著者

並木 徳之

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.135, no.2, pp.237-243, 2015 (Released:2015-02-01)

参考文献数

5

被引用文献数

2 9

---

Orally disintegrating tablets (ODTs) are currently widely used in drug therapy and are clinically attractive, because they are suitable for administration to patients with dysphagia and improve adherence, both of which increase the possibility of achieving the expected therapeutic effect. These properties of ODTs, which increase treatment effectiveness, are termed their “clinical functionality”, and ODTs with a high clinical functionality are required to meet the increasing need for these tablets. For example, there is a need for development of a clinically effective ODT with superior disintegrating properties while maintaining high tablet strength, bioequivalence with normal tablets while masking the bitterness with a fine particle coating, and a disintegration mechanism while maintaining moisture resistance and good storage quality. Thus, next-generation ODTs that overcome these conflicting properties, “trade-offs”, will be developed, using innovative formulation research technology. In this symposium, we will discuss a next-generation OD formulation known as PLETAAL OD, a high-dose antiplatelet agent, and will present the results of validation tests performed in our laboratory pertaining to high tablet strength, superior disintegration property, high wicking capacity, and storage stability with high moisture resistance. We will also introduce a second-generation antihistamine ALLELOCK OD and discuss its high clinical functionality achieved by masking the bitterness and obtaining bioequivalence with normal tablets by using granules while maintaining high tablet strength with EXLUB and SOLBLET technology.

著者

古川

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.98, 1890-04-26

著者

小村 弘 河原 亥一郎 茂本 友貴枝 松田 健一 阿野 理恵子 村山 洋子 森脇 俊哉 吉田 長弘

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.125, no.1, pp.121-130, 2005-01-01 (Released:2005-01-01)

参考文献数

27

被引用文献数

3 5

---

The application of combinatorial chemistry and high-throughput screening to biological targets has led to efficient identification of lead compounds in wide therapeutic areas. However, the physicochemical properties of some lead compounds are lipophilic with low water soluble. Since these parameters determine in vivo absorption, we established robust screening methods for solubility and Caco-2 membrane permeability which are applicable to our screening strategy based on the structure-pharmacokinetic parameter relationship (SPR). Of test compounds with different core structures, turbidimetric solubility and apparent solubility as determined by HPLC-UV analysis after dilution of aqueous media from DMSO stock solution was overestimated in comparison with the corresponding thermodynamic solubility obtained using a traditional shake-flask method. A new powder-dissolution method providing thermodynamic solubility similar to that in the traditional method was developed using 96-well plates for equilibrium dialysis. The throughput of the method was the almost the same as that using the apparent solubility method. In a conventional Caco-2 assay, membrane permeability (Papp) of some lipophilic compounds was underestimated due to low solubility in the apical site and adhesion to the device, resulting in a poor relationship between the in vivo absorption fraction and the Papp values. The addition of 0.1% Gelucire 44/14 into the apical site and 4% bovine serum albumin into the basolateral site improved the relationship. These newly developed methods are therefore useful to optimize lead compounds with less water solubility and high lipophilicity on the basis of SPR.

著者

田原

出版者

公益社団法人日本薬学会

雑誌

藥學雜誌 (ISSN:00316903)

巻号頁・発行日

no.176, pp.1015-1016, 1896-10-26

著者

山岸 三郎 小山 泰正 深草 佑一 興村 伸夫 大石 洵一 浜道 則光 新井 正

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.91, no.3, pp.351-357, 1971-03-25 (Released:2008-05-30)

参考文献数

24

被引用文献数

14 21

---

The metabolites of Streptomyces luteoreticuli KATOH et ARAI were investigated. Four new compounds, luteoreticulin, (V), C19H19O5N, luteothin, (VI), C22H25O5N, metabolite X, (X), C15H12O3N2, and metabolite XI, (XI), C15H14O3N2, were isolated from the acetone extract of the mycelial cake. 1-Methoxyphenazine (VII) and methyl phenazine-1-carboxylate (IX), which were first isolated from natural origin, were obtained in addition to aureothricin (I), thiolutin (II), aureothin (IV), and 1, 6-dimethoxyphenazine (VIII). The other two metabolites (III and XII) were also isolated but not identified.

