EP0516792A1 - Derives d'heparine - Google Patents

Derives d'heparine

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Publication number
EP0516792A1
EP0516792A1 EP92901426A EP92901426A EP0516792A1 EP 0516792 A1 EP0516792 A1 EP 0516792A1 EP 92901426 A EP92901426 A EP 92901426A EP 92901426 A EP92901426 A EP 92901426A EP 0516792 A1 EP0516792 A1 EP 0516792A1
Authority
EP
European Patent Office
Prior art keywords
heparin
process according
salts
molecular weight
heparin derivatives
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92901426A
Other languages
German (de)
English (en)
Inventor
Francesco Della Valle
Aurelio Romeo
Günter Kirschner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fidia SpA
Original Assignee
Fidia SpA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fidia SpA filed Critical Fidia SpA
Publication of EP0516792A1 publication Critical patent/EP0516792A1/fr
Withdrawn legal-status Critical Current

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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
    • 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
    • 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

Definitions

  • the present invention concerns new heparin derivatives with pharmacological properties which are modified with respect to those of the heparin preparations currently available on the market and used in anticoagulant therapies.
  • the relationship between the anti-thrombin activity and the activity on the Xa factor and the platelet factor 4 (PF of the new derivatives differs from that of heparin. In other words, their considerable affinity for PF 4 is accompanied by reduced activity on the reaction between anti-thrombin III and thro bin, catalyzed by heparin.
  • the reaction between antithrombin III and the Xa factor, catalyzed by heparin itself, is even more sensitive to the new derivatives. Because of their different ratio of activity from that of heparin, on PF 4 and on the reactions activated by thrombin and Xa factor, the derivatives of the invention are able to prevent thrombosis without the risk of hemorrhage which accompanies the anti-thrombotic action of heparin. It must be noted that hemorrhagic activity can be caused by an excessive action of thrombin inhibition.
  • the new heparin derivatives whose aforesaid pharmacological properties are different from those of heparin, also have a modified chemical structure and different molecular weight; their chemical structure has not yet been completely defined. It has however been ascertained that they: a) constitute a mixture of mostly depoly erized products and therefore have a medium-to-low molecular weight compared the starting products, which are rich in fragments similar to one another and with molecular weights coming within the same narrow range, and with a minimum of fragments which deviate from this mean. b) Compared to their starting products, they have a notably diminished ratio between the iduronic-type saccharide unit and the glucuronic-type unit.
  • heparin esters such as those described in British patent No. 1501095. If these esters undergo alkaline treatment, such as that included in the second phase of the procedure of the present invention, different heparin fragments are obtained, as can be demonstrated by NMR analysis.
  • the new "low-molecular-weight heparin" of the invention is a complex mixture of oligosaccharides, sulfated both at N and at O, reflecting the heterogeneity of the starting heparin. Its fundamental constituents IdoA and GlcnAc, differently sulfated, and secondary constituents (essentially GlcA) link together, giving rise to different sequential combinations.
  • the product which is the object of the present invention shows a considerable decrease in the IdoA/GlcN ratio, this decrease being detectable by NMR. Accordingly, the signals of the ano eric sites of the typical IdoA sequence (2S0 3 ) -GlcNS0 3 ) (6S0 3 ) (102 and 99.5 pp for carbon; 5.18 and 5.32 ppm for the proton) prove to be drastically diminished. Such transformations cannot be detected in the known, low-molecular-weight heparins, or if they can, it is to a far lesser degree. Concomitantly, markedly intense signals appear of a new unsaturated monosaccharide unit (see point 4) .
  • oligosaccharides terminate with an unsaturated monosaccharide unit, three-substituted in positions 1-2, as can be shown by NMR (signals at 147 and 172 ppm in C-13: doublet at 6 ppm for the proton) . These signals are absent or very reduced in the other known, low-molecular-weight heparins.
  • the heparin-like products of the present invention are new and different from the heparin fragments already described in the literature.
