WO2004033503A1 - Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant - Google Patents
Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant Download PDFInfo
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- WO2004033503A1 WO2004033503A1 PCT/FR2003/002960 FR0302960W WO2004033503A1 WO 2004033503 A1 WO2004033503 A1 WO 2004033503A1 FR 0302960 W FR0302960 W FR 0302960W WO 2004033503 A1 WO2004033503 A1 WO 2004033503A1
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to mixtures of heparin-derived polysaccharides, to a process for their preparation and to pharmaceutical compositions containing them.
- Heparin is a mixture of sulfated ucopolysaccharides of animal origin, used in particular for its anticoagulant and antithrombotic properties.
- Heparin however, has drawbacks that limit the conditions of its use.
- its important anticoagulant activity anti-lia
- anti-lia can cause haemorrhages.
- Low molecular weight heparins obtained by basic depolymerization of heparin esters have been proposed (EP40144); However, these products still have significant anti-IIa activity.
- heparins of very low molecular weight are prepared by a process different from
- One of the objectives of the invention is therefore to improve the anti-Xa activity and the Anti-Xa / Anti-IIa ratio by modifying the processes described in the prior art, in particular by controlling the percentage of water at the same time. step of depolymerization.
- the heparins thus obtained thus have an excellent antitrombotic activity and possess an aXa activity close to that of heparin while reducing the risk of haemorrhage with a very low alla activity.
- the products of the invention have half-life times much higher than that of heparin.
- the invention therefore relates to novel mixtures of heparin-derived polysaccharides having a more selective activity with respect to activated factor X (factor Xa) and activated factor II (factor IIa) than heparin.
- oligosaccharides having an average molecular weight of 1500 to 3000 Da may be referred to as oligosaccharides.
- the subject of the present invention is therefore mixtures of sulphated oligosaccharides having the general structure of the constituent polysaccharides of heparin and having the following characteristics:
- the constituent oligosaccharides of the mixtures contain 2 to 26 saccharide units, have an uronic acid-4,5 unsaturated 2-O-sulfate unit at one of their ends, and contain the ⁇ lIa-IIs-Is exasaccharide of formula:
- the ⁇ lIa-IIs-Is hexasaccharide contained in the oligosaccharide mixture described in the present invention is a sequence strongly affine to ATIII and characterized by an aa activity greater than 740 U / mg.
- the oligosaccharide mixture described in the present invention is in the form of an alkali or alkaline earth metal salt.
- the alkali or alkaline earth metal salt the sodium, potassium, calcium and magnesium salts are preferred.
- the average molecular weight is determined by high pressure liquid chromatography using two columns in series, for example those marketed under the name of
- TSK G3000 XL and TSK G2000 XL The detection is carried out by refractometry.
- the eluent used is lithium nitrate and the flow rate is 0.6 ml / min.
- the system is calibrated with standards prepared by fractionation of Enoxaparin (AVENTIS) by agarose-polyacrylamide gel (IBF) chromatography. This preparation is carried out according to the technique described by Barrowcliffe et al., Thromb. Res., 12, 27-36 (1977-78) or D.A. Lane et al., Thromb. Res., 12, 257-271 (1977-78). The results are calculated using the GPC6 software (Per in Elmer).
- Anti-Xa activity is measured by the amydolytic method on a chromogenic substrate described by Teien et al., Thromb. Res., 10, 399-410 (1977), with as standard the first international standard for low molecular weight heparins.
- the anti-IIa activity is measured by the technique described by Anderson L.O. et al., Thromb. Res., 15, 531-541 (1979), with as standard the first international standard of low molecular weight heparins.
- the hexasaccharide fraction preferably represents from 15 to 25% of the oligosaccharide mixture.
- the mixtures according to the invention contain from 8 to 15% of the ⁇ lIa-IIs-Is hexasaccharide in the hexasaccharide fraction of the oligosaccharide mixture.
- the percentage of the hexasaccharide fraction can be determined analytically by high pressure liquid chromatography on TSK G3000 XL and TSK G2000 XL columns or by preparative separation of the hexasaccharide fraction.
- the mixture is chromatographed on columns filled with agarose-type polyacrylamide gel, such as that sold under the trademark Ultrogel ACA202 R (Biosepra).
- the mixture is eluted with sodium hydrogencarbonate solution.
- the sodium hydrogen carbonate solution is a solution of 0.1 mol / l to 1 mol / l. Even more preferentially, the separation is carried out at a concentration of 1 mol / l.
- the detection is carried out by UV spectrometry (254 nm).
- the hexasaccharide fraction in solution in sodium hydrogencarbonate is neutralized with glacial acetic acid.
- the solution is then concentrated under reduced pressure so as to obtain a concentration of sodium acetate greater than 30% by weight.
- the hexasaccharide fraction is precipitated by the addition of 3 to 5 volumes of ethanol.
- the fraction of hexasaccharides is recovered by filtration on sintered glass n ° 3.
