Method of producing depolymerized heparin

专利摘要:
Heparin fragments having selective anticoagulation activity having 14-18 sugar units, the disaccharide unit L-induronosyl-2-O-sulphate-N-sulpho-U-glucosamine-6-O-sulphate being the main component, and where unsulphated L-induronic acid is in a position situated 3-5 sugar units from the unreducing terminal. Pharmaceutical compositions containing such heparin fragments. Processes for the preparation of the heparin fragments.
公开号:SU1209033A3
申请号:SU813244902
申请日:1981-02-06
公开日:1986-01-30
发明作者:Пер Фредрик Линдал Ульф；Элизабет Бекстрен Гудрун；Юнгве Леннарт Тунберг Джон；Франссон Ларс-Оке；Андерссон Ларс-Олов；Юнгве Холмер Эрик；Хелена Сандберг Инга；Гунилла Седерстрем Эва
申请人:Каби Аб (Фирма)；
IPC主号:

专利说明:

This invention relates to the chemistry of polysaccharides, specifically to the preparation of depolymerized heparin, which has a high biological activity.
The aim of the invention is to reduce the duration of the process.
The following examples illustrate the invention.
Example 1.0.5g of pigs extracted from the intestine of heparin; dissolve in 150 ml of water, cool, and put to 4 ° C and pass through coloN
Gy
ku 3 X 7 cm, filled with Dowex 50 W -ZS (form), particle size 200-400 mesh (0.074 - 0.037 m). The column is then washed with 100 ml of water and the industrial liquid is mixed with the stock solution. 250 ml of dimethoxyethane, cooled to -20 ° C, and 10 ml of isoamylnitrile are added thereto, and the resulting mixture is held for 2 minutes at 10 ° C. The reaction is stopped by introducing into the reaction mixture 10 ml of a 10% sodium acetate solution. Then, 5.2 liters of ethanol are introduced, the precipitated depolymerized heparin is isolated by centrifugation.
The resulting product is dissolved in 500 ml of a 0.05 M solution of NaCl-0.05 M solution of Tris-HCl, pH 7.4. The solution is fractionated, divided into 100 ml portions by chemisorption chromatography using a column containing 75 ml of anti-bromine — Sepharose® (approximately 5 mg of protein per 1 ml of gel. The column is eluted using a salt gradient (500 ml of 0.05 M NaCl solution - 0.05 M Tris-HC1 solution:: (500 ml of 3 M NaCl solution - 0.05 Tris-HCl solution), the main part of the product used passes through the column or is eluted at a low ionic strength (less than 0 , 4 mol. TlaCl, this product is not about
Editor L. Veselovska
Compiled by T. Martinska
Tehred A. Babinets Proofreader, T. Kolb
Order 310/61. Circulation 471 Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Raushsk nab. 4/5
Branch PSh1 Patent; Uzhgorod, Proektna St., 4
2D90332
It has biological activity. The active components (purified heparin solvents) are eluted in the broad upper part of O, 5 M plant, thief NaCl and 3 M NaCl solution, which corresponds to 4% of the starting material. These fractions are collected and desalted by gel chromatography. Heparin derivatives obtained
10 and purified in this way have a molecular size corresponding to the size of tetradecaoctadeca saccharide (mol. Weight 3600-4800). Structural analysis shows the availability of those
5 of the same structural components as in the starting material, and 1.-idolonosyl-2-0-sulfate- (1w-4) -M sulfo-B-glucosamine-b-sulfate is the dominant disaccharide unit of the molecule . The amount of non-sulfated iduronic acid increases from 6% in the starting material to 16%,
Example 2. About 5 g of heparin is dissolved in 250 ml of an aqueous solution containing 0.02 mol NalO, 0.2 mol NaClO and 0.05 sodium citrate buffer, pH 3. After weighing for 3 hours in the dark at 4 ° C, the oxidation is stopped by the introduction of a molar excess of D-mannitol followed by dialysis of the solution and with sps at a temperature below 0 ° C. The cleavage of the polysaccharide chain is carried out by treating the product with alkali (5 mg / ml aqueous solution at pH 12j at room temperature. After 10 minutes, the solution is neutralized with 1 M solution of acetic acid and desalting shot by gel chromatography on dextran (Sephadex C - 25). The resulting product can be reduced with sodium borohydride,
45 Gel chromatography shows that the resulting heparin has a size of molecules corresponding to 10–25 ° C charide units m.
25

