DK3010940T3 - Nye fremgangsmåder til fremstilling af kemisk modificerede hepariner - Google Patents
Nye fremgangsmåder til fremstilling af kemisk modificerede hepariner Download PDFInfo
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- DK3010940T3 DK3010940T3 DK14739914.1T DK14739914T DK3010940T3 DK 3010940 T3 DK3010940 T3 DK 3010940T3 DK 14739914 T DK14739914 T DK 14739914T DK 3010940 T3 DK3010940 T3 DK 3010940T3
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- heparin
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- heparin derivative
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical class OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 194
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/04—Drugs for genital or sexual disorders; Contraceptives for inducing labour or abortion; Uterotonics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
- C08B37/0078—Degradation products
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Polymers & Plastics (AREA)
- Materials Engineering (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Saccharide Compounds (AREA)
Claims (15)
1. Fremgangsmåde til fremstilling af et heparinderivat med en gennemsnitlig molekylvægt fra ca. 4,6 til ca. 6,9 kDa og en anti-faktor Xa-aktivitet på mindre end ca. 10 lE/mg, og hvor heparinderivatet har en overvejende forekommende disaccharid som vist i formel I nedenfor,
og n er et heltal fra 2 til 20, svarende til molekylvægte mellem 1,2 og 12 kDa, og hvor heparinderivatet har signaler i regionen 5,0 ppm til 6,5 ppm i et 1H NMR-spektrum med en intensitet (%-forhold) på mindre end eller lig med ca. 4% i forhold til signalet ved 5,42 ppm af 1H NMR-spektret af ufraktioneret heparin, omfattende de på hinanden følgende trin: (i) at oxidere en sur vandig opløsning af ufraktioneret heparin ved tilsætning af et oxidationsmiddel; (ii) at depolymerisere det oxiderede heparin ved at udsætte produktet af trin (i) for alkali til dannelse af en alkalisk opløsning; (iii) at fastholde opløsningen fra trin (ii) ved en alkalisk pH-værdi i et tidsrum, der er påkrævet for at tilvejebringe depolymeriseret heparin med en molekylvægt inden for det førnævnte område; og (iv) at reducere terminale aldehyd-grupper af det depolymeriserede heparin ved tilsætning af hydridreduktionsmiddel til opløsningen opnået fra trin (iii), hvor tidsrummet mellem afslutningen af trin (i) og påbegyndelsen af trin (iv) styres for at minimere virkningen af resterende oxidationsmidler; og hvor tidsrummet i trin (iii) bestemmes ved analyse af opløsningen eller ved reference til et tidligere udført i det væsentlige identisk trin (iii).
2. Fremgangsmåde ifølge krav 1, hvor, i heparin-derivatet, mindst 70 % af molekylerne har en molekylvægt på mere end ca. 3 kDa.
3. Fremgangsmåde ifølge krav 1 eller krav 2, hvor heparinderivatet omfatter polysaccharider med en fordeling af kumulative molekylvægte som anført i tabellen nedenfor:
4. Fremgangsmåde ifølge et af de foregående krav, hvor, i heparinderivatet, signalerne i 1H NMR-spektret forekommer ved ca. 5,95 ppm og ca. 6,15 ppm.
5. Fremgangsmåde ifølge et af de foregående krav, hvor fremgangsmåden er til fremstilling af et heparinderivat, som også har en anti-faktor I la-aktivitet på mindre end 10 lE/mg.
6. Fremgangsmåde ifølge et af de foregående krav, hvor, i heparinderivatet, de polysaccharidkæder, der forekommer i heparinderivatet, i det væsentlige er uden kemisk intakte saccharidsekvenser, der medierer den antikoagule-rende virkning.
7. Fremgangsmåde ifølge et af de foregående krav, hvor, i heparinderivatet, mindst ca. 90 % af ikke-sulfaterede vicinale diol-dele i det ufraktionerede he-parin-udgangsmateriale er blevet omdannet.
8. Fremgangsmåde ifølge krav 10, hvor de ikke-sulfaterede vicinale diol-dele omfatter iduron- og gluconsyre-resterne af heparin.
9. Fremgangsmåde ifølge et af de foregående krav, hvor oxidationsmidlet anvendt i trin (i) er natriummetaperiodat.
10. Fremgangsmåde ifølge et af de foregående krav, hvor trin (i) kræver oxidation af en vandig opløsning af ufraktioneret heparin ved tilsætning af natriummetaperiodat, ved en pH-værdi fra ca. 4,5 til ca. 5,5 og ved reduceret temperatur.
