WO2011063595A1 - 低聚凤梨参糖胺聚糖及其制备方法 - Google Patents
低聚凤梨参糖胺聚糖及其制备方法 Download PDFInfo
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- WO2011063595A1 WO2011063595A1 PCT/CN2010/001678 CN2010001678W WO2011063595A1 WO 2011063595 A1 WO2011063595 A1 WO 2011063595A1 CN 2010001678 W CN2010001678 W CN 2010001678W WO 2011063595 A1 WO2011063595 A1 WO 2011063595A1
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- WIPO (PCT)
- Prior art keywords
- dthg
- glycosaminoglycan
- oligomeric
- thg
- pineapple
- Prior art date
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Classifications
-
- 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
- A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
-
- 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
-
- 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
-
- 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
Definitions
- Fucose-branched Glycosaminoglycan (fiicose-containing glycos-aminoglycan or Fucosylated Glycosaminoglycan, FGAG) or Fucose-branched Chondroitin Sulfate (FCS) refers to a type of extract obtained from the body wall or internal organs of the echinoderms.
- a special glycosaminoglycan with a sulfated fucose-substituted group (Fan et al., Acta Pharmacea Sinica, 1980, 18(3): 203; Ricardo P. et al., J. Biol. Chem., 1988, 263 (34): 18176; Yutaka K. et al., J. Biol. Chem., 1990, 265:5081).
- Body Wall 1 1.28 :0.68 : 1.72 , , Food and Fermentation Industry, 2006, 32: 123
- GalNAc (Lubor Borsig et al. J. Biol. Chem. 2007, 282: 14984).
- the antithrombotic and anticoagulant activities of FGAG and its derivatives derived from sea cucumber and its derivatives, pharmacological action target data show that FGAG has anticoagulant mechanism different from heparin and dermatan dermatan, and its anticoagulation /Antithrombotic targets may involve:
- the research data on the chemical and biological activities of sea cucumber FGAG mainly come from L. grisea and sea cucumber.
- the oligomeric pineapple glycosaminoglycan is a depolymerization product of fucosylated glycosaminoglycan (THG) derived from Thelenota ananas, which has the formula Structure:
- a method of preparing the above oligomeric pineapple glycosaminoglycan which comprises the following steps:
- step 1) may generally include steps of cutting/pulverization, enzymatic hydrolysis, alkaline hydrolysis, decolorization, separation, and the like.
- Pineapple can be fresh or dried to the internal organs.
- the dried pineapple ginseng product In order to achieve the purpose of increasing the extraction yield, the dried pineapple ginseng product generally needs to be cut into a sheet or a small piece, and then immersed in water. For the fresh product, it can be cut and directly pulverized into a suspension, and then Enzymatic and/or alkaline treatment is carried out.
- the collected dTHG can be purified by methods known in the art to remove low and/or high molecular impurity components.
- Purification methods include, but are not limited to, removal of low and/or high molecular impurity components by dialysis, preparation of THG salts by ion exchange, and/or purification by gel chromatography/anion exchange chromatography.
- the method for preparing an oligomeric pineapple glycosaminoglycan of the present invention may comprise the steps of:
- a pharmaceutical composition comprising dTHG of the present invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient.
- the pharmaceutical composition can be prepared into various dosage forms such as oral preparations (including solid and liquid preparations), injections (including injections and lyophilized powder injections), but the inventors have found that oral absorption of dTHG is weak, and subcutaneous injection or the like. Administration by injection route has good bioavailability. Therefore, the pharmaceutical composition of the present invention is preferably prepared as an injection, and since dTHG has good water solubility, its solution type preparation and lyophilized preparation can be easily prepared by a technical method commonly used in the art.
- the dTHG of the present invention is a potent endogenous factor X enzyme inhibitor having good anticoagulant and antithrombotic activity, and thus the above pharmaceutical composition containing dTHG can be used for preventing and/or treating thrombotic diseases, for example, various techniques.
- the use and dosage of the prevention/and/or treatment of different diseases should be determined by the clinician.
- Figure 3 shows the 13 C NMR and DEPT spectra of THG and sea cucumber FGAG (ie SJG );
- Figure 4 shows the NMR homonuclear/heteronuclear correlation spectrum of dTHG-6;
- the mixture was allowed to stand, centrifuged, centrifuged and dissolved in 20 times (v/w) water, and centrifuged to remove insoluble matter.
- TMG pineapple glycosaminoglycan
- lOg SJG and 10g HLG were respectively taken and operated under the above depolymerization conditions, and the time point for depolymerizing the reaction liquid was set to two, that is, 3 hours and 5 hours after the start of the reaction.
- the obtained depolymerized products were recorded as dSJG-1, dSJG-2 and dHLG-1, dHLG-2, and the total amount of dSJG was 7.5 g, and the total amount of dHLG was 8.0 g.