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING DEPOLIMERIZED HEPARIN by treatment with a depolymerizing agent and isolation of the target product, characterized in that, in order to reduce the duration of the process, nitrous acid or a mixture of periodate and sodium perchlorate are used as the depolymerizing agent, and the treatment is carried out with 20 ml of nitrous acid per 1 wt.h. heparin in a mixture of water and dimethoxyethane at a ratio of 1: 1 at 10 ° C for 2 minutes, followed by the introduction of 2 parts by weight sodium acetate per 1 parts by weight heparin or an aqueous mixture of periodate and: <g sodium perchlorate in a molar ratio of 0.04: 0.4 per 1 wt.h. heparin and pH 3 in the dark.
ΐ

类似技术:

---

公开号 | 公开日 | 专利标题

---

SU1209033A3|1986-01-30|Method of producing depolymerized heparin

---

Nishimura et al.1986|Bioactive chitin derivatives. Activation of mouse-peritoneal macrophages by O-| chitins

---

US4500519A|1985-02-19|Mucopolysaccharides having biological properties, preparation and method of use

---

JP2703777B2|1998-01-26|New pentasaccharide

---

FR2538404A1|1984-06-29|

---

HU203565B|1991-08-28|Process for producing heparin, heparane-sulfat and dermatane-sulfat of small molecular mass and pharmaceutical compositions containing them as active components

---

HU210925B|1995-09-28|Process to prepare polisaccharide mixtures wita low moleculare weight and pharmaceutical compns. contg. them

---

EP0319559A1|1989-06-14|Novel heparin derivatives

---

MXPA02003945A|2002-10-23|Novel oligosaccharides, preparation method and pharmaceutical compositions containing same.

---

JP5053512B2|2012-10-17|Epimerized derivatives of K5 polysaccharide with very high degree of sulfation

---

US10870711B2|2020-12-22|Process for the preparation of polysaccharides

---

DK174284B1|2002-11-11|Biologically active tetrasaccharides

---

US6486137B1|2002-11-26|Oligosaccharide mixtures having antithrombotic activity

---

US20090005341A1|2009-01-01|Process for the preparation of n-acyl-|k5-amine-o-sulfate-derivatives and products thus obtained

---

US20050010044A1|2005-01-13|Polysaccharides and methods and intermediates useful for their preparation

---

EP1188773A1|2002-03-20|Nitroderivatives of polysaccharides

---

JPH0643446B2|1994-06-08|Chitosan 6-sulfate and process for producing the same

---

RU2333222C2|2008-09-10|Epimerised k5 polysaccharide derivatives with high sulfation degree

---

JPH0616687A|1994-01-25|Heparin unsaturated tetrose and its production

---

KR20050024339A|2005-03-10|Process for the manufacture of n-acyl-|k5-amine-o-sulfate-derivatives and products thus obtained

同族专利:

---

公开号 | 公开日

---

EP0014184A2|1980-08-06|

---

DK160764C|1991-09-23|

---

NL930104I2|1997-02-03|

---

US4303651A|1981-12-01|

---

AT8998T|1984-09-15|

---

NO150801B|1984-09-10|

---

NO150801C|1984-12-27|

---

EP0014184A3|1980-10-01|

---

EP0014184B2|1989-10-18|

---

JPS56500066A|1981-01-22|

---

CA1136620A|1982-11-30|

---

DK380280A|1980-09-05|

---

NO802626L|1980-09-05|

---

DE3068924D1|1984-09-20|

---

EP0014184B1|1984-08-15|

---

WO1980001383A1|1980-07-10|

---

NL930104I1|1993-10-01|

---

DK160764B|1991-04-15|

---

JPS6344764B2|1988-09-06|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

RU2612813C1|2015-12-07|2017-03-13|Павел Андреевич Канаев|Method of producing heparin|US3135660A|1956-11-09|1964-06-02|Riker Laboratories Inc|Method for purifying sulfated carbohydrates with oxidizing agents|

