WO2001012675A1 - Derives de glycosaminoglycane et leur utilisation - Google Patents

Derives de glycosaminoglycane et leur utilisation Download PDF

Info

Publication number
WO2001012675A1
WO2001012675A1 PCT/JP2000/005337 JP0005337W WO0112675A1 WO 2001012675 A1 WO2001012675 A1 WO 2001012675A1 JP 0005337 W JP0005337 W JP 0005337W WO 0112675 A1 WO0112675 A1 WO 0112675A1
Authority
WO
WIPO (PCT)
Prior art keywords
heparin
derivative
salt
group
glycosaminoglycan
Prior art date
Application number
PCT/JP2000/005337
Other languages
English (en)
Japanese (ja)
Inventor
Takehisa Matsuda
Original Assignee
Seikagaku Corporation
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 Seikagaku Corporation filed Critical Seikagaku Corporation
Priority to AU64729/00A priority Critical patent/AU6472900A/en
Priority to JP2001517573A priority patent/JP4754137B2/ja
Publication of WO2001012675A1 publication Critical patent/WO2001012675A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
    • A61L33/06—Use of macromolecular materials
    • A61L33/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • 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

  • the present invention relates to a glycosaminoglycan derivative and a drug containing the glycosaminoglycan derivative as an active ingredient, in particular, a smooth muscle cell growth inhibitor and an antithrombotic agent, and furthermore, a sufficient anti-thrombotic agent for various insoluble substrates.
  • the present invention relates to a treatment agent capable of imparting thrombotic properties, and a medical material comprising the glycosaminoglycan derivative adsorbed on the surface of an insoluble substrate.
  • Thrombus formation is a major medical problem.
  • thrombus formation is an important issue in medical devices that come into direct contact with blood and in restenosis after atherosclerosis and revascularization.
  • the method (A) requires introduction of a cationic group into the artificial material to be used, restricts the material of the artificial material, and easily removes heparin under ordinary use conditions. The prolonged use tends to reduce antithrombotic properties.
  • the material used for the artificial material is limited as in (A), and the mechanical strength of the artificial material may be reduced due to the covalent bond of heparin.
  • the anticoagulant effect of heparin is reduced by immobilizing heparin on the material.
  • lipids may form micelles and heparin may have a reduced antithrombotic effect.
  • the exposure of the lipid portion to the surface layer promotes the formation of a thrombus rather than the fact that there is a case where the conformation of heparin is changed due to lipid binding and the antithrombotic property is not sufficiently exhibited. Remaining, it is hard to say that it is sufficiently versatile.
  • the conventional antithrombotic surface-treated artificial material has sufficient antithrombotic properties. There were problems to be improved, such as being unable to give.
  • a percutaneous coronary angioplasty (hereinafter also referred to as PTCA) or the like is an effective method for revascularization.
  • PTCA percutaneous coronary angioplasty
  • restenosis occurs at a frequency of 30 to 50% several months after the operation.
  • vascular endothelial cells naturally have antithrombotic activity and prevent pathological thrombus formation.
  • thrombus formation occurs when stimuli or disruptions that surpass the antithrombotic action of vascular endothelial cells such as PTCA are added.
  • vascular wall smooth muscle cells proliferate due to the production of thrombin and the release of vasoactive substances such as PDGF- from activated platelet factor in the event of thrombus formation, resulting in arterial stenosis.
  • the conventional antithrombotic surface-treated artificial material has problems to be improved, such as not being able to impart sufficient antithrombotic properties.
  • an object of the present invention is to solve the above-mentioned drawbacks of the prior art, and to perform an antithrombotic surface treatment on a medical device or a whole system having a complicated structure that comes into contact with blood.
  • An object of the present invention is to provide a glycosaminoglycan derivative or a salt thereof, which can be administered to a patient to suppress the proliferation of vascular smooth muscle cells and prevent stenosis or occlusion of blood vessels such as coronary arteries.
  • Another object of the present invention is to provide a medicament having a clinically clear utility in treating arteriosclerosis and preventing stenosis or occlusion of arteries, in particular, an antithrombotic agent and a smooth muscle cell proliferation inhibitor. is there.
  • a further object of the present invention is to provide an antithrombotic surface treating agent capable of imparting sufficient antithrombotic properties to the surface of an insoluble substrate for a long period of time.
  • the present invention relates to a glycosaminoglycan derivative having a specific structure or a salt thereof having an anticoagulant (antithrombotic) activity and a smooth muscle cell growth inhibitory activity, a drug containing the same, particularly a smooth muscle cell growth inhibitor, an antithrombotic agent, and the like.
  • the present invention relates to an agent, an antithrombotic surface treatment agent, and a medical material.
  • glycosaminoglycan derivative or a salt thereof according to the above (1) which is represented by the following general formula (1).
  • RR 2 is not it it mutually identical, one is hydrogen and the other one OH, - NH 2, from one OS 0 3 H, one NH C 0 CH 3 and one NH S 0 3 H It represents a group selected; R 3, R 'is not it it it mutually identical, one Ri hydrogen der, the other is - OH, represents a group selected from -OS 0 3 H and GAG residues; R 5 and R 5 are not identical to each other, one is hydrogen, and the other is a group selected from —0H, 10 S 0 3 H and a GAG residue (provided that R 3 , RR s , .
  • R s is GAG residue
  • R ' is - CH 2 0H, - CH 2 0 S 0 3 H or represents an C00H