- the resulting hexasaccharide mixture can be analyzed by HPLC (High Performance Liquid Chromatography) to determine the ⁇ IIa-IIs-Is hexasaccharide content.
- the ⁇ lIa-IIs-Is hexasaccharide can be isolated by preparative HPLC chromatography or affinity chromatography on antithrombin III sepharose column according to the techniques used by those skilled in the art (Hook M., I. Bjork, J. Hopwood and U. Lindahl, F. E. B. S letters, vol 656 (1) (1976)).
- the mixtures according to the invention have an anti-Xa activity of between 150 IU / mg and 200 IU / mg.
- the mixtures according to the invention have an anti-IIa activity of less than 5 IU / mg, and most preferably 0.5 to 3.5 IU / mg.
- the examples of applications described below show values between 1.1 and 1.6 IU / mg when the preferred features of the process
- the mixtures have an anti-Xa activity / anti-IIa activity ratio greater than 50 and most preferably greater than 100.
- the mixtures according to the invention have an average molecular weight of between 2000 and 3000 Daltons, and all particularly an average molecular weight of between 2400 and 2650 Da.
- the subject of the invention is therefore particularly the mixtures as defined above, having an anti-Xa activity of between 150 and 200 IU / mg, an Antilla activity of between 0.5 and 3.5 IU / mg and an average molecular weight of between 2400 and 2650 Da.
- the oligosaccharide mixtures according to the invention can be prepared by depolymerization of a quaternary ammonium salt of the benzyl ester of heparin in an organic medium, by means of a strong organic base of pKa, preferably greater than 20.
- pKa preferably greater than 20.
- the process according to the invention takes up the main steps of the process as described in WO 0208295 while adding an essential characteristic which makes it possible to obtain the mixtures of oligosaccharides according to the invention with the physico-chemical characteristics and the activities described above. .
- the process according to the present invention is in fact characterized by a control of the high selectivity of the base during the depolymerization. It allows to depolymerize heparin while preserving as much as possible the sequences AIIII-affinates such as the ⁇ lIa-IIs-Is hexasaccharide described in the present invention. This critical stage of the process makes it possible to obtain the polysaccharides according to the invention.
- This characteristic of the process results in unexpected aXa activities with respect to the average molecular weight of the oligosaccharide mixtures (150 IU / mg ⁇ aXa ⁇ 200 IU / mg for an average molecular weight between 2000 Da and 3000 Da).
- This selectivity is due to the very particular physicochemical characteristics of phosphazene bases which have a pKa greater than 20, a very strong steric hindrance and a low nucleophilicity.
- the following table summarizes the impact of the water content on the selectivity of the depolymerization (only this parameter is variable in the tests: the stoichiometries of the reagents, the dilutions, the temperatures remain constant according to the criteria of the man of the
- the base used is the phosphazene base: 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,3-diaza phosphorine.
- the subject of the invention is therefore particularly the step of depolymerization of the quaternary ammonium salt of the benzyl ester of heparin obtained according to the methods known to those skilled in the art, characterized in that a base of the family of phosphazenes, especially in dichloromethane solution, containing a percentage of water less than 0.6%. Preferably, this percentage of water should be chosen less than 0.3% and especially less than 0.2%.
- the molar base / ester ratio is between 0.2 and 5, preferably between 0.6 and 2 and most preferably between 0.8 and 1.2.
- the use of the equimolar ratio is therefore one of the preferred embodiments of the invention.
- the quaternary ammonium salt of the benzyl ester of heparin is preferably the salt of benzethonium, cetylpyridinium or cetyltrimethylammonium.
- the bases of the family of phosphazenes are preferably those of formula:
- radicals R 1 to R 7 are identical or different and represent alkyl radicals.
- the alkyl radicals contain 1 to 6 carbon atoms in straight or branched chain.
- the subject of the invention is therefore a process for preparing the oligosaccharide mixtures according to the invention comprising the following steps: a) Transalification of sodium heparin by the action of benzethonium chloride, b) Esterification of benzethonium heparinate by action of benzyl chloride, c) Transalification of the benzyl ester obtained in the quaternary ammonium salt, d) Depolymerization of the quaternary ammonium salt of the benzyl ester of heparin by the method as defined above, e ) Transformation of the quaternary ammonium salt into sodium salt, f) Possibly saponification of heparin by the action of a base such as sodium hydroxide g) Optionally purification, in particular by the action of an oxidation agent such as water oxygenated.
- an oxidation agent such as water oxygenated.
- n X + Y + Z (overall sulfation rate of the average dissacha ⁇ de)
- step e The conversion of the quaternary ammonium salt of the benzyl ester of the depolymerized heparin to the sodium salt (step e) is carried out, generally, by treatment of the reaction medium with an alcoholic solution of sodium acetate and, preferably with a 10% solution of sodium acetate in methanol (w / v) at a temperature between 15 and 25 ° C.
- the equivalent in weight added acetate is preferably 3 times greater than the mass of quaternary ammonium salt of the benzyl ester of heparin engaged in the depolymerization reaction.
