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Dermatan Sulfate Composition

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Dermatan Sulfate Composition Europäisches Patentamt *EP000671414B1* (19) European Patent Office Office européen des brevets (11) EP 0 671 414 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.7: C08B 37/00, A61K 31/715 of the grant of the patent: 02.01.2002 Bulletin 2002/01 (86) International application number: PCT/JP94/01643 (21) Application number: 94927827.9 (87) International publication number: (22) Date of filing: 30.09.1994 WO 95/09188 (06.04.1995 Gazette 1995/15) (54) DERMATAN SULFATE COMPOSITION AS ANTITHROMBOTIC DERMATANSULFATEZUSAMMENSETZUNG ALS ANTITHROMOTISCHES MITTEL COMPOSITION DE DERMATANE SULFATE UTILISE COMME ANTITHROMBOTIQUE (84) Designated Contracting States: • YOSHIDA, Keiichi AT BE CH DE DK ES FR GB IT LI NL PT SE Tokyo 189 (JP) (30) Priority: 30.09.1993 JP 26975893 (74) Representative: Davies, Jonathan Mark Reddie & Grose 16 Theobalds Road (43) Date of publication of application: London WC1X 8PL (GB) 13.09.1995 Bulletin 1995/37 (56) References cited: (60) Divisional application: EP-A- 0 112 122 EP-A- 0 199 033 01201321.5 / 1 125 977 EP-A- 0 238 994 WO-A-93/05074 JP-A- 59 138 202 JP-B- 2 100 241 (73) Proprietor: SEIKAGAKU KOGYO KABUSHIKI JP-B- 6 009 042 KAISHA Tokyo 103 (JP) • CARBOHYDRATE RESEARCH , vol. 131, no. 2, 1984 NL, pages 301-314, K. NAGASAWA ET AL. (72) Inventors: ’The structure of rooster-comb dermatan • TAKADA, Akikazu sulfate. Characterization and quantitative Shizuoka 431-31 (JP) determination of copolymeric, isomeric tetra- • ONAYA, Junichi and hexa-saccharides’ Higashiyamato-shi Tokyo 207 (JP) • ARAI, Mikio Remarks: Higashiyamato-shi Tokyo 207 (JP) The file contains technical information submitted • MIYAUCHI, Satoshi after the application was filed and not included in this Tokyo 208 (JP) specification • KYOGASHIMA, Mamoru Tokyo 207 (JP) Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 0 671 414 B1 Printed by Jouve, 75001 PARIS (FR) EP 0 671 414 B1 Description [0001] This invention relates to antithrombotic agents which prevent the extension of thrombi and stimulate lysis thereof. 5 [0002] Thrombosis is a disease caused by blood coagulation in living blood vessels due to the imbalance of platelets, coagulation and fibrinolytic system which basically should maintain fluidity of blood in the blood vessels. Thrombi in coronary arteries cause myocardial infarction and those in venous vessels in the lower limbs and so forth cause deep vein thrombosis. Abnormal activation of coagulation system due to severe infectious diseases or tumors leads to throm- bi in systemic capillary blood vessels and results in disseminated intravascular coagulation syndrome (hereinafter 10 referred to DIC). The DIC caused by severe infectious diseases often complicates by multiple organ failure and very poor prognosis. Various countermeasures have been developed to treat the thrombosis which shows extremely various symptoms depending on the sites of onset. Urokinase, tissue plasminogen activator (hereinafter referred to t-PA) or heparin and so forth have been used for the treatment of myocardial infarction and deep vein thrombosis and heparin has also been applied to DIC. However, urokinase has drawbacks of low affinity to fibrin, and t-PA is expensive and 15 has very short half-life. In addition, percutaneous transluminal coronary recanalization and reperfusion therapy by direct peripheral intravenous administration with t-PA are liable to cause recurrence of thrombosis. Heparin has prob- lems which requires at a definite concentration or over of antithrombin III to secure the desired effect to exert its ther- apeutic effect. Furthermore, these drugs cause serious adverse effect of bleeding, thus synthetic anti-protease drugs have been developed to cope with the difficulties. However, no sufficient solution of the adverse effect has been obtained 20 and problems such as an extremely short half-life remain unsolved. [0003] Dermatan sulfates have been reported to exert anticoagulant activity via heparin cofactor II, but on their fibri- nolytic activity, acceleration of release of t-PA by dermatan sulfates has been reported (Abbadini, M. et al., Blood, 1987, 70, 1858-1860), while, no effect of dermatan sulfates on the amount of t-PA or fibrinolytic activity (Tripodi, A. et al., Thromb. Res., 1991, 62, 663-672) has been reported and definite effect on fibrinolytic system is unclear. 