylic acid and methacrylate, Eudispert®, was used to make the hydrogel formulations. As absorption enhancers, 2,6-di-O-methyl-β-cyclodextrin (DM-β-CyD), lauric acid (C12), or the sodium salt of C12 (C12Na), were incorporated into the hydrogels. In an in vitro release test, the release rate of insulin from the hydrogels decreased as the polymer concentration of the hydrogel increased. The addition of C12Na to the hydrogel further increased the insulin release rate, which was greater at higher concentrations of the enhancer. A portion of the C12Na was found to remain bound to the acrylic polymer in dissolution medium. Serum insulin levels were determined at various time points after the administration of insulin solution or insulin-loaded (50 units/kg body weight) Eudispert® hydrogels containing 5% (w/w) of C12, C12Na, or DM-β-CyD to in situ loops in various regions of the rat intestine. The most effective enhancement of insulin release was observed with formulations containing C12Na. The bioavailability of insulin from the hydrogels was lower than that from the insulin solutions. Hydrogel formulations containing 7% or 10% Eudispert® remained in the rectum for 5 h after rectal administration. However, the 5% (w/w) C12Na solution stained with Evan’s-blue had diffused out and the dye had reached the upper intestinal tract within 2 h. Finally, the rectal administration of insulin-loaded hydrogels, containing 4%, 7%, or 10% (w/w) Eudispert® and 5% (w/w) of enhancer (C12, C12Na, or DM-β-CyD) to normal rats was shown to decrease serum glucose concentrations. The greatest effect was found with insulin-loaded 7% (Eudispert®) hydrogel containing C12Na which having cosiderable large insulin release rate and bioadhesive characteristics.
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  • In Vitro Release of Metoclopramide from Hydrophobic Matrix Tablets. Influence of Hydrodynamic Conditions on Kinetic Release Parameters
    Paloma FRUTOS, Cristina PABÓN, José L. LASTRES, Gloria F ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1267-1271
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1267
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    There has been growing interest in the subject of drug delivery and the design and evaluation of controlled-release systems. The simplest way to control the release of an active agent is to disperse it in an inert polymeric matrix. Controlled-release systems are of interest because they are technologically simple, relatively cheap, and practically unaffected by physiological changes. In this study, a new matrix system was formed by an active principle, metoclopramide hydrochloride, scattered into a biocompatible hydrophobic polymerical mesh, polyamide 12, to achieve sustained and controlled delivery of metoclopramide hydrochloride. This research was conducted to investigate the in vitro drug release behavior from these new inert polymeric matrix tablets. The drug release process was investigated both experimentally and by means of mathematical models. Different models were applied for the evaluation of drug release data. On the basis of our results, a biexponential equation was proposed, Q=Q1fast(1−e−Kfastt)+Q2slow(1−e−Kslowt), in an attempt to explain the mechanism responsible for the release process. Additionally, the influence of the experimental conditions of the dissolution devices, such as rate of flow and pH of dissolution medium, on the parameters that characterize the release mechanism was studied, and it was found that the main factor was the hydrodynamic condition of rate of flow.
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  • Design and Synthesis of Carboxylate Inhibitors for Matrix Metalloproteinases
    Tetsunori FUJISAWA, Shin-ichi KATAKURA, Shinjiro ODAKE, Yasuo MORITA, ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1272-1279
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1272
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    A series of carboxylate compounds were prepared from Nα-substituted 2,3-diaminopropionic acid and were tested for efficacy as matrix metalloproteinase (MMP) inhibitors. During modeling of the initial compound 10a, we utilized three-dimensional structure modeling software (InsightII/Discover Ver. 2.98). Some of the prepared carboxylate derivatives, such as carbamate compounds (12c, d, 22) and sulfonamide compounds (14b, c), proved to be effective MMP-1 inhibitors (with IC50 values of a 10-6 M order), depending on the substituent at the Nα-position of 2,3-diaminopropionic acid. Some of them were also evaluated for inhibition of stromelysin-1 (MMP-3), and the sulfonamide compound 14c exceeded the lead compound 5b in its MMP-3 inhibitory potency. For the carbamate compounds, we investigated the minimum molecular size at which the MMP-1 inhibitory potency was maintained, and found that this was P3−P'1 compound 10b.