---

US3066076A|1958-12-15|1962-11-27|Fo We Forschungs Und Verwertun|Soluble heparin product and process for preparing same|

---

FR2100735B1|1970-06-08|1974-08-30|Mar Pha Etu Expl Marques|

---

DE2148011C3|1970-10-05|1978-11-09|Aminkemi Ab|Process for producing non-thrombogenic plastic surfaces|

---

US3766167A|1971-03-26|1973-10-16|Research Corp|Orally active anticoagulant|

---

GB1399824A|1971-08-16|1975-07-02|Mar Pha Etu Expl Marques|Heparin esters|

---

IT1083903B|1977-08-09|1985-05-25|Lobo Srl|OLIGO-ETEROPOLISACCARIDI WITH HEPARINOSIMIL ACTIVITIES, PROCEDURE FOR THEIR OBTAINING AND RELATED THERAPEUTIC COMPOSITIONS|US4692435A|1978-11-06|1987-09-08|Choay, S.A.|Mucopolysaccharide composition having a regulatory action on coagulation, medicament containing same and process of preparation|

---

SE449753B|1978-11-06|1987-05-18|Choay Sa|MUCOPOLYSACCARIDE COMPOSITION WITH REGULATORY EFFECTS ON COAGULATION, MEDICINAL CONTAINING ITS SAME AND PROCEDURE FOR PREPARING THEREOF|

---

FR2440376B1|1978-11-06|1981-06-12|Choay Sa|

---

US4500519A|1978-11-06|1985-02-19|Choay S.A.|Mucopolysaccharides having biological properties, preparation and method of use|

---

FR2478646B2|1980-03-20|1983-06-24|Choay Sa|

---

FR2482611B1|1980-05-14|1986-03-07|Pharmindustrie|NOVEL SULFATED POLYSACCHARIDES, METHODS FOR THEIR PREPARATION AND THEIR USE AS MEDICAMENTS|

---

US4438261A|1980-05-19|1984-03-20|Riker Laboratories, Inc.|Anticoagulant substance|

---

CA1171375A|1980-09-15|1984-07-24|Ulf P.F. Lindahl|Oligosaccharides having selective anticoagulationactivity|

---

EP0049877B1|1980-10-09|1984-05-23|Roche Diagnostics GmbH|Method and reagent for the determination of antithrombin-bm|

---

FR2503714B1|1981-04-10|1986-11-21|Choay Sa|PROCESS FOR OBTAINING BIOLOGICALLY ACTIVE MUCOPOLYSACCHARIDES, OF HIGH PURITY, BY DEPOLYMERIZATION OF HEPARIN|

---

FR2504535B1|1981-04-28|1987-08-14|Choay Sa|DISACCHARIDES DERIVED FROM URONIC ACID AND GLUCOSAMINE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM FOR THE CONTROL OF BLOOD COAGULATION|

---

US4818816A|1981-04-28|1989-04-04|Choay, S.A.|Process for the organic synthesis of oligosaccharides and derivatives thereof|

---

AT15142T|1981-05-21|1985-09-15|Akzo Nv|ANTITHROMBOTIC BASED ON POLYSACCHARIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICAL COMPOSITIONS.|

---

US4396762A|1981-08-24|1983-08-02|Massachusetts Institute Of Technology|Heparinase derived anticoagulants|

---

CA1265132A|1982-01-15|1990-01-30|Mahmoud Nassr|Process for the organic synthesis of oligosaccharides and derivatives thereof|

---

AU563351C|1982-01-15|2003-06-19|Glaxo Group Limited|Synthesis of oligosaccharides|

---

US4539398A|1982-01-22|1985-09-03|Riker Laboratories, Inc.|Affinity fractionation of heparin on immobilized Concanavalin A|

---

CA1195322A|1982-07-19|1985-10-15|Eduardo Amaya|Process for manufacturing low molecular weightheparins by depolymerization of normal heparin|