11. Fremgangsmåde ifølge et af de foregående krav, hvor trin (ii) kræver de-polymerisering af det oxiderede heparin ved at udsætte produktet af trin (i) for alkali til dannelse af en opløsning med en pH-værdi fra ca. 8 til ca. 13.
12. Fremgangsmåde ifølge et af de foregående krav, hvor fremgangsmåden yderligere omfatter et eller flere af trinnene: (iiia) at udsætte opløsningen opnået fra trin (iii) for syre til dannelse af en opløsning med en pH-værdi fra ca. 5,5 til ca. 6,5; (iva) at quenche reduktionsreaktionen ved at sænke pH-værdien til dannelse af en sur opløsning og eventuelt (ivb) at justere pH-værdien af opløsningen fra trin (iva) til ca. neutral; og (v) at genindvinde heparinderivatet fra opløsningen opnået fra trin (iv) (eller i givet fald trin (iva) eller (ivb)).
13. Fremgangsmåde ifølge et af de foregående krav, hvor reduktionsmidlet anvendt i trin (iv) er natriumborhydrid.
14. Fremgangsmåde ifølge et af de foregående krav, hvor tidsrummet mellem afslutningen af trin (i) og påbegyndelsen af trin (iii) er højst 6 timer.
15. Fremgangsmåde til fremstilling af en farmaceutisk sammensætning omfattende et heparinderivat ifølge et hvilket som helst af kravene 1 til 8, hvilken fremgangsmåde omfatter trinnene: (a) at fremstille et heparinderivat under anvendelse af en fremgangsmåde ifølge et hvilket som helst af kravene 1 til 14; og (b) at kombinere heparinderivatet opnået i trin (a) med en eller flere farmaceutisk acceptable adjuvanser, excipienser eller fortyndingsmidler.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1310928.5A GB2515315A (en) | 2013-06-19 | 2013-06-19 | New Processes |
| PCT/GB2014/051878 WO2014202982A1 (en) | 2013-06-19 | 2014-06-19 | New processes for the production of chemically-modified heparins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK3010940T3 true DK3010940T3 (da) | 2017-10-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK14739914.1T DK3010940T3 (da) | 2013-06-19 | 2014-06-19 | Nye fremgangsmåder til fremstilling af kemisk modificerede hepariner |
Country Status (15)
| Country | Link |
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| US (1) | US10023659B2 (da) |
| EP (1) | EP3010940B1 (da) |
| JP (1) | JP6378328B2 (da) |
| CN (1) | CN105324398B (da) |
| CA (1) | CA2914256C (da) |
| DK (1) | DK3010940T3 (da) |
| ES (1) | ES2646337T3 (da) |
| GB (1) | GB2515315A (da) |
| HU (1) | HUE037037T2 (da) |
| IL (1) | IL242888B (da) |
| LT (1) | LT3010940T (da) |
| PL (1) | PL3010940T3 (da) |
| PT (1) | PT3010940T (da) |
| TW (1) | TWI672146B (da) |
| WO (1) | WO2014202982A1 (da) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108424474B (zh) * | 2017-02-15 | 2023-07-25 | 清华大学 | 去抗凝肝素衍生物及其用于炎症性肠病的治疗 |
| CN115103679A (zh) | 2020-02-17 | 2022-09-23 | 迪乐方有限责任公司 | 用于治疗先兆子痫的他福昔肝素 |
| EP4272749A1 (en) | 2022-05-03 | 2023-11-08 | Dilafor AB | New medical use of tafoxiparin |
| JP2025514038A (ja) | 2022-05-03 | 2025-05-02 | ディラフォール アクチエボラグ | タフォキシパリンの新規な医学的使用 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2614026B1 (fr) * | 1987-04-16 | 1992-04-17 | Sanofi Sa | Heparines de bas poids moleculaire, a structure reguliere, leur preparation et leurs applications biologiques |
| FR2663639B1 (fr) * | 1990-06-26 | 1994-03-18 | Rhone Poulenc Sante | Melanges de polysaccharides de bas poids moleculaires procede de preparation et utilisation. |
| SE9101155D0 (sv) | 1991-04-18 | 1991-04-18 | Kabi Pharmacia Ab | Novel heparin derivatives |
| GB2299998B (en) * | 1995-03-31 | 1997-03-26 | Hamilton Civic Hospitals Res | Compositions for inhibiting thrombogenesis |