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  • Pyrrolo[2,3-d]pyrimidine Thymidylate Synthase Inhibitors: Design and Synthesis of One-Carbon Bridge Derivatives
    Kazuyoshi ASO, Yumi IMAI, Koichi YUKISHIGE, Koichiro OOTSU, Hiroshi AK ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1280-1287
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1280
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    A series of novel pyrrolo[2,3-d]pyrimidine derivatives was designed and synthesized as thymidylate synthase (TS) inhibitors. Molecular design was performed on the human TS complex model built on the basis of the reported structure of TS-deoxyuridinemonophosphate (dUMP)-CB3717 ternary complex. From a docking study, we expected that a one-carbon bridge between pyrrolo[2,3-d]pyrimidine and an aromatic ring was suitable. Moreover, we found that the bridge carbon could be replaced with an alkyl group to fill out the unoccupied space. Based on this design, we synthesized five pyrrolo[2,3-d]pyrimidine derivatives with one-carbon bridge and evaluated their TS inhibitory activities. All synthesized compounds inhibited TS more potently than compound 2 (LY231514), and the C8-ethyl analogue (7) showed a remarkable inhibitory activity against TS (IC50=0.017 μM).
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  • Studies on Anthracenes. 3. Synthesis, Lipid Peroxidation and Cytotoxic Evaluation of 10-Substituted 1,5-Dichloro-9(10H)-anthracenone Derivatives
    Hsu-Shan HUANG, Pen-Yuan LIN, Jing-Min HWANG, Chi-Wei TAO, Hsien-Chin ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1288-1291
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1288
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    The synthesis of a series of 1,5-dichloro-9(10H)-anthracenones bearing O-linked and N-linked substituents in the 10-position are described. Previous studies have shown that 9-acyloxy 1,5-dichloroanthracenes and 9-acyloxy 1,8-dichloroanthracenes displayed a potential cytotoxic effect. These results have encouraged us in further investigation of potential anthracenone derivatives. Therefore, a series of 10-substituted 1,8-dichloro-9(10H)-anthracenone derivatives were synthesized. These compounds were evaluated for their ability to inhibit the growth of human oral epidermoid carcinoma cells (KB cell line), human cervical carcinoma cells of ME 180 (GBM 8401) and Chinese hamster ovary (CHO) cells, respectively. Compounds 3c and 4c of this series compare favorably in the KB cellular assay with mitoxantrone. Compound 4c showed combined inhibitory action against KB, GBM and CHO cell growth, respectively. In addition, redox property of the compounds for the inhibition of lipid peroxidation in model membranes was determined. Compounds 4b and 4d exhibited stronger antioxidant activity than ascorbic acid, (+)-α-tocopherol and mitoxantrone, respectively.
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  • Alkaloids from the Leaves of Cryptocarya chinensis HEMSL.
    Fu-Wen LIN, Pei-Lin WU, Tian-Shung WU
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1292-1294
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1292
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    Investigation of the leaves of Cryptocarya chinensis resulted in the isolation of three new alkaloids, named (−)-isocaryachine-N-oxide, isoboldine-β-N-oxide, and 1-hydroxycryprochine, together with seven known compounds. Their structures were elucidated by spectral analysis. The structures of (−)-isocaryachine-N-oxide and 1-hydroxycryprochine were further confirmed by X-ray techniques.
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  • Five New Peltogynoids from Underground Parts of Iris bungei: A Mongolian Medicinal Plant
    Muhammad Iqbal CHOUDHARY, Muhammad NUR-E-ALAM, Farzana AKHTAR, Shakil ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1295-1298
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1295
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    Five new peltogynoids, irisoids A—E (1—5), have been isolated from the underground parts of Iris bungei. The structures of the new compounds were established on the basis of spectroscopic methods and were found to be 1,8,10-trihydroxy-9-methoxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (1), 1,8-dihydroxy-9,10-dimethoxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (2), 1,10-dihydroxy-8,9-dimethoxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (3), 1,8-dihydroxy-9,10-methylenedioxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (4), and 1,8,11-trihydroxy-9,10-methylenedioxy-[1]benzopyrano-[3,2-c][2]-benzopyran-7(5H)-one (5). The structures of irisoid B (2) was established unambiguously by X-ray diffraction study.