  • they are different from the fragments described in European patent No. 0 302 034, obtained by alkaline treatment of heparin esters, these fragments being suitable for the formation of complexes with copper ions having an angiogenic action.
  • the heparin fragments described in U.S. patent No. 4,440,926, obtained starting from well-defined heparin esters by treatment with NaOH (0.1-0.5 N) between 20° and 60 ⁇ C, are not identical to the products of the present invention.
  • Figure 1 shows the anticoagulant activity in vitro of PE compared to UFH and CY 216 in terms of thrombin time (sec).
  • the data obtained are mean values of 7-10 replications for each test product.
  • Figure 2 shows the ex vivo anticoagulant activity of PE, compared to UFH and CY 216, according to the effect on thrombin time after i.v. administration.
  • the data are mean values from experiments on 5 rabbits for each test product.
  • Figure 3 illustrates the ex vivo anticongulant activity of PE, compared to UFH and CY 216, based on anti-FXa activity (disappearance kinetics after s.c. administration) .
  • the data are mean values from experiments on 5 rabbits per test product.
  • Figure 4 shows the ex vivo activity for PF 4 after i.v. administration of PE, in comparison to UFH and CY 216.
  • test products were dissolved in sterile saline and tested at concentrations ranging from 0.5 to 12.5 ⁇ g/ml. Parameters
  • Thrombin time (as an indicator of anticoagulant activity)
  • Anti-FXa activity (as an indicator of anticoagulant activity)
  • the anticoagulant activity of PE is considerably inferior to that of unfractionated heparin UFH (thrombin time increases at concentrations about 4-5 times greater than UFH) .
  • the data are means of 3 experiments per concentration, one for each test product.
  • ex vivo in vitro measurement of blood withdrawn from an animal to which the chemical substance has been administered. Examined in particular were the following: a) thrombin time, on arterial blood after acute bolus intravenous administration (i.v.) of the test products; b) anti-FXa activity, on arterial blood after acute subcutaneous administration (s.c). This method, being highly sensitive, is indicative of the "bioavailability" of the test products, since it allows the kinetics of the disappearance of the test products to be monitored after subcutaneous administration.
  • test products were dissolved in sterile saline solution and administered acutely at 0.86 mg/kg by the i.v. route and at 1-2 mg/kg by the s.c. route.
  • Fig. 3 shows that:
  • the affinity of the new heparin derivative PE of the present invention was assessed for human PF 4 , i.e. the "binding properties" of such products for PF 4 .
  • test products able to bind PF 4 should therefore greatly prolong its presence in the circulation. This effect is proportional to the quantity of GAG injected and to its affinity for PF 4 .
  • the test products were dissolved in sterile saline solution and administered at 0.86 mg/kg i.v. Description of the test Administration of the test products was acute (intravenous bolus), at a dose of 0.86 mg/kg. Samples of arterial blood were taken 2-3 ins later from the central artery of the ear (baseline sample) . 5 minutes after administration of the first bolus, a second bolus of purified human PF 4 was given (30 ⁇ g/kg) .
  • - PE has affinity for platelet factor PF 4 and gradually disappears from the circulation reaching low values about 30 minutes after administration.
  • the experiment described hereafter assessed the antithrombotic activity in vivo of the new heparin derivative PE.
  • the objective was to test the efficacy of the products in preventing the formation of an arterial thrombus in an acute model of arterial thrombosis in the rabbit carotid artery, following endothelial damage and reduction of the vascular dia eter .
  • test products were dissolved in sterile saline and administered by the i.v. route at concentrations ranging from 1.2 to 6 mg/kg.
  • test products were then infused i.v. for eight minutes in all, with mechanical damage being performed after two minutes of infusion.
  • the flow was monitored constantly until at least one hour after the end of treatment.
  • the animal was sacrificed by an overdose of anesthetic at the end of the experiment.
  • the antithro botic efficacy of PE is inferior (about 5x) to that of unfractionated heparin UFH (which can be seen to inhibit the formation of occlusive thrombi at a dose as low as 1.2 mg/kg) ; the pharmacological efficacy of PE is similar to that of CY 216.
  • the experiment described hereafter was performed to assess the antithrombotic efficacy in vivo of PE in a model of venous thrombosis in the rat.
  • the venous stasis technique was used, by occluding the vena cava inferior, as this method causes the formation of a mainly fibrinic thrombus due to the variation in blood flow at the level of the bifurcation of the vena cava with the left renal vein.