---

FR2535324A1|1982-10-27|1984-05-04|Choay Sa|PERFECTED STATION FOR THE PURIFICATION OF WASTEWATER|

---

FR2538404B1|1982-12-28|1985-08-23|Anic Spa|

---

IT1195497B|1983-03-08|1988-10-19|Opocrin Spa|PROCEDURE FOR THE PREPARATION OF OLIGOSACCHARIDIC FRACTIONS EQUIPPED WITH PHARMACOLOGICAL PROPERTIES FOR CHEMICAL DEGRADATION OF HEPARIN|

---

FR2548672A1|1983-07-04|1985-01-11|Pharmuka Lab|SULPHATE OLIGOSACCHARIDES AND THEIR USE AS MEDICAMENTS|

---

GB8614189D0|1986-06-11|1986-07-16|Leo Pharm Prod Ltd|Pharmaceutical composition|

---

US4942156A|1986-08-20|1990-07-17|Hepar Industries, Inc.|Low molecular weight heparin derivatives having improved anti-Xa specificity|

---

US4745106A|1986-08-20|1988-05-17|Griffin Charles C|Heparin derivatives having improved anti-Xa specificity|

---

IT1213384B|1986-11-24|1989-12-20|Lab Derivati Organici Mediolan|PROCESS FOR THE CONTROLLED PREPARATION OF LOW MOLECULAR WEIGHT GILCOSAMINOGLICANS.|

---

FR2614026B1|1987-04-16|1992-04-17|Sanofi Sa|LOW MOLECULAR WEIGHT HEPARINS WITH REGULAR STRUCTURE, THEIR PREPARATION AND THEIR BIOLOGICAL APPLICATIONS|

---

EP0337327A1|1988-04-09|1989-10-18|Bioiberica, S.A.|Process for the preparation of new oligosaccharide fractions by controlled chemical depolimerization of heparin|

---

IT1230582B|1988-10-21|1991-10-28|Opocrin S P A Lab Farmabiologi|DERMATAN SULPHATE AND HEPARIN OILGOSACCHARID WITH ANTI-THEROSCLEROTIC ACTIVITIES|

---

WO1991015217A1|1990-04-06|1991-10-17|Washington University|Anticoagulant oligosaccharides|

---

USRE38743E1|1990-06-26|2005-06-14|Aventis Pharma S.A.|Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events|

---

US5665379A|1990-09-28|1997-09-09|Pharmacia & Upjohn Aktiebolag|Lipid particle forming matrix, preparation and use thereof|

---

FI921689A|1991-04-16|1992-10-17|Seikagagu Kogyo Kabushiki Kais|OLIGOSACKARID MED AFFINITET FOER FIBROBLASTTILLVAEXTFAKTOR OCH FOERFARANDE FOER FRAMSTAELLNING AV DENNA|

---

SE9101155D0|1991-04-18|1991-04-18|Kabi Pharmacia Ab|NOVEL HEPARIN DERIVATIVES|

---

GB9206291D0|1992-03-23|1992-05-06|Cancer Res Campaign Tech|Oligosaccharides having growth factor binding affinity|

---

DE4217916C2|1992-05-30|1995-05-18|Job Prof Dr Med Harenberg|N-alkylamine and N-arylalkylamine derivatives of heparin, process for their preparation and their use|

---

GB9306255D0|1993-03-25|1993-05-19|Cancer Res Campaign Tech|Heparan sulphate oligosaccharides having hepatocyte growth factor binding affinity|

---

SE9302135D0|1993-06-18|1993-06-18|Kabi Pharmacia Ab|NEW PHARMACEUTICAL COMPOSITION|

---

GB2299998B|1995-03-31|1997-03-26|Hamilton Civic Hospitals Res|Compositions for inhibiting thrombogenesis|

---

PT946185E|1996-11-27|2005-02-28|Aventis Pharm Prod Inc|PHARMACEUTICAL COMPOSITION COMPOSING A COMPOUND WHICH HAS ANTI-XA ACTIVITY AND AN ANTAGONIST COMPOUND OF THE PLAQUETARY AGGREGATION|