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  • Structural and Thermodynamic Behavior of Eukaryotic Initiation Factor 4E in Supramolecular Formation with 4E-Binding Protein 1 and mRNA Cap Analogue, Studied by Spectroscopic Methods
    Xu SHEN, Koji TOMOO, Susumu UCHIYAMA, Yuji KOBAYASHI, Toshimasa ISHIDA
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1299-1303
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1299
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    The structural and thermodynamic behavior of the complex formation of eIF4E with either or both mRNA cap analogue (m7GTP, m7GpppA, or m7GpppG) and 4EBP1 has been investigated by spectroscopic measurements. Although the circular dichroism (CD) spectrum of eIF4E was little affected by the association with any cap analogue, the association constant of eIF4E with m7GpppA/G, estimated from the fluorescence quenching, was about 10 times larger than that with m7GTP. The van’t Hoff analyses showed that the m7GpppA/G binding is enthalpy-driven with a large negative ΔH°, and this is in contrast with the entropy-driven binding of m7GTP, where the positive ΔS° is large enough to overcome an increase of ΔH°. This different behavior obviously originates in the interaction of the second nucleotide in m7GpppA with eIF4E, suggesting the importance of the nucleotide sequence linked to the m7Gppp terminal moiety, in addition to the specific interaction with the m7G base, for the recognition of mRNA cap structure by eIF4E. On the other hand, the CD spectra indicated that the binding of 4EBP1, an endogenous eIF4E-regulatory protein without having any defined secondary structure, shifted the m7GTP- or m7GpppA/G-bound eIF4E to an irregular structure, although such a structural change was not observed for eIF4E alone. The association constant of 4EBP1 with m7GTP- or m7GpppA/G-bound eIF4E was by two orders of magnitude larger than that with eIF4E alone. These results suggest the close interrelation in the supramolecular formation of 4EBP-eIF4E-mRNA cap structure.
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  • 1-Oxo-2-hydroxy-1,2-dihydroacronycine: A Useful Synthon in the Acronycine Series for the Introduction of Amino Substituents at 6-Position and for the Conversion into Isopropylfuroacridones
    Prokopios MAGIATIS, Sofia MITAKU, Alexios-Leandros SKALTSOUNIS, Fran&c ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1304-1307
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1304
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    Thermic aromatic nucleophilic displacement of the methoxy group at C-6 of (±)-1-oxo-2-hydroxy-1,2-dihydroacronycine (2) by an amine is a reaction that gives a facile entry to acronycine derivatives bearing an amino substituent at this position. The introduction of the amino substituents was confirmed with a long-range 1H-15N correlation NMR spectrum at natural abundance. Under basic conditions, compound 2 can also be rearranged to the corresponding isopropylfuroacridone 12, in 80% yield.
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  • Stereochemistry of New Nitrogen Containing Heterocyclic Aldehyde. VII. Potentiometric, Conductometric and Thermodynamic Studies of Novel Quinoline Azodyes and Their Metal Complexes with Some Transition Metals
    Adel Zaki EL-SONBATI, Ashraf Abdel-Aziz EL-BINDARY, Abdel-Ghany Farag ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1308-1313
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1308
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    A novel series of quinoline azodyes (5-(4'-derivatives phenyldiazo)-8-hydroxy-7-quinolinecarboxaldehyde)) (HL1-HL5) has been prepared and characterized by elemental analyses, 1H-NMR and IR spectra. The IR spectral data indicate that the compounds can exist in two resonance structures. Proton-ligand dissociation constants of quinoline azodyes and their subsituted derivatives, and metal-ligand stability constants of their complexes with bivalent (Mn2+, Co2+, Ni2+, Cu2+) metal ions have been determined potentiometrically in 0.1 M KCl and 40% (v/v) dimethylformamide (DMF)-water mixture. The influence of substituents on the dissociation and stability constants was examined on the basis of the electron repelling property of the substituent. The order of the stability constants of the formed complexes was found to be Mn2+<Co2+<Ni2+<Cu2+. The effect of temperature was studied and the corresponding thermodynamic parameters (ΔG, ΔH, ΔS) were derived and discussed. The stoichiometries of these complexes were determined conductometrically and indicated the formation of 1:1 and 1:2 (metal:ligand) complexes was indicated.
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  • New μ-Opioid Receptor Agonists with Piperazine Moiety
    Teruo KOMOTO, Tomomi OKADA, Susumu SATO, Yasuhiro NIINO, Tetsuo OKA, T ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1314-1320
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1314
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    New μ-opioid receptor (MOR) agonists containing piperazine and homopiperazine moieties in the structures were synthesized and their affinities to and agonist potencies on MOR were evaluated. Among the synthesized compounds, 4-[4-(2-methoxyphenyl)piperazin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide (20Aa) showed the highest affinity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells, and the highest agonist potency on the MOR in isolated guinea-pig ileum preparation.
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  • Characterization of Polymorphs of a Novel Quinolinone Derivative, TA-270 (4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone)
    Nobuyuki KIMURA, Hiroyuki FUKUI, Hidetsugu TAKAGAKI, Etsuo YONEMOCHI, ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1321-1325
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1321
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    The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 °C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The β- and δ-forms were transformed into the α-form by heating. The amorphous form was also easily crystallized into α-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis.