- the saponification (step f) is generally carried out using an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an aqueous medium, at a temperature of between 0 and 20 ° C. and preferably 0 and 10 ° C. Generally 1 to 5 molar equivalents of alkali metal hydroxide will be used. Preferably, the saponification will be carried out in the presence of 1 to 2 molar equivalents of the alkali metal hydroxide.
- an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide
- the final product may optionally be purified (step g) by any known method of purification of the depolymerized heparins (for example EP 0037319B1).
- it is purified by means of hydrogen peroxide in an aqueous medium at a temperature of 10 to 50 ° C.
- this operation will be performed between 20 and 40 ° C.
- the quaternary ammonium salt of the benzyl ester of heparin can be prepared according to the following reaction scheme: a) conversion of sodium heparin using benzethonium chloride to obtain benzethonium heparinate (Transalification), b) esterification of the benzethonium salt obtained previously using benzyl chloride then treatment with an alcoholic solution of sodium acetate to obtain the sodium salt of the benzyl ester of heparin, c) transalification of the sodium salt of the benzyl ester of heparin to the quaternary ammonium salt and, preferably, to the benzethonium salt, cetyl pyrinium or cetyltrimethylammonium salt.
- step a) is carried out by the action of excess benzethonium chloride on sodium heparin at a temperature in the region of 15 to 25 ° C.
- the salt / heparin sodium molar ratio is between 3 and 4.
- the starting heparin used is preferably a porcine heparin. This can be purified beforehand to reduce its level of dermatan sulfate according to the process described in patent FR2663639.
- the esterification of step b) is preferably carried out in a chlorinated organic solvent (chloroform, methylene chloride for example) at a temperature of between 25 and 45 ° C. and preferably between 30 and 40 ° C. ° C.
- the ester in the benzethonium salt form is then recovered as the sodium salt by precipitation with 10% by weight sodium acetate in an alcohol such as methanol.
- an alcohol such as methanol.
- Generally 1 to 1.2 volumes of alcohol per volume of reaction medium are employed.
- the amount of benzyl chloride and the reaction time are adapted to obtain an esterification rate of between 50 and 100% and preferably between 70 and 90%.
- Preferably, 0.5 to 1.5 parts by weight of benzyl chloride are used per 1 part by weight of the benzethonium salt of heparin.
- the reaction time will be between 10 and 35 h.
- step c) is carried out by means of a quaternary ammonium chloride and, preferably, by means of benzethonium chloride, cetylpyri dinium chloride or cetyltrimethylammonium chloride, in an aqueous medium, at a temperature between 10 and 25 ° C.
- the ratio by mole of quaternary ammonium chloride / sodium salt of the benzyl ester of heparin is between 2 and 3.
- mixtures according to the invention in the form of sodium salt can be converted into another salt of an alkali metal or alkaline earth metal. It is possible to pass from one salt to another using the method described in patent FR 73 13 580.
- the mixtures according to the invention are not toxic and can thus be used as medicaments.
- the oligosaccharide mixtures of the present invention can be used as antithrombotic agents.
- they are useful for the treatment or prevention of venous and arterial thromboses, the deep vein thrombosis, pulmonary embolism, unstable angina, myocardial infarction, cardiac ischemia, occlusive diseases of the peripheral arteries and atrial fibrillation.
- They are also useful in the prevention and treatment of the proliferation of smooth muscle cells atherosclerosis and arteriosclerosis, for the treatment and prevention of cancer by modulating angiogenesis and growth factors, and for treating and the prevention of diabetic disorders such as diabetic retinopathies and nephropathies.
- the present invention also relates to pharmaceutical compositions containing as active ingredient a mixture of formula (I) optionally in combination with one or more inert excipients.
- compositions are, for example, solutions that can be injected subcutaneously or intravenously. They are also useful for pulmonary (inhalation) or oral administration.
- the dosage may vary depending on the age, weight and health status of the patient. For an adult, it is usually between 20 and 100 mg per day intramuscularly or subcutaneously.
- the Erlenmeyer flask B is rinsed with 200 ml of distilled water and the washing water is introduced into the Erlenmeyer flask A.
- the stirring is then stopped and the suspension is left to settle for 12 hours. This time elapsed, the clear part of the supernatant is removed and removed.
- 560 ml of water is added and stirred for 20 minutes. The precipitate is left to sediment in approximately 30 minutes. The supernatant is removed and discarded (560 ml).
- this wash operation is repeated twice with about 560 ml of distilled water. In the last washing operation, the precipitate is left in suspension and filtered on sintered glass 3.
- the cake is then washed with 4 times 200 ml of distilled water.
- the wet white solid is drained and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 60 ° C. After 12 hours of drying, 87.5 g of benzyl heparinate, benzethonium salt, are obtained. The yield obtained is 94.9%.
