Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Waste or feces
Patent
1995-08-17
1998-11-10
Adams, Donald E.
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Waste or feces
424 943, 530381, A61K 3522, A61K 3854, A61K 3514
Patent
active
058340289
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a composition containing as its critical components at least one species of soluble thrombomodulin and at least one member selected from maltose, lactose, sucrose, and arginine and a salt thereof; and a method for producing such composition.
This invention also relates to a composition containing as its critical components at least one species of soluble thrombomodulin and a nonionic surface-active agent; and a method for producing such composition.
Furthermore, this invention also relates to a composition containing as its critical components at least one species of soluble thrombomodulin; at least one member selected from maltose, lactose, sucrose, and arginine and a salt thereof; and a nonionic surface-active agent; and a method for producing such composition.
Still further, this invention relates to a stabilizing agent for a soluble thrombomodulin containing at least one member selected from maltose, lactose, sucrose, and arginine and a salt thereof.
Still further, this invention relates to a method for stabilizing a soluble thrombomodulin comprising the step of adding at least one member selected from maltose, lactose, sucrose, and arginine and a salt thereof to the soluble thrombomodulin.
Still further, this invention relates to an anti-adsorption agent for a soluble thrombomodulin containing a nonionic surface-active agent.
Still further, this invention relates to a method for preventing adsorption of a soluble thrombomodulin comprising the step of adding a nonionic surface-active agent to the soluble thrombomodulin.
BACKGROUND ART
Thrombomodulin is a protein found at vascular endotherial cell surface that has a unique nature of converting thrombin from a coagulant enzyme to an anti-coagulant enzyme, and it was reported in 1981 (Esmon et al., Proc. Natl. Acad. Sci. USA, 78, 2249-2254, 1981). In the subsequent report, Esmon et al. reported that they have succeeded in isolating the thrombomodulin from rabbit lung tissue (Esmon et al., J. Biol. Chem., 257(2), 859-864, 1982). The entire DNA sequence and the amino acid sequence of human thrombomodulin were then reported (EMBO J., 6, 1891-1897, 1987; Biochemistry, 26(14), 4350-4357, 1987), and various studies have been conducted to reveal the functions of different domains of the thrombomodulin. Today, it is conceived that thrombomodulin binds with thrombin to form a thrombin-thrombomodulin complex, and the blood coagulation activity of the thrombin is thereby lost; and in turn, the resulting thrombin-thrombomodulin complex activates protein C to induce anti-coagulation activity. In other words, the thrombomodulin may simultaneously induce the blood coagulation inhibitory action and the fibrinolytic action, and clinical application of thrombomodulin is highly awaited.
Conventional therapeutic agents that have been used for diseases related to blood coagulation activity disorders include agents having an anti-coagulation activity such as antithrombin III and heparin as well as agents having a thrombolytic activity such as urokinase, streptokinase, and tissue plasminogen activator. These agents, however, suffer from side effects such as tendency to hemorrhages, and their actions are either inclined to blood coagulation or thrombolysis. In view of such situation, a great expectation is held for the clinical application of a substance that may simultaneously have the anti-coagulation activity and the thrombolytic activity such as thrombomodulin, and a thrombomodulin-like substance that may have the thrombomodulin activity, i.e. both the affinity for thrombin and the protein C-activating activity.
Human thrombomodulin has a low solubility, and when the human thrombomodulin is used for a medicament, such low solubility results in the difficulty of purification as well as the difficulty in producing the preparation. More illustratively, thrombomodulin is a membrane-bound protein comprising five domains, that is, amino terminal domain, domain of EGF-like structure, domain of O-glycosilation site, transmembrane
REFERENCES:
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Mohri et al, American Journal of Hematology, 45: 298-303 (1994).
Ketchum, et al., Menaquinol-nitrate oxidoreductase of Bacillus halodenitrificans, J Bacteriol, 173 (8) p. 2498-2505, see Abstract, Apr. 1991.
Hoover J. et al. Remington's Pharmaceutical Sciences 18th edition; Philadelphia College of Pharmacy and Science, 1990.
Hata Seishichi
Kudoh Yumio
Kunihiro Yasuyuki
Suzuki Shigeharu
Tanaka Ryo
Adams Donald E.
Mochida Pharmaceutical Co. Ltd.
Park Hankyel T.
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