  • the model under examination therefore proves to be sensitive to the activity of anticoagulant drugs and in particular to the antithrombotic potential of heparin (after administration and stasis) .
  • the test products were dissolved in sterile saline and administered intravenously at doses ranging from 0.5 to 3 mg/kg i.v. (15 minutes before stasis induction) .
  • the experiment described hereafter assessed the effect of PE on bleeding time 15 minutes after intravenous administration of the test products.
  • the test products were dissolved in sterile saline and administered i.v. at concentrations ranging from l to 3 mg/kg.
  • the present experiment assessed the maximum tolerated dose of the compound PE after administration by the intravenous and subcutaneous route in the mouse.
  • test products were dissolved in sterile saline and tested at concentrations ranging between 125 and 2000 mg/kg i.v. and s.c.
  • mice Groups of five male and five female mice were treated (for each compound and each administration route) with the highest tolerated dose found on screening. The animals were observed for 14 days, during which mortality and the presence of altered behaviour and general toxicity symptoms were observed. In the case of mortality a lower dose was used, until the maximum tolerated dose was found. Where possible, autopsy was performed on the deceased animals. Results
  • PE has greater tolerance dose than unfractionated heparin UFH.
  • the subcutaneous tolerance data therefore show a difference between the compounds PE and CY 216.
  • Treatment Deceased animals/Treated animals Time of death (mg/kg i.v.) males females days after treatment immediate
  • the activity of PE differs slightly from that of CY 216, which is one of the best low-molecular-weight heparins currently on sale in France, and shows in particular better local tolerability after s.c. administration in the mouse. Indeed, although the maximum tolerated doses are the same, all animals treated with CY 216 (2000 mg/kg s.c.) had evident necrosis of the skin at the injection site, while the skin of the animals treated with PE was unaffected.
  • PE has:
  • the derivative PE at a dose of 1.5 mg/kg i.v., does not induce any alterations in bleeding time, unlike UFH.
  • the new, low-molecular-weight heparin derivatives according to the present invention can therefore be used in the place of unfractionated heparin in all its indications, as an anticoagulant and thrombocyte aggregation inhibitor.
  • the dose is adapted to each particular case, and is normally around 1-7 mg/kg per day, by the intravenous route.
  • the heparins to be used in the previously described procedure of the present invention can be of any type and of various origin, for example heparins extracted from the intestine of pigs, cattle, and sheep and from ox heart, especially any one of the products which are commercially available or described in the literature.
  • Such products have widely ranging molecular weights, for example between 2,000 and 30,000 daltons, especially unfractionated heparin UFH, and also low-molecular-weight heparins obtained by fractionation of standard heparins (2,000-10,000 daltons) and heparin fragments with a molecular weight of 500-10,000 daltons obtained by partial depolymerization of standard heparins by chemical or enzymatic means.
  • the quaternary ammonium salts to be used as starting material for said procedure can be prepared in the known way, for instance by ion exchange of the heparin in aqueous solution as a sodium or potassium salt with resins based on quaternary ammonium salts, for example a salified sulfonic resin with a quaternary ammonium base.
  • the quaternary ammonium salt can be obtained by freeze-drying the eluate.
  • tetraalkylammonium salts derived from lower alkyls may be advantageously used, particularly tetraalkylammonium salts with alkyl groups having a maximum of 6 carbon atoms.
  • alkyl-aryl-ammonium salts may also be used, for example those having long-chained alkyl groups.
  • tetraalkylammonium salts tetrabutylammonium salts are preferably used.
  • the quaternary ammonium salts to be used as starting substance for the procedure of the present invention are those obtainable by ion exchange in the aforesaid manner using alkaline salts, for example sodium or potassium salts, of heparin of the type used commercially, that is, neutral salts. They are reacted with an excess of quaternary ammonium ions so as to obtain also the corresponding neutral salts.
  • Quaternary ammonium salts are soluble both in the aforesaid heterocyclic solvents, and in aprotic organic solvents, such as dimethylsulfoxide and dimethylformamide.