25 [0004] Dermatan sulfates which have been used in various experiments or as a medicine under development are derived from intestine or skin of porcine or bovine (Fareed, J. et al., Recent Advances in Blood Coagulation, 1993, 6, 169-187). No activity of dermatan sulfates derived from the other origins has been known. Disclosure of Invention 30 [0005] The inventors of the present invention have been investigating the effect of dermatan sulfates on the fibrinolytic system and found that thrombolytic activity is enhanced by their presence in comparison to that in their absence. In addition, the inventors found that cumulated antithrombotic activity of dermatan sulfate administered in the living body composed of both anticoagulation and fibrinolytic activities is particularly significant for specific compositions compris- 35 ing (a) dermatan sulfates or salt thereof having intrinsic viscosity of 0.8 dL/g or over, preferably dermatan sulfates derived from crest or comb, dermatan sulfates having ∆Di-0S (2-acetamido-2-deoxy-3-0-(4-deoxy-α-threo-hex-L- 4-enopyrano syluronic acid)-D-galactose) at a rate of 2-7% in their constructing disaccharide, or specific dermatan sulfates having average molecular weight of 25,000-100,000 Dalton determined by the method described later, and (b) very low content of heparin or heparan sulfate as recited in claim 1. The present invention is accomplished by the 40 above mentioned findings and provides the compositions as show in the accompanying claims. [0006] The present invention relates to the antithrombotic containing the effective ingredient of dermatan sulfates compositions shown above or to combined use of such dermatan sulfate compositions with tissue plasminogen activator (t-PA). [0007] Dermatan sulfates have a main structure of repeating disaccharide composed of N-acetyl-D-galactosamine- 45 4-sulfate and L-iduronic acid including a small amount of D-glucuronic acid and have different contents of sulfuric acid and D-glucuronic acid, and different binding sites of sulfuric acid and so forth, depending on the source of animal species and organs and so on. [0008] Dermatan sulfates can be produced generally from raw materials of mammals and so forth such as bovine or porcine intestinal mucosa or skin, or crests or combs. 50 [0009] The present inventors found that the activation of plasminogen with single- or two-chain t-PA can be enhanced in the presence of dermatan sulfates obtained from these raw materials or their pharmacologically acceptable salts comparing to the case in the absence thereof. The present inventors found that the specific dermatan sulfates com- positions of the present invention having intrinsic viscosity of 0.8 dL/g or over, preferably 0.9-2.0 dL/g, preferably being derived from crest or comb, preferably 2-7% of ∆Di-OS, preferably 3-6%, in their constructing disaccharide, and pref- 55 erably an average molecular weight of 25,000-100,000, preferably 30,000-60,000 Dalton determined by gel filtration described later in Biochim. Biophys. Acta, 1117, 60-70 (1992), as well as having the required very low content of heparin or heparan sulfate or those with dermatan sulfate pharmacologically acceptable salts thereof administered in the living body can be maintained for a longer duration in the blood than the other dermatan sulfates and exhibit pharmacological 2 EP 0 671 414 B1 effect of all-embracing antithrombotic activity not only with fibrinolytic activity but also with anticoagulant activity and accomplished the present invention. [0010] The pharmacologically acceptable salts of dermatan sulfates include such as sodium, potassium, lithium and calcium salts, but sodium salts are generally administered. The tissue plasminogen activators (t-PAs) used for the 5 present invention include both endogenous and exogenous, single- and two-chain, and natural and gene recombinant products. Furthermore, t-PA analogues partially defective in amino acid composition or having extra amino acids may be used in so far as they exhibit plasminogen activating property (see EP-A-112122). [0011] Dermatan sulfates or pharmacologically acceptable salts thereof (hereinafter may be referred to DS) suffi- ciently exhibit their pharmacological activity with single and sole, or once or repetitive administration. The dermatan 10 sulfates can be administered by intravenous, intraarterial or intracoronary arterial injections and may be used subcu- taneously or intramuscularly. DS and t-PA can be administered simultaneously in the same routes or separately. [0012] When the blood concentrations of DS and t-PA are expected to become excessive to the effective concen- trations by aforementioned intracoronary arterial or intravenous administrations, then intramuscular or subcutaneous administration may be adopted other than the aforementioned routes. 15 [0013] Pharmaceutical preparations
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