- Decasodium salt of 4-deoxy- ⁇ -L-threo-hex-enepyranosyluronic acid (1 ⁇ 4) -2-deoxy-2-acetamido-6-O-sulfo- ⁇ -D-glucopyranosyl- (1) -> 4) - ⁇ -D-glucopyranosyluronic acid- (1 ⁇ 4) -2-deoxy-2-sulfamido-3,6-di-O-sulfo- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) 2-O-sulfo- ⁇ -L-idopyranosyluronic acid (1-4) -2-desoxy-2-sulfamido-6-O-sulfo- ⁇ -D-glucopyranose.
- Examples 1-7 and 12 illustrate the influence of the water content on the selectivity of the polymerization reaction and the aXa activity and on the products obtained.
- Examples 8 to 10 illustrate the influence of the number base equivalents on the aXa activity and the product obtained (with a water content of 0.1%).
- Example 11 illustrates the use of another phosphazene base as 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,2,3-diaza-phosphorine:
- the cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 1.31 g of crude depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 66%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 14 ml of methanol are poured.
- the solution is then cooled to 10 ° C and stirred for about 15 minutes.
- 36 ml of methanol are then added and the mixture is stirred for one hour.
- Stirring is then stopped and the suspension is allowed to settle for about 15 minutes.
- the supernatant is then removed and then discarded (50 ml).
- 50 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 25 minutes.
- the supernatant is removed and discarded (50 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 1.13 g of pure depolymerized heparin (sodium salt) are obtained. The yield obtained is 87%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2600 Daltons Anti-Xa activity: 177 IU / mg Anti-IIa activity: 1.5 IU / mg Anti-Xa activity / anti-IIa activity ratio: 118
- the solution is then filtered through a 0.45 ⁇ m membrane and then 14 ml of methanol are poured.
- the solution is then cooled to 10 ° C. and stirred for 15 minutes.
- 36 ml of methanol are then added and the mixture is stirred for one hour.
- Stirring is then stopped and the suspension is left to sediment for 15 minutes.
- the supernatant is then removed and discarded (40 ml).
- 40 ml of methanol is added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 20 minutes.
- the supernatant is removed and discarded (50 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the precipitate in suspension is then filtered on sintered glass 3.
- the cake obtained is then washed with 100 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 2.57 g of crude depolymerized heparin, sodium salt in celite (5 g) are obtained. The yield obtained is 66%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 14 ml of methanol are poured.
- the filtrate is then cooled to 10 ° C. and stirred for 15 minutes.
- 36 ml of methanol are then added and the mixture is then stirred for approximately one hour.
- Stirring is then stopped and the suspension is left to sediment for 40 minutes.
- the supernatant is then removed and then discarded (50 ml).
- 50 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 25 minutes.
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 1.24 g of pure depolymerized heparin (sodium salt) are obtained. The yield obtained is 89%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2400 Daltons Anti-Xa activity: 132 IU / mg Anti-IIa activity: 1.4 IU / mg
- Anti-Xa activity / anti-IIa activity ratio 94
- the precipitate is allowed to settle again approximately 1 hour. The supernatant is removed and discarded (80 ml). On the sedimented precipitate, 80 ml of methanol are added and stirred for 5 minutes. The precipitate in suspension is then filtered on sintered glass 3. The cake obtained is then washed with 150 ml of methanol. The pale yellow wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature in the region of 40 ° C. After 18 hours of drying, 3.25 g of crude depolymerized heparin, sodium salt in celite (5 g) are obtained. The yield obtained is 83%.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature close to 40 ° C. After 48 hours of drying, 1.9 g of crude depolymerized heparin (sodium salt) are obtained. The yield obtained is 67%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 14 ml of methanol are poured in and the mixture is stirred for 15 minutes. 36 ml of methanol are then added and the mixture is stirred for one hour. Stirring is then stopped and the suspension is left to sediment for 15 minutes. The supernatant is then removed and discarded (40 ml). On the sedimented precipitate, 40 ml of methanol are added and the mixture is stirred for 5 minutes. The precipitate is allowed to settle for about 20 minutes. The supernatant is removed and discarded (50 ml). On the sedimented precipitate, 500 ml of methanol are added and stirred for 5 minutes. The precipitate is left to sediment for approximately 20 minutes.
- the cake obtained is then washed with twice 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 4.53 g of crude depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 74%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 38 ml of methanol are cast at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 100 ml of methanol are then added and the mixture is stirred for one hour.
- the agitation is then stopped and allowed to settle the suspension for 20 minutes.
- the supernatant is then removed and discarded (90 ml).
- 90 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 25 minutes.
- the supernatant is removed and discarded (100 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of 50 ° C. After 18 hours of drying, 3.7 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 82%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2200 Daltons Anti-Xa activity: 120 IU / mg Anti-IIa activity: 1.4 IU / mg Anti-Xa activity / anti-IIa activity ratio: 86
- the cake obtained is then washed with twice 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of about 50 ° C. After 18 hours of drying, 5.53 g of crude depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 80%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 49 ml of methanol are poured at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 126 ml of methanol are then added and the mixture is stirred for one hour.
- Stirring is then stopped and the suspension is allowed to settle for 20 minutes.
- the supernatant is then removed and discarded (105 ml).
- 105 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 25 minutes.