著者

高倉 喜信

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.116, no.7, pp.519-532, 1996-07-25 (Released:2008-05-30)

参考文献数

59

被引用文献数

5 7

---

With a rapid progress in biotechnology, a variety of endogenous macromolecular substances have become a novel class of therapeutic agents. This review will focus on the development of delivery systems for macromolecular drugs. Current status and future perspectives in this research field are reviewed mainly based on the results obtained in our laboratory. First of all, we studied pharmacokinetic characteristics of macromolecules in relation to their physicochemical properties such as molecular weight and electric charge. Based on this information, we first developed macromolecular prodrugs as a delivery system for low molecular weight drugs. An antitumor antibiotic, mitomycin C (MMC) were covalently conjugated with dextran and various types of macromolecular prodrug of MMC were developed for tumor targeting. Secondly, delivery systems for protein drugs such as soybean trypsin inhibitor, uricase, and recombinant superoxide dismutase (SOD) were developed. In particular, successful targeting of SOD to the liver, kidney and blood circulation was achieved by chemical modification of the protein drug. Finally, we have been trying to develop delivery systems for nucleic acid drugs involving antisense oligonucleotides and plasmid DNA. Prior to the development of delivery systems, we found that the pharmacokinetics of the nucleic acid drugs are decided by their physicochemical properties as polyanions even if these materials contain genetic information. Several approaches were tested to control the in vivo behavior of the oligonucleotides and plasmid DNA based on the finding. Thus, we have established the strategy for rational design of delivery systems for various types of macromolecular drugs based on the pharmacokinetic considerations. This methodology can be a formidable tool for the development of clinically applicable macromolecular drugs.

著者

生塩 孝則 遠藤 寛二 山本 恵司

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.116, no.11, pp.866-875, 1996-11-25 (Released:2008-05-30)

参考文献数

21

被引用文献数

3 4

---

The physicochemical properties of the enantiomer and racemates of suplatast tosilate (ST) were investigated by means of infrared spectroscopy, solid-state 13C CP/MAS NMR spectroscopy, thermal analysis, and X-ray diffraction analysis, and by measuring the solubility and hygroscopy. The infrared and NMR spectra and X-ray diffraction pattern of the enantiomer were distinctly different from those of the racemate. The melting point of the enantiomer was lower than that of the racemate by 5°C, while the solubility of the enantiomer was 1.3 times higher than that of the racemate. The hygroscopic rate of the enantiomer was greater than that of the racemate. These results suggested that ST was classified into a racemic compound crystal. Furthermore, by comparing the relative peak intensity ratios on X-ray diffraction patterns of crystals with various optical purities prepared by recrystallization, it was found that a mixture of racemic compound crystals and either of racemic mixture crystals or racemic solid solutions was obtained by recrystallization of ST in the content of 0 to 64%ee, while the recrystallization of ST in the content of more than 64%ee led to the formation of racemic mixture crystals or racemic solid solutions.

著者

太田 和子

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.87, no.4, pp.444-450, 1967-04-25 (Released:2008-05-30)

参考文献数

14

---

Some considerations were made on the action mechanism of 2-naphthalenealkylamines, with O-7 carbons in the alkyl chain, and their N-alkyl- or N-aralkyl-N-methyl derivatives by measuring their kinetic activity, applying Fergusson's rule to their pharmacological activity. It was thereby found that the atropine-like and antihistamine activities of these compounds are specific action and contribution of the physicochemical properties of the base is very small. On the other hand, their papaverine-like action in the intestine is not so specific like atropine-like activity although in a strong base like the compounds of this series, a certain contribution of the cation is expected. Local anesthetic action was found to be non-specific, being dependent on the physicochemical properties of the non-ionic base or neutral molecule. This fact was further endorsed by the relationship between surface anesthetic action and pH.

著者

太田 和子

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.86, no.9, pp.756-759, 1966-09-25 (Released:2008-05-30)

参考文献数

5

被引用文献数

1

---

Local anesthetic action of recently synthesized 2-naphthalenealkylamines was tested. Surface anesthetic action was tested by the corneal reflex of a guinea pig and N-alkyl-N-methyl-2-naphthaleneethyl (or propyl) amines (XIb∼f, XIIb∼f) all showed activites stronger than that of procaine, and N-methyl-N-pentyl-2-naphtha1eneethylamine (XIf) was especially strong, the potency being 16 times that of procaine. The activity decreased when the compounds of this series were derived to methiodide, and only the N-butyl and N-pentyl compounds showed a weak activity. This fact seems to indicate the possibility that the base of a compound takes part in appearance of the activity. Primary amines (IIa to Xa) generally had strong irritant psoperty N, N-Dimethyl derivatives (IIb to Xb) showed the activity only when the number of carbon atoms in the side chain was 2 (IVb) or 3 (Vb), and all higher homologs had strong toxicity necrosis. Conduction anesthetic activity was examined with frog sciatic nerve in compounds of XI and XII series and their potency was compared with that of procaine. Approximately similar structure-activity relationship as in the case of surface anesthetic activity was found.