  • the reaction with the alkylating agent, according to the first step of the procedure can be performed both in the aforesaid heterocyclic solvents, or in a solution of the same in one of the aforesaid aprotic organic solvents, preferably in a concentrated solution.
  • heterocyclic solvents the preferred ones are above all those which are not substituted in the cyclic structure, that is, N-alkyl-o-aryl-2-pyrrolidone, or their derivatives containing a heterocyclic atom in the cyclic structure, such as the corresponding derivatives of imidazoline, piperazine or morpholine.
  • the N-alkyl groups of heterocyclic solvents are derived preferably from a lower alkyl with a maximum of 6 carbon atoms, and the aryl group is primarily a phenyl group, optionally substituted by 1 to 3 lower alkyl groups, especially methyl groups.
  • N-methyl-2-pyrrolidone is used.
  • An alkylating agent derived from a hydrocarbon having from 6 to 30 carbon atoms, preferably from 8 to 18 carbon atoms, is a compound easily capable of yielding the corresponding hydrocarbyl groups, such as a reagent ester group of an acid with an alcohol with a corresponding number of carbon atoms, which can be an aliphatic or araliphatic alcohol having preferably a maximum of 18 carbon atoms, for example a hexyl, heptyl, octyl or nonyl alcohol.
  • the reagent esters can be derived from inorganic or organic acids, such as hydracids, sulfuric or sulfurous acid, or alkyl- or aryl-sulfonic acids, for example methane-sulfonic or p-toluenesulfonic acid.
  • the esters of the hydracids are in particular chlorides, bromides and iodides.
  • the reaction between the quaternary ammonium salt of the aforesaid alkylating agent is performed at room temperature (20°C.)or slightly higher, for example at a temperature of from 30 - 35 ⁇ C. but not exceeding 60°C, and is maintained for a prolonged period of time of about 5 to 20 hours, typically about 16 hours.
  • the reaction product can be isolated and subsequently submitted to the second step of the procedure, that is, to alkaline treatment, or it can be converted directly into the final product, performing the alkaline treatment directly on the solution, optionally concentrated, of the reaction product of the first step. It is also possible to evaporate the solvent under bland (mild) conditions after the first step of the procedure and to perform alkaline treatment on the residue. It is therefore possible to perform the procedure of the invention as a "one-pot" process.
  • the basic treatment of the reaction product between the quaternary ammonium salt of heparin with the alkylating agent is performed at a temperature of from 5° to 120"C, suitably at a temperature between 50°C and 120 " C, preferably about 70*C, for about two hours.
  • Alkaline hydrates are used, such as NaOH or KOH, or other inorganic and/or organic bases, preferably at a concentration of between 0.1 and 1M.
  • the bases are used in aqueous or alcoholic solutions, but other solvents can be present which are miscible with water or with an aqueous-alcoholic mixture, such as, for example, the residue solvents used in the first step of the procedure in the case of the aforesaid "one-pot" process.
  • the reaction product of the first step of the procedure can be precipitated by the addition of an organic polar solvent, preferably an aliphatic alcohol such as methyl or ethyl alcohol, to which a basic buffer has preferably been added, such as especially a basic salt of a carboxylic acid, e.g., an acetate or propionate of sodium or potassium.
  • a basic buffer can be used, such as alkaline bicarbonates or alkaline phosphates.
  • the precipitated product is preferably washed with the polar solvent used in the precipitation, for example methanol. It is advisable to purify the precipitated product further by reprecipitating it once more or several times, that is, by dissolving the product in water and precipitating it with an alcohol.
  • the reaction product comprising the low-molecular-weight heparin derivative and having the previously described properties, can be released in free form either from a metal salt or from an organic base in the conventional way.
  • the alkaline salt corresponding to the alkaline hydrate used in the second step of the procedure may be obtained by neutralizing the solution with an acid, e.g., 2M hydrochloric acid, purifying the solution, extracting it with an organic solvent which cannot be mixed with water, for example methylene chloride, and repeating this operation several times.
  • the salt is then dialyzed with distilled water and sodium chloride and freeze-dried.