- the supernatant is removed and discarded (110 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of about 55 ° C. After 18 hours of drying, 4.53 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 82%.
- Anti-Xa activity 105 IU / mg
- Anti-IIa activity 3.1 IU / mg
- Anti-Xa activity ratio / anti-IIa activity 34
- Saponification 7.78 g (0.0119 mol) of the crude depolymerized heparin, sodium salt in celite (10 g) obtained above and 79 ml of water are introduced into a 50 ml Erlenmeyer flask. The suspension is filtered on sintered glass 3 and rinsed twice 15 ml of water. The filtrate obtained is loaded into a 150 ml Erlenmeyer flask. With magnetic stirring, 1.3 ml (0.012 mol) of 30% sodium hydroxide solution are introduced at a temperature in the region of 4 ° C. After addition, the mixture is stirred for 2 hours. The solution is neutralized by addition of 1N HCl and 10 g of sodium chloride are added.
- the cake obtained is then washed with twice 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of 50 ° C. After 18 hours of drying, 5.87 g of crude depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 82%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 49 ml of methanol are poured at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 126 ml of methanol are then added and the mixture is stirred for one hour.
- the agitation is then stopped and we allow to sediment the suspension for 20 minutes.
- the supernatant is then removed and discarded (105 ml).
- 105 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 25 minutes.
- the supernatant is removed and discarded (110 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of about 55 ° C. After 18 hours of drying, 5.21 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 89%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 3550 Daltons Anti-Xa activity: 99 IU / mg
- the solution is then filtered through a 0.45 ⁇ m membrane and then 27 ml of methanol are poured at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 65 ml of methanol are then added and the mixture is stirred for 30 minutes.
- Stirring is then stopped and the suspension is allowed to settle for 30 minutes.
- the supernatant is then removed and discarded (80 ml).
- 80 ml of methanol are added and stirred for 30 minutes.
- the precipitate is left to sediment for approximately 30 minutes.
- the supernatant is removed and discarded (70 ml).
- 70 ml of methanol are added and stirred for 30 minutes.
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with twice 30 ml of methanol.
- the moist solid is drained and then dried under reduced pressure at a temperature of 60 ° C. After drying, 2.8 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 80%.
- Anti-Xa activity 146.1 IU / mg
- Anti-IIa activity 5.1 IU / mg
- the solution is then filtered through a 0.45 ⁇ m membrane and then 25 ml of methanol are poured at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 63 ml of methanol are then added and the mixture is stirred for 30 minutes.
- Stirring is then stopped and the suspension is allowed to settle for 30 minutes.
- the supernatant is then removed and discarded (70 ml).
- 70 ml of methanol are added and stirred for 30 minutes.
- the precipitate is allowed to settle again for a few minutes.
- the suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with twice 30 ml of methanol.
- the moist solid is drained and then dried under reduced pressure at a temperature of 60 ° C. After drying, 2.5 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 71.4%
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2600 Daltons Anti-Xa activity: 150.5 IU / mg Anti-IIa activity: 3.2 IU / mg Anti-Xa activity / anti-activity activity ratio IIa: 47
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After drying, 1.6 g of crude depolymerized heparin (sodium salt) are obtained. The yield obtained is 57%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 14 ml of methanol are cast at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 36 ml of methanol are then added and the mixture is stirred for 1 hour.
- Stirring is then stopped and the suspension is allowed to settle for 30 minutes.
- the supernatant is then removed and then discarded (50 ml).
- 50 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 30 minutes.
- the supernatant is removed and discarded (50 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature in the region of 40 ° C. After drying, 1.25 g of pure depolymerized heparin (sodium salt) are obtained. The yield obtained is 78%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2400 Daltons Anti-Xa activity: 154.3 IU / mg Anti-IIa activity: 1.6 IU / mg Anti-Xa activity / anti-activity activity IIa: 96.4
- the supernatant is removed and discarded (250 ml). On the sedimented precipitate, 250 ml of methanol are added and stirred for 5 minutes. The precipitate in suspension is then filtered on sintered glass 3. The cake obtained is then washed with 200 ml of methanol. The pale yellow wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature in the region of 40 ° C. After drying, 5.39 g of depolymerized heparin (benzyl ester, sodium salt) are obtained. The yield obtained is 69%.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 48 hours of drying, 2.7 g of crude depolymerized heparin (sodium salt) are obtained. The yield obtained is 59%.
- the solution is then filtered through a 0.45 ⁇ m membrane and then 21 ml of methanol are cast at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 54 ml of methanol are then added and the mixture is stirred for one hour. Stirring is then stopped and the suspension is allowed to settle for 20 minutes.
- the supernatant is then removed and then discarded (50 ml).
- 50 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 20 minutes.
- the supernatant is removed and discarded (50 ml).
- the precipitate in suspension is then filtered on sintered glass 3.
- the white cake obtained is then washed with 50 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature of 40 ° C. After 18 hours of drying, 2.35 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 90%.