著者

太田 和子

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.85, no.1, pp.21-27, 1965-01-25 (Released:2010-02-19)

参考文献数

6

---

N-Alkyl (or Aralkyl) derivatives of N-methyl-2-naphthaleneëthylamine (Ia) and N-methyl-2-naphthalenepropylamine (IIa) and their methiodides were synthesized. Tertiary amines (I and II, b-j) obtained and their methiodides were tested for atropine- and papaverine-like activities by the Magnus method, and the relationships between the structures and pharmacological activities were discussed.

著者

太田 和子

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.85, no.1, pp.14-20, 1965-01-25 (Released:2010-02-19)

参考文献数

12

被引用文献数

3 5

---

Syntheses of 2-naphthalenealkylamine derivatives, whose carbon number (n) of the alkyl group was varied from n=0-7 and n=10 (IIIa-XIa), and their N, N-dimethyl derivatives (IIIb-XIb) as well as their methiodide (IIIc-XIc) were carried out in order to examine their pharmacological activities.Anti-acetylcholine activities and anti-histamine activities were tested according to the Magnus method. Both activities showed a tendency to strengthen as the carbon number of alkyl group increased. However, the anti-acetylcholine activities of primary amine, whose n is 10, was observed to be a little lower than that of the amine of n=7. As to the anti-histamine activities, dimethylamino derivative of n=2 was found to be the strongest, that of 3 and 4 were weaker and it became stronger as the carbon number increased. The activities of methiodide of n=1 was a little stronger than that of n=2 in both activities.As to the blood pressure activities of primary amines, n=0 showed depression and n=1-4 showed, after a little depression, a rise type, whose degree was observed to be the maximum with n=2 and later weakened to a depress type. Dimethyl compounds were depressive andmethiodide showed usually a continuous rise, after the depression.

著者

井原 賢 張 晗 花本 征也 田中 宏明

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.138, no.3, pp.281-287, 2018 (Released:2018-03-01)

参考文献数

16

---

Pharmaceuticals are widely found in aquatic environments worldwide. Concern about their potential risks to aquatic species has been raised because they are designed to be biologically active. To address this concern, we must know whether biological activity of pharmaceuticals can be detected in waters. Nearly half of all marketed pharmaceuticals act by binding to the G protein-coupled receptor (GPCR). In this study, we measured the physiological activity of GPCR-acting pharmaceuticals in effluent from a wastewater treatment plant (WWTP) and upstream and downstream of its outfall in Japan during 2 years. We used the in vitro transforming growth factor-α (TGFα) shedding assay, which accurately and sensitively detects GPCR activation, to investigate the antagonistic activities of water extracts against receptors for dopamine (D2) and histamine (H1). Activities detected in waters were quantified as antagonist equivalent quantities (EQs). In WWTP effluent extracts, antagonistic activity was detected at several hundred ng/L of sulpiride-EQ (D2) and several μg/L of diphenhydramine (DIP)-EQ (H1). In downstream river water extracts, antagonistic activity against H1 was around several hundred ng/L of DIP-EQ, higher than that upstream owing to the WWTP effluent. This review discusses the research needed to resolve the concern about potential risks of pharmaceuticals in waters to aquatic species.

著者

武田 豊彦 鈴木 裕介 稲津 邦平 坂元 照男 前川 秀幸

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.109, no.6, pp.395-401, 1989-06-25 (Released:2008-05-30)

参考文献数

13

被引用文献数

2 6

---

Cephalothine sodium (CET-Na) in crystals can be obtained by freezing the aqueous solution and subsequent warming at a fixed temperature for facilitating crystallization prior to vacuum application for drying. The product has, however, been found to unavoidably contain traces of the amorphous CET-Na, which causes a rapid color development during storage. By using thermal analysis, differential scanning calorimetry (DSC), electric conductometry, and polarized light cryomicrographic techniques, the solubilities in water, freezing point, eutectic point, and melting behavior of CET-Na in aqueous solution were investigated. The investigation demonstrated that CET-Na in supersaturated aqueous solution is very stable, and that seeding with microcrystalline CET-Na to the supersaturated solution and subsequent cooling of the mixture till its freezing point gives neither any evidence for crystallization nor for growth of the seed crystals. The freeze-drying of CET-Na in the supersaturated solution after seeding has been demonstrated to give crystalline CET-Na contaning neither of amorphous nor of quasicrystalline form.