  • the products of the invention are used mainly in the form of their metal salts or organic base salts. If it is desired to obtain metal salts other than alkaline salts corresponding to the ions of the alkaline hydrates used in the aforesaid alkaline treatment, it is possible to use ion exchange methods by known techniques. Alternatively, it is possible to isolate the heparin product in its acid form, adding the alkaline salt obtained with the calculated quantity of a diluted strong acid, such as hydrochloric acid or sulfuric acid, extracting the product with a suitable organic solvent, isolating the heparin compound in free form and then converting it into the desired salt.
  • a diluted strong acid such as hydrochloric acid or sulfuric acid
  • metal or organic base salts which can be used according to the present invention, of particular importance are those which are therapeutically acceptable, such as alkali and alkaline-earth metals, for example sodium, potassium, ammonium, calcium, and magnesium salts, or heavy metal salts, such as copper and iron salts.
  • the salts of organic bases can be derived from primary, secondary or tertiary aliphatic,- aromatic or heterocyclic amines, such as methylamine, ethylamine, propylamine, piperidine, morpholine, ephedrine, furfurylaminecholine, ethylenediamine and aminoethanol.
  • Salts which cannot be directly used in therapy which are also part of the invention, are for example those which can be used for the purification of the new heparin derivatives of the invention, such as some of the heavy metal salts.
  • the invention also includes pharmaceutical preparations containing as active substance a new low-molecular-weight heparin derivative obtainable by the procedure described herein, especially in the form of their therapeutically acceptable salts.
  • Such preparations can be for parenteral use, for example for subcutaneous or intravenous administration, or for topical use, for example in the form of creams or ointments, or suppositories, or nose sprays.
  • the invention includes, besides the new low-molecular-weight heparin derivatives, the aforesaid procedure for their pr paration. Included in the invention is also the performance of the single steps of the preparation procedure, that is, the reaction of a quaternary ammonium salt of heparin with an alkylating agent as defined above in one of said solvents and the alkaline treatment of the reaction product.
  • PE g 150 300 other components water for injection in ml 4 8
  • Example 1.5 the preservative chlorbutanol can be substituted by: benzyl alcohol mg 50 100 or by: chlorocresol mg 5 10
  • sucrose may be substituted by fructose
  • the ratios between the phosphatidylcholine and phosphatidylserine present in the formulations may vary 2.5 (gastroresistant tablet)
  • the ratios between the phosphatidylcholine and phosphatidylserine present in the formulations may vary 2.7 (solution to be administered orally as drops) PE mg 30 60 120 other components: citric acid mg 7.5 15 30 purified water to ml 0.25 0.5 1
  • PE fine white powder mg 20 40 The active principle, as a fine white powder, is contained in a gelatin capsule to be broken open when ready for use and loaded into suitable apparatus for inhalation.
  • the active principle as a fine white powder, is contained in a gelatin capsule to be broken open when ready for use and loaded into suitable apparatus for inhalation.
  • the low molecular weight heparin derivatives and salts thereof according to the present invention are obtainable by treatment of a quaternary ammonium salt of a heparin, dissolved in a heterocyclic organic solvent chosen from the group formed by N-alkyl- pyrrolidine-2-one , N-alky1-piperidine-2-one , unsubstituted or substituted by lower alkyl groups, and their derivatives interrupted in the heterocyclic ring by another heteroatom or heterogroup selected from -O-, -S-, and -NH-, or in a concentrated solution of said compound in an aprotic solvent, with an alkylating (etherifying) agent derived from a hydrocarbon having from 6 to 30 carbon atoms, preferably from 8 to 18 carbon atoms, at a temperature of from about 20° (room
  • the resulting reaction product is then treated at a temperature of from 5 ⁇ to 120"C, preferably about 70 ⁇ C, with an inorganic or organic base in an aqueous solution.
  • the product resulting from this alkaline treatment is then isolated in free form or as an alkali metal or alkaline earth metal salt thereof. Salts of other metals or organic base salts may be obtained therefrom by conversion from one to the other.
  • the reaction product is treated with an alkaline hydroxide in aqueous solution.
  • the resulting low molecular weight heparin derivatives and salts thereof are useful therapeutically, for example, as anti-thrombotic agents.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Materials Engineering (AREA)
  • Polymers & Plastics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
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Abstract