- the characteristics of the depolymerized heparin thus obtained are as follows: Average molecular weight: 2400 Daltons Anti-Xa activity: 167.5 IU / mg Anti-IIa activity: 1.1 IU / mg Anti-Xa activity / anti-activity activity ratio IIa: 152
- the reaction mixture of the Erlenmeyer flask A is poured into the methanolic solution of sodium acetate at a temperature in the region of 4 ° C. for approximately 2 minutes. After stirring for 15 minutes, the suspension is allowed to settle for 1 hour. The clear portion of the supernatant is removed and discarded (420 ml). On the sedimented precipitate, 420 ml of methanol are added and stirred for 15 minutes. The precipitate is allowed to settle again approximately 1 hour. The supernatant is removed and discarded (450 ml). On the sedimented precipitate, add 450 ml of methanol and stirred for 15 minutes. The suspension is then filtered on sintered glass 3.
- the cake obtained is then washed with 200 ml of methanol.
- the pale yellow wet solid is drained and then dried under reduced pressure (6 kPa), at a temperature in the region of 50 ° C. After drying for 16 hours, 5.36 g of crude depolymerized heparin, sodium salt in celite (10 g) are obtained.
- the yield obtained is 68.6 g. ⁇ .
- the solution is then filtered through a 0.45 ⁇ m membrane and then 21 ml of methanol are cast at a temperature in the region of 10 ° C.
- the solution is then brought to 20 ° C. and stirred for 15 minutes.
- 54 ml of methanol are then added and the mixture is stirred for one hour. Stirring is then stopped and the suspension is allowed to settle for 45 minutes.
- the supernatant is then removed and discarded (46 ml).
- 46 ml of methanol are added and stirred for 5 minutes.
- the precipitate is left to sediment for approximately 30 minutes.
- the supernatant is removed and discarded (50 ml). 50 ml of methanol are added and the precipitate in suspension is then filtered on sintered glass 4.
- the white cake obtained is then washed with 2 portions of 10 ml of methanol.
- the wet solid is drained and then dried under reduced pressure (6 kPa) at a temperature of 50 ° C. After 18 hours of drying, 2.63 g of pure depolymerized heparin (sodium salt) are obtained.
- the yield obtained is 89.1%.
- Anti-Xa activity 192 IU / mg
- Anti-IIa activity 1.3 IU / mg
- Anti-Xa activity / anti-IIa activity ratio 148
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Abstract
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Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
UAA200504331A UA81925C2 (uk) | 2002-10-10 | 2003-08-10 | Суміш сульфатованих олігосахаридів - похідних гепарину, спосіб їх приготування та фармацевтична композиція |
DK03807882.0T DK1556414T3 (da) | 2002-10-10 | 2003-10-08 | Blandinger af heparinafledte oligosaccharider, fremstilling deraf og farmaceutisk præparater, der indeholder dem |
AT03807882T ATE548393T1 (de) | 2002-10-10 | 2003-10-08 | Mischungen von aus heparin hergestellten oligosacchariden, deren herstellung und diese enthaltenden pharmazeutischen zusammensetzungen |
NZ539229A NZ539229A (en) | 2002-10-10 | 2003-10-08 | Heparin-derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing same |
CA2501546A CA2501546C (fr) | 2002-10-10 | 2003-10-08 | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
JP2004542566A JP5021898B2 (ja) | 2002-10-10 | 2003-10-08 | ヘパリン誘導多糖類混合物、その製造およびそれを含有する医薬組成物 |
ARP030103661A AR041555A1 (es) | 2002-10-10 | 2003-10-08 | Mezclas de polisacaridos derivados de heparina, su preparacion y las composiciones farmaceuticas que las contienen |
ES03807882T ES2383597T3 (es) | 2002-10-10 | 2003-10-08 | Mezclas de oligosacáridos derivados de heparina, su preparación y las composiciones farmacéuticas que las contienen |
EP03807882A EP1556414B1 (fr) | 2002-10-10 | 2003-10-08 | Melanges d'oligosaccharides derives d'heparine, leur preparation et compositions pharmaceutiques les contenant |
BR0315149-2A BR0315149A (pt) | 2002-10-10 | 2003-10-08 | Misturas de polissacarìdeos derivados de heparina, sua preparação e as composições farmacêuticas que as contêm |
SI200332145T SI1556414T1 (sl) | 2002-10-10 | 2003-10-08 | Zmesi oligosaharidov, izvedenih iz heparina, njihova priprava in farmacevtski sestavki, ki jih vsebujejo |
KR1020057006186A KR101104107B1 (ko) | 2002-10-10 | 2003-10-08 | 헤파린으로부터 유도된 다당류의 혼합물, 이의 제조방법 및이를 함유하는 약제학적 조성물 |
