Teva Pharma Japan Inc.

Nakamura, Japan

Teva Pharma Japan Inc.

Nakamura, Japan
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Katsura S.,Teva Pharma Japan Inc. | Katsura S.,Hoshi University | Katsura S.,Taiho Pharmaceutical Co | Yamada N.,Teva Pharma Japan Inc. | And 8 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2017

We observed that uncoated furosemide tablets turned yellow in a light-shielded automatic packaging machine and discoloration of the furosemide tablets was heterogeneity and occurred on the surface of the tablets only. The machine was equipped with an internal blower to maintain a constant temperature. Therefore, we investigated the effect of air flow on the discoloration of the furosemide tablets using a blower in a dark environment. The color difference (δE) of the furosemide tablets increased linearly as the blowing time increased. We performed structural analysis of the yellow compound in the furosemide tablets by LC-MS and identified the compound as a hydrolysate of furosemide. This suggested that furosemide hydrolysis was accelerated by the air flow. The furosemide tablets were prepared with the most stable furosemide polymorph, form I. X-Ray powder diffractometry and IR spectroscopy showed that during tablet preparation, no crystal transition occurred to an unstable furosemide polymorph. Furthermore, IR spectroscopy showed that the crystal form of furosemide in the yellow portion of the tablets was form I. To elucidate the factors producing the discoloration, we investigated the effect of humidity and atmosphere (air, oxygen, and nitrogen) on the discoloration of the furosemide tablets. The results suggested that the discoloration of the furosemide tablets was accelerated by oxidation, although humidity did not affect the hydrolysis. Therefore, we concluded that the discoloration of the furosemide tablets in the automatic packing machine was caused by acceleration of oxidative degradation by air flow. © 2017 The Pharmaceutical Society of Japan.


Suzuki T.,Japan National Institute of Health Sciences | Ishii-Watabe A.,Japan National Institute of Health Sciences | Hashii N.,Japan National Institute of Health Sciences | Nakagawa Y.,Pharmaceutical and Medical Device Regulatory Science Society of Japan | And 20 more authors.
Biologicals | Year: 2013

Heparin is used as an anticoagulant drug. The anticoagulation process is mainly caused by the interaction of heparin with antithrombin followed by inhibition of anticoagulant factor IIa and factor Xa. The anti-factor IIa and anti-factor Xa activities of heparin are critical for its anticoagulant effect; however, physicochemical methods that can reflect these activities have not been established. Thus, the measurements of anti-IIa and anti-Xa activities by biological assay are critical for the quality control of heparin products. Currently in the Japanese Pharmacopoeia (JP), the activities of heparin sodium and heparin calcium are measured by an anti-Xa activity assay (anti-Xa assay), but anti-IIa activity is not measured. Here, we established an anti-IIa activity assay (anti-IIa assay) and an anti-Xa assay having good accuracy and precision. When samples having a relative activity of 0.8, 1.0 and 1.2 were measured by the established anti-IIa and anti-Xa assays in nine laboratories, good accuracy (100.0-102.8% and 101.6-102.8%, respectively), good intermediate precision (1.9-2.1% and 2.4-4.2%, respectively) and good reproducibility (4.0-4.8% and 3.6-6.4%, respectively) were obtained. The established anti-IIa and anti-Xa assays have similar protocols, and could be performed by a single person without a special machine. The established assays would be useful for quality control of heparin. © 2013 The International Alliance for Biological Standardization.


Itoh S.,Japan National Institute of Health Sciences | Hiruta Y.,Japan National Institute of Health Sciences | Hashii N.,Japan National Institute of Health Sciences | Fujita N.,Ajinomoto Co. | And 16 more authors.
Biologicals | Year: 2013

Heparin is a sulfated glycosaminoglycan (GAG), which contains N-acetylated or N-sulfated glucosamine (GlcN). Heparin, which is generally obtained from the healthy porcine intestines, is widely used as an anticoagulant during dialysis and treatments of thrombosis such as disseminated intravascular coagulation. Dermatan sulfate (DS) and chondroitin sulfate (CS), which are galactosamine (GalN)-containing GAGs, are major process-related impurities of heparin products. The varying DS and CS contents between heparin products can be responsible for the different anticoagulant activities of heparin. Therefore, a test to determine the concentrations of GalN-containing GAG is essential to ensure the quality and safety of heparin products. In this study, we developed a method for determination of relative content of GalN from GalN-containing GAG in heparin active pharmaceutical ingredients (APIs). The method validation and collaborative study with heparin manufacturers and suppliers showed that our method has enough specificity, sensitivity, linearity, repeatability, reproducibility, and recovery as the limiting test for GalN from GalN-containing GAGs. We believe that our method will be useful for ensuring quality, efficacy, and safety of pharmaceutical heparins. On July 30, 2010, the GalN limiting test based on our method was adopted in the heparin sodium monograph in the Japanese Pharmacopoeia. © 2013 The International Alliance for Biological Standardization.