On prépare des dérivés d'héparine à faible poids moléculaire et leurs sels par le traitement d'un sel d'ammonium quaternaire d'une héparine, dissous dans un solvant organique hétérocyclique ou dans un solvant exempt de protons, avec un agent d'alkylation possédant de 6 à 30 atomes de carbone, à une température comprise entre environ 20 °C et environ 60 °C et pour une durée prolongée; par le traitement du produit réactionnel ainsi obtenu à une température comprise entre environ 5 °C et environ 120 °C et avec une base organique ou non, telle qu'un hydroxyde alcalin, dans une solution aqueuse; et par l'isolation, sous forme libre ou sous forme de leurs sels alcalins, des dérivés d'héparine ainsi obtenus. Les dérivés d'héparine ainsi obtenus constituent un mélange de produits pour la plupart dépolymérisés dont les poids moléculaires sont proches les uns des autres. Ces produits sont utiles en tant qu'agents antithrombotiques.
EP92901426A 1990-12-20 1991-12-20 Derives d'heparine Withdrawn EP0516792A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT4175290 1990-12-20
IT04175290A IT1243300B (it) 1990-12-20 1990-12-20 Derivati dell'eparina

Publications (1)

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EP0516792A1 true EP0516792A1 (fr) 1992-12-09

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EP (1) EP0516792A1 (fr)
JP (1) JPH05504785A (fr)
KR (1) KR920703644A (fr)
CN (1) CN1062537A (fr)
AU (1) AU658594B2 (fr)
BR (1) BR9106234A (fr)
CA (1) CA2075970A1 (fr)
FI (1) FI923762A7 (fr)
HU (1) HUT62917A (fr)
IT (1) IT1243300B (fr)
NO (1) NO923240L (fr)
PT (1) PT99898A (fr)
WO (1) WO1992011294A1 (fr)

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FR2663639B1 (fr) * 1990-06-26 1994-03-18 Rhone Poulenc Sante Melanges de polysaccharides de bas poids moleculaires procede de preparation et utilisation.
FR2704861B1 (fr) * 1993-05-07 1995-07-28 Sanofi Elf Fractions d'héparine purifiées, procédé d'obtention et compositions pharmaceutiques les contenant.
ES2077533B1 (es) * 1994-02-28 1996-07-01 Bioiberica Procedimiento de obtencion de fracciones de oligosacaridos por despolimerizacion quimica de heparina.
US5639469A (en) * 1994-06-15 1997-06-17 Minnesota Mining And Manufacturing Company Transmucosal delivery system
US5744457A (en) * 1995-03-31 1998-04-28 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis
US6001820A (en) * 1995-03-31 1999-12-14 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis
US5763427A (en) * 1995-03-31 1998-06-09 Hamilton Civic Hospitals Research Development Inc. Compositions and methods for inhibiting thrombogenesis
WO1997033593A1 (fr) * 1996-03-15 1997-09-18 Takara Shuzo Co., Ltd. Produit obtenu par traitement thermique d'acide uronique, et aliments, boissons ou medicaments contenant ce produit
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
FR2763848B1 (fr) 1997-05-28 2000-01-28 Rhone Poulenc Rorer Sa Utilisation des heparines de bas poids moleculaire pour la prevention et le traitement du trauma du systeme nerveux central
EP1503742A2 (fr) * 2002-04-19 2005-02-09 Bioghurt Biogarde GmbH & Co. KG. Matrice a constituant bioactif contenant des phospholipides
DE10217557A1 (de) * 2002-04-19 2003-11-06 Degussa Bioactives Gmbh Funktionsnahrungsmittel enthaltend eine Phospholipid-haltige stabile Matrix
CN100335506C (zh) * 2004-05-20 2007-09-05 汕头市金丰医疗器械科技有限公司 一种肝素化合物及其制备方法和应用

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FR2482603A1 (fr) * 1980-05-14 1981-11-20 Pharmindustrie Nouveaux esters d'heparine utilisables pour la preparation de medicaments, et procedes pour leur preparation
EP0256880B1 (fr) * 1986-08-20 1995-05-03 Miami University Alkylesters d'héparine ayant un bas poids moléculaire
SE8702254D0 (sv) * 1987-05-29 1987-05-29 Kabivitrum Ab Novel heparin derivatives

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Publication number Publication date
KR920703644A (ko) 1992-12-18
CN1062537A (zh) 1992-07-08
FI923762A0 (fi) 1992-08-20
PT99898A (pt) 1992-12-31
WO1992011294A1 (fr) 1992-07-09
CA2075970A1 (fr) 1992-06-21
HUT62917A (en) 1993-06-28
BR9106234A (pt) 1993-03-30
IT1243300B (it) 1994-05-26
NO923240L (no) 1992-10-19
IT9041752A0 (it) 1990-12-20
AU9096491A (en) 1992-07-22
FI923762L (fi) 1992-08-20
JPH05504785A (ja) 1993-07-22
NO923240D0 (no) 1992-08-18
IT9041752A1 (it) 1992-06-21
FI923762A7 (fi) 1992-08-20
AU658594B2 (en) 1995-04-27

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