YUP-2005/0274A RS20050274A (en) | 2002-10-10 | 2003-10-08 | Heparin-derived polysaccharide mixtures,preparation thereof and pharmaceutical compositions containing same |
AU2003300161A AU2003300161B2 (en) | 2002-10-10 | 2003-10-08 | Heparin-derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing same |
MXPA05003321A MXPA05003321A (es) | 2002-10-10 | 2003-10-08 | Mezclas de polisacaridos derivados de heparina, su preparacion y las composiciones farmaceuticas que las contienen. |
IL167868A IL167868A (en) | 2002-10-10 | 2005-04-05 | Heparin derived polysaccharide mixtures, preparation thereof and pharmaceutical compositions containing them |
TNP2005000101A TNSN05101A1 (fr) | 2002-10-10 | 2005-04-07 | Melanges de polysaccharides derives d'heparine leur preparation et les compositions pharmaceutiques les contenant |
NO20052170A NO20052170L (no) | 2002-10-10 | 2005-05-03 | Heparin-deriverte polysakkaridblandinger, fremstilling derav og farmasoytiske sammensetninger inneholdende det samme |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0212584A FR2845686B1 (fr) | 2002-10-10 | 2002-10-10 | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
FR0212584 | 2002-10-10 |
Publications (1)
Publication Number | Publication Date |
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WO2004033503A1 true WO2004033503A1 (fr) | 2004-04-22 |
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ID=32039597
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2003/002960 WO2004033503A1 (fr) | 2002-10-10 | 2003-10-08 | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
Country Status (35)
Country | Link |
---|---|
EP (1) | EP1556414B1 (fr) |
JP (2) | JP5021898B2 (fr) |
CN (6) | CN1798771A (fr) |
AT (1) | ATE548393T1 (fr) |
AU (1) | AU2003300161B2 (fr) |
BR (1) | BR0315149A (fr) |
CA (1) | CA2501546C (fr) |
CY (1) | CY1112808T1 (fr) |
DK (1) | DK1556414T3 (fr) |
EC (1) | ECSP055722A (fr) |
ES (1) | ES2383597T3 (fr) |
FR (1) | FR2845686B1 (fr) |
GT (1) | GT200300181A (fr) |
HN (1) | HN2003000312A (fr) |
IL (1) | IL167868A (fr) |
MA (1) | MA27398A1 (fr) |
MX (1) | MXPA05003321A (fr) |
MY (1) | MY142376A (fr) |
NI (1) | NI200300087A (fr) |
NO (1) | NO20052170L (fr) |
NZ (1) | NZ539229A (fr) |
OA (1) | OA12940A (fr) |
PA (1) | PA8584201A1 (fr) |
PE (1) | PE20040507A1 (fr) |
PT (1) | PT1556414E (fr) |
RS (1) | RS20050274A (fr) |
RU (1) | RU2332424C2 (fr) |
SI (1) | SI1556414T1 (fr) |
SV (1) | SV2004001626A (fr) |
TN (1) | TNSN05101A1 (fr) |
TW (1) | TWI332010B (fr) |
UA (1) | UA81925C2 (fr) |
UY (1) | UY28016A1 (fr) |
WO (1) | WO2004033503A1 (fr) |
ZA (1) | ZA200502787B (fr) |
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WO2005010051A2 (fr) * | 2003-07-24 | 2005-02-03 | Aventis Pharma S.A. | Melanges d'oligosaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
WO2007140231A2 (fr) * | 2006-05-25 | 2007-12-06 | Momenta Pharmaceutical, Inc. | Composition d'héparine de bas poids moléculaire et utilisations de celle-ci |
WO2010106519A1 (fr) | 2009-03-19 | 2010-09-23 | Sanofi-Aventis | Dose d'ave5026 destinée au traitement de thromboembolie veineuse chez des patients présentant une insuffisance rénale grave |
EP2399591A1 (fr) | 2010-06-25 | 2011-12-28 | Aventis Pharma S.A. | Sémuloparine pour la prévention d'un événement mortel et/ou morbide chez un patient subissant une intervention chirurgicale orthopédique majeure |
EP2399592A1 (fr) | 2010-06-25 | 2011-12-28 | Aventis Pharma S.A. | Sémuloparine pour la prévention d'un événement mortel et/ou morbide chez un patient subissant une intervention chirurgicale orthopédique majeure |
EP2399593A1 (fr) | 2010-06-28 | 2011-12-28 | Aventis Pharma S.A. | Sémuloparine pour la prévention d'un événement mortel et/ou morbide chez un patient subissant une intervention chirurgicale orthopédique majeure |
EP2399590A1 (fr) | 2010-06-25 | 2011-12-28 | Aventis Pharma S.A. | Sémuloparine pour la prévention d'un événement mortel et/ou morbide chez un patient subissant une intervention chirurgicale orthopédique majeure |
WO2012055843A1 (fr) | 2010-10-28 | 2012-05-03 | Aventis Pharma S.A. | Sémuloparine pour la prévention d'une trombo-embolie veineuse majeure chez un patient subissant une chirurgie abdominale majeure |