| US5767269A (en) | 1996-10-01 | 1998-06-16 | Hamilton Civic Hospitals Research Development Inc. | Processes for the preparation of low-affinity, low molecular weight heparins useful as antithrombotics |
| EP1033375A4 (en) | 1997-11-20 | 2002-04-24 | Ikuo Yamashina | MODIFICATION OF LOW MOLECULAR MASS HEPARIN AND REMEDY FOR SKIN Ulcer |
| DE69931038T2 (de) | 1998-02-26 | 2006-11-23 | Seikagaku Corp. | Neue polysaccharidderivate, verfahren zu ihrer herstellung und medizinische zusammensetzungen die diese als aktives bestandteil enthalten |
| JP4585072B2 (ja) * | 2000-02-29 | 2010-11-24 | 扶桑薬品工業株式会社 | ヘパリン解重合法、解重合ヘパリン、その誘導体および医薬組成物 |
| US20060040896A1 (en) | 2004-08-18 | 2006-02-23 | Paringenix, Inc. | Method and medicament for anticoagulation using a sulfated polysaccharide with enhanced anti-inflammatory activity |
| US20070021378A1 (en) | 2005-07-22 | 2007-01-25 | The Regents Of The University Of California | Heparin compositions and selectin inhibition |
| JP2008120441A (ja) * | 2006-11-15 | 2008-05-29 | Maruichi Valve Co Ltd | エアゾール容器用噴射装置 |
| CN100467493C (zh) * | 2007-02-01 | 2009-03-11 | 高树华 | 一种低分子量肝素钙生产工艺 |
| WO2009007224A1 (en) * | 2007-07-10 | 2009-01-15 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Low molecular weight heparin derivatives having neuroprotective activity |
| US8592393B2 (en) | 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 |
| CA2703848C (en) | 2007-11-02 | 2016-10-11 | Momenta Pharmaceuticals, Inc. | Non-anticoagulant polysaccharide compositions |
| BR112014014454B1 (pt) * | 2011-12-19 | 2021-03-09 | Dilafor Ab | glicosaminoglicanos não anti-coagulativos compreendendo unidade de dissacarìdo repetida e seus usos médicos |
| WO2013095215A1 (en) | 2011-12-19 | 2013-06-27 | Dilaforette Ab | Low anticoagulant heparins |
| JP2018034714A (ja) * | 2016-09-01 | 2018-03-08 | 日立金属株式会社 | 車両用ホイール |
-
2013
- 2013-06-19 GB GB1310928.5A patent/GB2515315A/en not_active Withdrawn
-
2014
- 2014-06-18 TW TW103120997A patent/TWI672146B/zh active
- 2014-06-19 PT PT147399141T patent/PT3010940T/pt unknown
- 2014-06-19 HU HUE14739914A patent/HUE037037T2/hu unknown
- 2014-06-19 WO PCT/GB2014/051878 patent/WO2014202982A1/en not_active Ceased
- 2014-06-19 EP EP14739914.1A patent/EP3010940B1/en active Active
- 2014-06-19 ES ES14739914.1T patent/ES2646337T3/es active Active
- 2014-06-19 US US14/898,862 patent/US10023659B2/en active Active
- 2014-06-19 JP JP2016520743A patent/JP6378328B2/ja active Active
- 2014-06-19 LT LTEP14739914.1T patent/LT3010940T/lt unknown
- 2014-06-19 CA CA2914256A patent/CA2914256C/en active Active
- 2014-06-19 CN CN201480034904.4A patent/CN105324398B/zh active Active
- 2014-06-19 DK DK14739914.1T patent/DK3010940T3/da active
- 2014-06-19 PL PL14739914T patent/PL3010940T3/pl unknown
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2015
- 2015-12-02 IL IL242888A patent/IL242888B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| PT3010940T (pt) | 2017-11-14 |
| CA2914256A1 (en) | 2014-12-24 |
| HK1220475A1 (en) | 2017-05-05 |
| IL242888B (en) | 2018-08-30 |
| HUE037037T2 (hu) | 2018-08-28 |
| CA2914256C (en) | 2021-03-02 |
| US10023659B2 (en) | 2018-07-17 |
| PL3010940T3 (pl) | 2018-01-31 |
| ES2646337T3 (es) | 2017-12-13 |
| CN105324398B (zh) | 2018-06-01 |
| GB201310928D0 (en) | 2013-07-31 |
| EP3010940B1 (en) | 2017-08-09 |
| GB2515315A (en) | 2014-12-24 |
| WO2014202982A1 (en) | 2014-12-24 |
| EP3010940A1 (en) | 2016-04-27 |
| JP2016522302A (ja) | 2016-07-28 |
| CN105324398A (zh) | 2016-02-10 |
| LT3010940T (lt) | 2017-09-25 |
| JP6378328B2 (ja) | 2018-08-22 |
| TWI672146B (zh) | 2019-09-21 |
| US20160137754A1 (en) | 2016-05-19 |
| TW201534309A (zh) | 2015-09-16 |
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