著者

芦澤 一英 内川 清彦 服部 禎一 石橋 泰雄 三宅 康夫 里 忠

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.110, no.3, pp.202-209, 1990-03-25 (Released:2008-05-30)

参考文献数

34

---

An X-ray diffraction methods and Fourier transform infrared analysis with photoacoustic detector (FTIR-PAS) for estimation of the degree of crystallinity of crystalline E1040 formulation was established. The X-ray procedure to determine the crystallinity of E1040 was based upon the measurement of the total scattering and the scattering from the crystalline region of the drug. The FTIR-PAS procedures are based upon the measurement of the peak height ratio at 1628 cm-1 and measurement of the spectral region between 2400 and 3700 cm-1 by the Partial least squares (PLS) techniques. The data of the degree of crystallinity from the X-ray diffraction methods are consistent with the data from FTIR-PAS methods. The increase of the degree of crystallinity of the drug formulation decreased the decomposition rate of E1040. As a result, it had become apparent that two analytical procedures were actually valid. This assured optimizing process conditions which affect the improvement of crystallinity.

著者

鈴木 裕介 武田 豊彦 稲津 邦平 坂元 照男

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.110, no.11, pp.858-868, 1990-11-25 (Released:2008-05-30)

参考文献数

7

---

Seeding and subsequent freeze-drying of aqueous cephalothin sodium (CET-Na) solution of supersaturated concentrations, which preliminarily received an excess of mechanical stress, have been reported to make the product unacceptable in pharmaceutical elegance and in chemical stability upon storage. In order to find out the cause, the CET-Na solution that preliminarily received mechanical stress has been examined as to its crystallization behavior during freezedrying process, by using polarizedlight cryomicroscopy, scanning electron microscopy, cryodifferential scanning calorimetry, refractometry, viscositometry, and surface tensiometry. Aqueous CET-Na solution of supersaturated concentrations, to which an excess of mechanical stress was given, has been demonstrated to exhibit the following features : in the process of seeding and subsequent freeze-drying, the solution shows an incomplete crystallization at -40°C ; in the crystal growth stage at -5°C, crystals are found to be difficult to grow sufficiently from the seeds as their nuclei. These findings indicate that the supersaturated solution has changed to an unusual state upon receiving such stress, the state being different from the state of untreated solution in that the solution thus treated shows physico-chemical properties capable of easy crystallization through a simple step of freezing. The change as such in physico-chemical properties has also been estimated to have resulted from a structural change of associated molecules of CET-Na in its supersaturated solution into a condensed state quite similarly to that of liquid crystals.

著者

鈴木 裕介 武田 豊彦 稲津 邦平 坂元 照男

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.110, no.11, pp.849-857, 1990-11-25 (Released:2008-05-30)

参考文献数

13

被引用文献数

1 2

---

A method of seeding and subsequent freeze-drying of aqueous cephalothin sodium (CET-Na) of supersaturated concentrations was employed in an experiment with a regular production scale. The freeze-dried plugs of non-uniformity in appearance were consequently obtained together with those of white in color and in high uniformity in appearance. Such plugs of irregular shape have been found to show a marked color development during storage, and the reconstitution time was also prolonged. Scanning electron microscopy, powder X-ray diffractometry, and thermogravimetry have all demonstrated that the plugs of irregular appearance show dense aggregates of fine crystals of a high non-crystallinity by an incomplete crystal growth. Investigation has then been made with supersaturated CET-Na solution, which has preliminarily received varying mechanical stresses in varying time courses of temperature, similarly to a regular production program, for the purpouse of achieving the reproducibility of such unacceptable plugs. It has been demonstrated that by a more prolonged storage at a lower temperature of CET-Na in supersaturated solution the plug may surely contain aggregates of more fine crystallites of a higher non-crystallinity, accordingly have a higher irregularity in appearance and exhibit a more marked deterioration in pharmaceutical qualities.