Nariai Y.,Teva Pharma Japan Inc. | Mizuguchi H.,Tokushima University | Ogasawara T.,Tokushima University | Nagai H.,Tokushima University | And 7 more authors.
Journal of Biological Chemistry | Year: 2015

Background: The molecular mechanism of anti-allergic (-)-maackiain remains unknown. Results: (-)-Maackiain and Hsp90 inhibitors inhibited PKCδ activation and suppressed H1R gene expression. Conclusion: (-)-Maackiain is a novel Hsp90 pathway inhibitor, and its anti-allergic activity underlies the disruption of Hsp90- PKCδinteraction. Significance: Hsp90 is involved in H1R gene up-regulation, and its inhibition could be a novel therapeutic strategy for allergic rhinitis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.


Katsura S.,Teva Pharma Japan Inc. | Katsura S.,Hoshi University | Yamada N.,Teva Pharma Japan Inc. | Nakashima A.,Teva Pharma Japan Inc. | And 3 more authors.
Chemical and Pharmaceutical Bulletin | Year: 2015

The aim of this study was to identify the chemical structure of the photodegradation products of furosemide in a water-acetonitrile mixture (1:1). Furosemide solution was irradiated with a D65 fluorescent lamp and the products were isolated by preparative HPLC. The fractions were evaporated to dryness in vacuo. The purity of the photodegradation products was measured by HPLC. The purity of products 1, 3, and 4 was greater than 90%, whereas that of product 2 was 13%, therefore, photodegradation product 2 was unstable. We identified photodegradation products 1 and 3 as 4-chloro-5-sulfamoylanthranilic acid and 4-hydroxy-N-furfuryl-5-sulfamoylanthranilic acid, respectively, by LC/MS and NMR. Additionally, we assumed that photodegradation product 4 was methyl 2-((furan-2-ylmethyl)amino)-4-hydroxy-3-(methyleneamino)-5-sulfamoylbenzoate by LC/MS and NMR. This showed that furosemide underwent hydrolysis and substitution, and reacted with the acetonitrile under the light of a D65 fluorescent lamp. We were furthermore able to determine the elution times of the photodegradation products of furosemide by applying the Japanese Pharmacopoeia chromatographic method for related substances to the isolated products. © 2015 The Pharmaceutical Society of Japan.


Patent
Iwata Label Co. and Teva Pharma Japan Inc. | Date: 2014-02-27

Slightly above a rupture-intended line, a peripheral surface of a projection portion of a stopper cap is pushed in a direction from an outer side to an inner side (in an arrow direction). The stopper cap is pushed over on the principle of leverage in an oblique direction with, as a fulcrum P, the side (the back side) opposite in a circumferential direction to the side (the near side) at which a pushing force PW acts, so that an intermittent portion is ruptured due to bending of the flexible stopper cap. Then, a residual area remains at the syringe side, and a separation area is separated together with the stopper cap from the syringe to perform unsealing. Thus, a syringe label which allows for easy unsealing along the intermittent portion and with which an unsealed state is easily confirmed, and a drug solution-filled syringe using the label, are provided.


Patent
Teva Pharma Japan Inc. | Date: 2016-01-06

Slightly above a rupture-intended line 2, a peripheral surface of a projection portion 103a of a stopper cap 103 is pushed in a direction from an outer side to an inner side (in an arrow direction). The stopper cap 103 is pushed over on the principle of leverage in an oblique direction with, as a fulcrum P, the side (the back side) opposite in a circumferential direction to the side (the near side) at which a pushing force PW acts, so that an intermittent portion is ruptured due to bending of the flexible stopper cap 103. Then, a residual area Z1 remains at the syringe 101 side, and a separation area Z2 is separated together with the stopper cap 103 from the syringe 101 to perform unsealing. Thus, a syringe label which allows for easy unsealing along the intermittent portion and with which an unsealed state is easily confirmed, and a drug solution-filled syringe using the label, are provided.

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