WO2012055844A1 (fr) | 2010-10-28 | 2012-05-03 | Aventis Pharma S.A. | Sémluparine destinée à être utilisée en tant que traitement antithrombotique dans une chirurgie abdominale majeure ayant une sécurité améliorée en termes de saignements cliniquement pertinents et de saignements majeurs |
WO2012072799A1 (fr) | 2010-12-02 | 2012-06-07 | Aventis Pharma S.A. | Procédés inédits de mesure in vitro de l'activité biologique d'un échantillon d'héparine de masse moléculaire ultra-faible |
WO2012140580A1 (fr) | 2011-04-11 | 2012-10-18 | Sanofi | Polysaccharides comprenant deux sites de liaison à l'antithrombine iii, leur préparation et utilisation à titre d'anti-thrombotiques |
EP2548561A1 (fr) | 2011-07-22 | 2013-01-23 | Aventis Pharma S.A. | Sémuloparine pour améliorer la survie de patients atteints d'un cancer localement avancé |
EP3398971A4 (fr) * | 2015-12-30 | 2019-09-25 | Shenzhen Hepalink Pharmaceutical Group Co., Ltd. | Oligosaccharide d'héparine sulfaté et procédé de préparation et application de celui-ci |
CN110917208A (zh) * | 2019-12-27 | 2020-03-27 | 浙江医院 | 硫酸化甘露葡萄糖醛酸六糖在防治动脉粥样硬化中的应用 |
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FR2845686B1 (fr) * | 2002-10-10 | 2013-08-30 | Aventis Pharma Sa | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
EP1994934A4 (fr) | 2006-12-05 | 2010-03-10 | Glycoscience Lab Inc | Agent thérapeutique pour l'arthrose |
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JP2012046511A (ja) * | 2010-07-30 | 2012-03-08 | Otsuka Chem Co Ltd | 低分子量多硫酸化ヒアルロン酸誘導体を含有する医薬 |
CN103209997B (zh) * | 2010-09-14 | 2016-03-16 | 国立大学法人宫崎大学 | 高纯度肝素及其制备方法 |
WO2013044793A1 (fr) * | 2011-09-26 | 2013-04-04 | Xu Meiying | Sel de l'ester benzylique de l'héparine de haute pureté, son procédé de préparation et son application |
CN102633908A (zh) * | 2012-05-02 | 2012-08-15 | 雷晓刚 | 一种高品质超低分子量肝素的制备方法 |
ES2445494B1 (es) * | 2012-08-02 | 2015-03-06 | Rovi Lab Farmaceut Sa | Procedimiento de obtención de heparinas de bajo y muy bajo peso molecular |
US9873712B2 (en) * | 2014-10-03 | 2018-01-23 | Amphastar Pharmaceuticals, Inc. | Method of purifying idraparinux sodium |
CZ308106B6 (cs) * | 2016-06-27 | 2020-01-08 | Contipro A.S. | Nenasycené deriváty polysacharidů, způsob jejich přípravy a jejich použití |
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EP0027089A1 (fr) | 1979-10-05 | 1981-04-15 | Choay S.A. | Fractions oligosaccharidiques et oligosaccharides possédant des propriétés biologiques, leurs procédés de préparation et leurs applications en tant que médicaments |
EP0040144A1 (fr) | 1980-05-14 | 1981-11-18 | Pharmuka Laboratoires | Nouveaux polysaccharides sulfatés, procédés pour leur préparation et leur utilisation comme médicaments |
WO2002008295A1 (fr) | 2000-07-21 | 2002-01-31 | Aventis Pharma S.A. | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
US6384021B1 (en) | 1999-07-23 | 2002-05-07 | Laboratorios Farmaceuticos Rovi | Heparin compositions of very low molecular weight |
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FR2504928A1 (fr) * | 1981-04-29 | 1982-11-05 | Choay Sa | Oligosaccharides a chaines courtes possedant des proprietes biologiques, leur preparation et leurs applications en tant que medicaments |
FR2584728B1 (fr) * | 1985-07-12 | 1987-11-20 | Choay Sa | Procede de sulfatation de glycosaminoglycanes et de leurs fragments |
FR2584606A1 (fr) * | 1985-07-12 | 1987-01-16 | Dropic | Utilisation de poly- et oligosaccharides pour l'obtention de medicaments actifs dans les pathologies du tissu conjonctif |
JP4897991B2 (ja) * | 1999-07-23 | 2012-03-14 | ラボラトリオス ファルマセウティコス ロビ ソシエダッド アノニマ | 超低分子量ヘパリン組成物 |
FR2807043B1 (fr) * | 2000-03-28 | 2002-11-22 | Aventis Pharma Sa | Composition pharmaceutique contenant des oligosaccharides, les nouveaux oligosaccharides et leur preparation |
FR2845686B1 (fr) * | 2002-10-10 | 2013-08-30 | Aventis Pharma Sa | Melanges de polysaccharides derives d'heparine, leur preparation et les compositions pharmaceutiques les contenant |
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2002
- 2002-10-10 FR FR0212584A patent/FR2845686B1/fr not_active Expired - Fee Related
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- 2003-09-24 SV SV2003001626A patent/SV2004001626A/es not_active Application Discontinuation
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Patent Citations (4)
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