著者

井上 正義 島 和弘 稲津 邦平

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.104, no.9, pp.973-980, 1984-09-25 (Released:2008-05-30)

参考文献数

14

---

Investigation has been made to obtain the crystallinity of cephalothin sodium in seeded and frozen aqueous solution from electrical conductivity (conductivity), with a result that crystallinity (αt) can be given by the equation of αt=λT-λt/λT, where λT is the initial conductivity and λt stands for the conductivity obtained after t hours. Observed values of crystallinity by the conductivity method are in good agreement with crystallinity data by infrared method and X-ray diffraction method of the freeze-dried material. Further investigation has been made to find out whether it is possible to apply the no-seeding conductivity method for the crystallinity of dicethiamin hydrochloride in solution capable of spontaneous nucleation and transformation to its crystalline state. The result has consequently demonstrated that, in some cases of no-seeding, the phase transition is not uniform, or otherwise, the conductivity change provides an incomplete indication of nucleation and growth of perfect crystals. From the above, it may as well be said to be safe to set a limit to a seeded system, when the authors' conductivity method is applied for obtaining the crystallinity of a drug in frozen solution.

著者

井上 正義 田中 廣義 島 和弘 稲津 邦平

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.105, no.3, pp.289-295, 1985-03-25 (Released:2008-05-30)

参考文献数

16

被引用文献数

1 1

---

The effect of organic solvent on the growth rate of cephalothin sodium (KF) after seeding in frozen solution was investigated. All of used solvents accelerated crystal growth of KF and it was found that the accelerative effect of solvent increased with an increase in dielectric constant of solvent. KF formed micelle in aqueous solution and the solvent lower the freezing temperature of the micelle and it can be assumed that the lowering of the freezing temperature of the micelle related to the volume of solvent existing in the micelle. Alcohol lower larger the freezing temperature of the micelle than ketone and nitrile, but the accelerative effect of alcohol on the growth rate was less than that of ketone and nitrile. The effect of the concentration of ethanol and acetone was investigated and it seemed that ethanol accelerated nucleation. Nevertheless, the accelerative effect of ethanol on the growth rate was less than that of acetone. These results suggested that simultaneous use of solvent having a different mode of action is effective for crystallization of KF in frozen solution by spontaneous nucleation.

著者

井上 正義 島 和弘 稲津 邦平

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.104, no.12, pp.1268-1274, 1984-12-25 (Released:2008-05-30)

参考文献数

10

被引用文献数

3 2

---

The growth rate of cephalothin sodium (KF) after seeding in frozen solution was measured. Crystal growth of KF followed equation (1) untill α=0.98. 1-(1-α)1/3=(1/3N) (Kt)N……(1) where α is crystallinity, K is rate constant, t is time, and N is parameter depending on the freezing temperature and the amount of seed. Crystal growth of KF in the frozen solution hardly changed when the concentration of KF was in the range of 19.4% to 28.6% but it was remarkably dependent on the amount of seed at the constant freezing temperature. According to the decrease in the amount of seed at the constant freezing temperature, the value of N increased and the rate constant (K) decreased. The growth rate increased with a rise of freezing temperature, and had the maximum value at a temperature little below the eutectic temperature. The activation energy of crystal growth of KF in the range of -5°C to -14°C was 49 kcal/mol.

著者

鈴木 裕介 武田 豊彦 稲津 邦平 坂元 照男 前川 秀幸

出版者

公益社団法人 日本薬学会

雑誌

YAKUGAKU ZASSHI (ISSN:00316903)

巻号頁・発行日

vol.109, no.6, pp.388-394, 1989-06-25 (Released:2008-05-30)

参考文献数

10

被引用文献数

1 1

---

Cephalothin sodium (CET-Na) prepared according to the conventional freeze-drying methods is known to easily develop color during storage. Since amorphous CET-Na has been reported to be markedly unstable, the color development is thought to be due to the presence of traces of CET-Na in an amorphous state observed with scanning electron microscopy. Quantitation by use of the powder X-ray diffractometry of such traces of amorphous CET-Na has proved to be of little use. Thermogravimetry (TG) and differential scanning calorimetry (DSC) have demonstrated that the freeze-dried CET-Na by the conventional methods contains three types of CET-Na : amorphous (unstable phase), quasi-crystalline (metastable phase). Pyrolysis initiation temperatures of these three types of CET-Na have been demonstrated to become higher in this order. A new parameter for the evaluation of non-crystallinity of CET-Na has been introduced, in which the ratio is calculated from the data of the total weight loss observed through the pyrolysis of both amorphous and quasi-crystalline CET-Na against the total weight loss of all components during the pyrolysis of sample specimen. The ratio thus calculated is defined as "non-crystallinity". This new parameter has successfully been introduced to establish a good correlation to the degree of increasing color intensity with aging of freeze-dried CET-Na.