---

EP0986581A1|1997-06-06|2000-03-22|Hamilton Civic Hospitals Research Development, Inc.|Modified low molecular weight heparin that inhibits clot associated coagulation factors|

---

EP1190364A2|1999-04-23|2002-03-27|Massachusetts Institute Of Technology|System and method for polymer notation|

---

IL147318D0|1999-06-30|2002-08-14|Hamilton Civic Hospitals Res|Heparin compositions that inhibit clot associated coagulation factors|

---

JP2002097143A|2000-07-18|2002-04-02|Koyo Chemical Kk|Bloodstream ameliorator and agent or food for preventing thrombus|

---

EP1315539A2|2000-09-08|2003-06-04|Leo Pharma A/S|Antithrombotic compositions|

---

JP2006096668A|2002-11-08|2006-04-13|Ono Pharmaceut Co Ltd|Medicine comprising combination of elastase inhibitor with enzyme inhibitor of blood coagulation system and/or fibrinolysis system|

---

US6933372B2|2003-03-07|2005-08-23|Warner-Lambert Company|Method to produce a solid form of heparin|

---

BRPI0410844A|2003-06-05|2006-06-27|Centelion|Plasmid coding fibroblast growth factor for the treatment of angiogenic defects associated with hypercholesterolemia or diabetes|

---

ITMI20031679A1|2003-08-29|2005-02-28|Opocrin Spa|PROCESS FOR THE PRODUCTION OF LOW WEIGHT EPARINES|

---

US20050096294A1|2003-10-31|2005-05-05|Takashi Komai|Novel anti-coagulant|

---

EP1582531A1|2004-03-24|2005-10-05|Aventis Pharma S.A.|Process for oxidizing unfractionated heparins and detecting presence or absence of glycoserine in heparin and heparin products|

---

EP1792621B1|2005-11-30|2012-04-04|Istituto di Ricerche Chimiche e Biochimiche "G. Ronzoni"|Orally administrable heparin derivatives|

---

ES2567079T3|2007-11-02|2016-04-19|Momenta Pharmaceuticals, Inc.|Polysaccharide compositions that are not anticoagulants|

---

US8569262B2|2007-11-02|2013-10-29|Momenta Pharmaceuticals, Inc.|Polysaccharide compositions and methods of use for the treatment and prevention of disorders associated with progenitor cell mobilization|

---

US8592393B2|2007-11-02|2013-11-26|Momenta Pharmaceuticals, Inc.|Polysaccharide compositions and methods of use for the treatment and prevention of disorders associated with progenitor cell mobilization|

---

AU2009250803A1|2008-05-20|2009-11-26|Crystal Clear Partnership|Separation of polysaccharides by charge density gradient|

---

ES2340902B1|2008-07-01|2011-05-03|Laboratorios Farmaceuticos Rovi, S.A.|PHARMACEUTICAL COMPOSITION WITH GLYCAMINOGLYGANS AND ITS USE IN THE TREATMENT OF CHRONIC ULCERAS.|

---

EP2558506B1|2010-04-16|2019-06-26|Momenta Pharmaceuticals, Inc.|Tissue targeting|

---

AU2011268470B2|2010-06-17|2017-02-02|Momenta Pharmaceuticals, Inc.|Methods and compositions for promoting hair growth|

---

ME02994B|2011-12-19|2018-10-20|Dilafor Ab|Non anti-coagulative glycosaminoglycans comprising repeating disaccharide unit and their medical use|

---

WO2013095215A1|2011-12-19|2013-06-27|Dilaforette Ab|Low anticoagulant heparins|

---

JP2016520613A|2013-05-28|2016-07-14|モメンタ ファーマシューティカルズ インコーポレイテッド|Pharmaceutical composition|

---

US20210040239A1|2018-02-14|2021-02-11|Biological E Limited|Improved process for the preparation of dalteparin sodium|

---

WO2021007429A1|2019-07-09|2021-01-14|Optimvia Llc|Methods for synthesizing anticoagulant polysaccharides|

法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

SE7900164|1979-01-08|

---