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  • Evaluation of Flow Properties of Dry Powder Inhalation of Salbutamol Sulfate with Lactose Carrier
    Kotaro IIDA, Youhei HAYAKAWA, Hirokazu OKAMOTO, Kazumi DANJO, Hans LEU ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1326-1330
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1326
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    The effects of the flow and packing properties of a drug/carrier powder mixture on emission of drug adhering to the carrier from capsules and inhalation devices were investigated. Model powder mixtures were designed consisting of lactose carriers with different particle shapes were prepared by surface treatment and micronized salbutamol sulfate. These powder mixtures were aerosolized by a Spinhaler®, and in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The flow properties of the mixed powders were evaluated by the Carr’s flowability index (FI) and Hausner’s ratio (HR). The packing properties of the mixed powders were determined employing the tapping method. Compared with the powder mixed with the untreated lactose carrier, the FI, HR, and the constant K in Kawakita’s equation of the powder mixture prepared using the surface-treated lactose carrier were significantly different, showing that the flow and packing properties of the drug/carrier powder mixture were improved. Using this surface-treated system, the handling of the powder mixture when packing into capsules is improved, which is desirable for handling dry powder inhalants. The fraction (%) of drug emitted from capsules and devices (EM) and the FI of the powder mixture were correlated. As the flow properties improved, the outflow of the powder mixture from capsules and devices became easier, and emission of drug adhering on the carrier from capsules and devices improved. Improvement of the inhalation process, such as the drug particles emitted from the inhalation system, is valuable for increasing inhalation properties of dry powder ihalation.
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  • Emulsifying Potency of New Amino Acid-Type Surfactant (II): Stable Water-in-Oil (W/O) Emulsions Containing 85 wt% Inner Water Phase
    Shoko YOKOYAMA, Junichi KOUCHI, Tatsuru TABOHASHI, Fuminori HARUSAWA, ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1331-1335
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1331
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    The ternary phase diagram for N-[3-lauryloxy-2-hydroxypropyl]-L-arginine L-glutamate (C12HEA-Glu), a new amino acid-type surfactant, /oleic acid (OA)/water system was established. The liquid crystal and gel complex formations between C12HEA-Glu and OA were applied to a preparation of water-in-oil (W/O) emulsions. Stable W/O emulsions containing liquid paraffin (LP) as the oil and a mixture of C12 HEA-Glu and OA as the emulsifier were formed. The preparation of stable W/O emulsions containing 85 wt% water phase was also possible, in which water droplets would be polygonally transformed and closely packed, since the maximum percentage of inner phase is 74% assuming uniformly spherical droplets. Water droplets would be taken into the liquid crystalline phase (or the gel complex) and the immovable water droplets would stabilize the W/O emulsion system. The viscosity of emulsions abruptly increased above the 75 wt% water phase (dispersed phase). The stability of W/O emulsions with a lower weight ratio of OA to C12HEA-Glu and a higher ratio of water phase was greater. This unusual phenomenon may be related to the formation of a liquid crystalline phase between C12HEA-Glu and OA, and the stability of the liquid crystal at a lower ratio of oil (continuous phase). W/O and oil-in-water (O/W) emulsions containing LP were selectively prepared using a mixture of C12HEA-Glu and OA since the desirable hydrophile-lipophile balance (HLB) number for the emulsification was obtainable by mixing the two emulsifiers.
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  • A New Method for Evaluating the Bitterness of Medicines by Semi-continuous Measurement of Adsorption Using a Taste Sensor
    Takahiro UCHIDA, Yoshikazu KOBAYASHI, Yohko MIYANAGA, Rieko TOUKUBO, H ...
    Article type: scientific monograph
    2001 Volume 49 Issue 10 Pages 1336-1339
    Published: 2001
    Released on J-STAGE: June 28, 2002
    DOIhttps://doi.org/10.1248/cpb.49.1336
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    We describe a new method for the evaluation of the bitterness of medicines by semi-continuous measurement of adsorption using a multichannel taste sensor or ‘electric tongue’. The bitterness of 10 basic medicines was evaluated by both the taste sensor and in human gustatory sensation tests with 11 volunteers. The sensor part of the taste sensor consists of eight electrodes made of lipid/polymer membranes. Three variables were obtained from the taste sensor data: sensor output (S), the change of membrane potential caused by adsorption, corresponding to aftertaste (C), and the ratio C/S. These variables were used to predict an estimated bitterness score in multiple regression analysis. Semi-continuous measurement of C (every 30 s up to 150 s) was adopted as an additional explanatory variable, and the attenuation rate of C was defined as C'. These data were also subjected to multiple regression analysis. The correlation coefficient (r) estimated for the bitterness score predicted by the taste sensor, using C' for channel 2 and C/S for channel 4, and the score obtained by human gustatory sensation, was 0.824. This value was greater than that obtained using C/S for both channels 2 and 4 (0.734). The method described in the present study seems to offer good predictability for the evaluation of bitterness.
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