- THG of the present invention differs from other known side chain substituents of sea cucumber FGAG, for example, data (Paulo AS et al., J. Biol. Chem. 1996, 271: 23973; Lubor Borsig etal, J. Biol Chem 2007 , 282, 14984) I3 C NMR spectrum and the following display, FGAG L. grisea derived from about 35 percent GalNAc 6-position sulfate group is not substituted;... information ( Fan et al., Pharmaceutics Journal, 1983, 18 (3): 203) showed that the GGANA main chain of G. japonicus GGANA had only 6-position sulfated and no 4-sulfated.
- GalNAc4S6S represents 4,6-disulfate-N-acetylaminogalactosyl
- GalNAc4S represents 4-acid-N-acetylaminogalactosyl
- Fuc-2S4S represents 2,4-disulfate fucose
- Fuc-3S represents 3-sulfate fucose group
- Fuc-4S represents 4-sulfate fucose group
- Fuc-OS represents fucosyl group without acid group.
- THG side chain fucoid In view of the structural differences between THG and SJG and HLG, mainly in the type of side chain acidified fucosyl group, it is speculated that the difference in platelet activity is due to the difference in fucose side chain, THG side chain fucoid
- the glycosyl type/feature effectively weakens its platelet aggregation activity.
- the platelet-inducing activity of dTHG has disappeared when the weight average molecular weight of THG is as low as about 20,000 Da, and the molecular weight of SJG and HLG needs to be low at about 9,000 - 12,000 Da to avoid platelets at high concentrations.
- LMWH Low molecular weight heparin sodium
- reagents include Reagents: R1: Human Factor X; R2: Activeation Reagent, human Factor IXa, containing human thrombin, calcium and synthetic phospholipids; R3: SXa-11, Chomogenic substrate, specific for Factor Xa; R4 :
- Tris-BSA Buffer Tris-BSA Buffer; HYPHEN BioMed (France).
- the AOD was calculated from the blank control (R4), and the IC 5 value of each sample was determined to suppress Ila according to the formula provided in the literature (Sheehan JP & Walke ⁇ . ⁇ , Blood, 2006, 107: 3876-3882).
- appropriate depolymerization THG may produce the highest possible potency ratio of anti-f.Xase to HC-II-dependent anti-Ila activity and/or as high as possible anti-f.Xase and prolongation while eliminating FGAG-induced platelet aggregation activity.
- the potency ratio of APTT activity may be produced by the highest possible potency ratio of anti-f.Xase to HC-II-dependent anti-Ila activity and/or as high as possible anti-f.Xase and prolongation while eliminating FGAG-induced platelet aggregation activity.
- the platelet-inducing activity of dTHG has a molecular weight (Mw) as low as about 20000 Da, and the anticoagulant activity (prolonged APTT time) is still present when the Mw is as low as about 6000 Da.
- Mw molecular weight
- prolonged APTT time the anticoagulant activity
- the results in Table 5 also indicate that LMWH has a relatively weak anti-f.Xase activity, whereas for dSJG, platelet-inducing activity limits the use of products with higher activity and/or higher "potency ratio".
- the present invention is based on (1) eliminating platelet-inducing activity, (2) obtaining as high an anti-Xase/anti-Ila potency ratio as possible, and/or (3) obtaining as high an anti-Xase/prolonged APTT potency ratio as possible,
- the weight average molecular weight (Mw) of dTHG selected in the present invention may range from about 8000 °.
- the preferred molecular weight range is from about 10,000 to 18,000 Da, and the more preferred molecular weight range is from about 12,000 to 16,000 Da.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- General Chemical & Material Sciences (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2010324437A AU2010324437B2 (en) | 2009-11-25 | 2010-10-25 | Depolymerized glycosaminoglycan from Thelenota ananas and preparation method thereof |
US13/512,142 US8809300B2 (en) | 2009-11-25 | 2010-10-25 | Depolymerized glycosaminoglycan from Thelenota ananas and preparation method thereof |
Applications Claiming Priority (2)
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---|---|---|---|
CN200910109861A CN101724086B (zh) | 2009-11-25 | 2009-11-25 | 低聚凤梨参糖胺聚糖及其制备方法 |
CN200910109861.2 | 2009-11-25 |
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WO2011063595A1 true WO2011063595A1 (zh) | 2011-06-03 |
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PCT/CN2010/001678 WO2011063595A1 (zh) | 2009-11-25 | 2010-10-25 | 低聚凤梨参糖胺聚糖及其制备方法 |
Country Status (4)
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US (1) | US8809300B2 (zh) |
CN (1) | CN101724086B (zh) |
AU (1) | AU2010324437B2 (zh) |
WO (1) | WO2011063595A1 (zh) |
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-
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- 2010-10-25 WO PCT/CN2010/001678 patent/WO2011063595A1/zh active Application Filing
- 2010-10-25 AU AU2010324437A patent/AU2010324437B2/en not_active Ceased
- 2010-10-25 US US13/512,142 patent/US8809300B2/en active Active
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Publication number | Publication date |
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CN101724086B (zh) | 2012-09-26 |
CN101724086A (zh) | 2010-06-09 |
AU2010324437B2 (en) | 2014-12-18 |
US8809300B2 (en) | 2014-08-19 |
AU2010324437A1 (en) | 2012-07-19 |
US20120270834A1 (en) | 2012-10-25 |
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