  • GAG residues heparin, heparan sulfate, de Rumatan sulfate, keratan sulfate, chondroitin sulfate represents the residue of glycosaminoglycan selected from the group consisting of hyaluronic acid and these modifications
  • L 1 is an C 0NHR or one CH 2 NHR Represents;.
  • R is as defined above noted one 0 S0 3 H in the above one C 00 H it it - ⁇ S 0 3 -, one C00 - also Include)
  • glycosaminoglycan is a lactone, and the carbonyl group and the primary amine represented by R—NH 2 (R is as defined above) are amide-bonded.
  • R—NH 2 R is as defined above
  • glycosaminoglycan derivative or a salt thereof according to any one of (1) to (5), wherein the glycosaminoglycan is heparin or heparan sulfate.
  • a medicament comprising the glycosaminoglycan derivative according to any one of (1) to (6) or a salt thereof as an active ingredient.
  • An antithrombotic surface treatment agent comprising the glycosaminoglycan derivative or a salt thereof according to any one of (1) to (6) as an active ingredient.
  • a fluorescence-labeled glycosaminoglycan derivative or a salt thereof wherein the glycosaminoglycan derivative or a salt thereof according to any one of (1) to (6) is labeled with a fluorescent substance.
  • glycosaminoglycan or a salt thereof includes heparin, heparan sulfate, dermatan sulfate, chondroitin sulfate, hyaluronic acid, keratin sulfate or a modified form thereof.
  • a salt thereof preferably heparin, heparan sulfate or dermatan sulfate or a modified form thereof, or a salt thereof, more preferably heparin or heparan sulfate or a modified form thereof, or These are the salts.
  • GAGs may be isolated from living tissue or synthesized enzymatically, microbially or chemically. In addition, even if those GAGs are enzymatically, microbiologically, chemically or physically reduced in molecular weight, or they are converted to GAGs by enzymatic, such as sulfation, acylation, desulfation, or deacetylation, etc. Microorganisms or chemical treatments may be applied, and these are defined as modified products in the present invention.
  • pharmaceutically acceptable salts are preferable, for example, inorganic salts such as alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt, and ammonium salt. And salts with organic bases such as diethanolamine salt, cyclohexylamine salt and amino acid salt, but are not limited thereto.
  • Examples of a method for producing a low molecular weight GAG used in the present invention include a nitrite decomposition method, a periodic acid oxidative decomposition method, a radical-induced redox decomposition method, a sulfuric acid decomposition method, and an enzymatic decomposition method.
  • a nitrite decomposition method a periodic acid oxidative decomposition method, a radical-induced redox decomposition method, a sulfuric acid decomposition method, and an enzymatic decomposition method.
  • the raw material is added to a solution of 0.01 to 1 M, preferably 0.05 to 0.5 M sodium nitrite.
  • dermatan sulfate when dermatan sulfate is reduced to a low molecular weight by a decomposing enzyme, for example, a 0.1 to 10% aqueous solution of dermatan sulfate is adjusted to pH 7 with an appropriate buffer (a buffer such as Tris, acetic acid or phosphate). Adjust to 0 to 8.0, add chondroitinase ABC, chondroitinase AC, chondroitinase B or a mixture of these enzymes to dermatan sulfate at 10 to 1 000 units / g, and at 15 ° C to 40 ° C. It is obtained by reacting for 1 to 24 hours.
  • a buffer such as Tris, acetic acid or phosphate
  • the weight average molecular weight of GAG (hereinafter simply referred to as molecular weight) is usually about 1,000 to 120,000 for heparin, heparan sulfate, keratan sulfate, dermatan sulfate, and chondroitin sulfate, and about 1,000 to 10000 for hyaluronic acid.
  • the molecular weight of GAG used in the present invention is not limited thereto.
  • the molecular weight of the reduced GAG as described above is usually about 1,000 to 10,000.
  • heparin examples include heparin sodium salt (derived from mucosal intestinal mucosa, molecular weight of 18000) manufactured by Wako Pure Chemical Industries, Ltd., and heparin sodium salt (derived from mucosal intestine, molecular weight of 1300 to 11 000) manufactured by Bayofar Corporation. And heparin sodium salt (derived from bush small intestine, molecular weight of 13,000 to 15000) manufactured by SPL, and heparin chemically modified kit manufactured by Seikagaku Corporation.
  • heparan sulfate examples include heparan sulfate derived from bovine intestinal mucosa (Sigma, molecular weight: about 7500) manufactured by Sigma, and heparan sulfate sodium salt manufactured by Seikagaku Corporation ) And a heparan sulfate chemically modified kit manufactured by Seikagaku Corporation.
  • Chondroitin sulfate includes chondroitin sodium salt, chondroitin sulfate A sodium salt (from sturgeon notochord), chondroitin sulfate A sodium salt (from whale cartilage), and chondroitin sulfate A sodium salt SSG (whale) manufactured by Seikagaku Corporation.
  • chondroitin sulfate B skin sulfate sodium salt (derived from bush skin, molecular weight 11000-25000), chondroitin sulfate C sodium salt SG (derived from shark cartilage), chondroitin sulfate C sodium salt SSG (derived from shark cartilage, molecular weight: 40,000 to 80,000); chondroitin sulfate D sodium salt (derived from shark cartilage); and chondroitin sulfate E sodium salt (derived from squid cartilage).
  • hyaluronic acid examples include those manufactured by Seikagaku Corporation such as sodium hyaluronate (derived from bush skin, molecular weight 40,000 to 60,000) and sodium hyaluronate (derived from human umbilical cord, molecular weight 80 to 120 X And sodium hyaluronate (derived from cockscomb, molecular weight 60 to 120 x 10 l), potassium hyaluronate (derived from human umbilical cord), potassium hyaluronate (derived from human umbilical cord), and the like.
  • sodium hyaluronate derived from bush skin, molecular weight 40,000 to 60,000
  • sodium hyaluronate derived from human umbilical cord, molecular weight 80 to 120 X And sodium hyaluronate (derived from cockscomb, molecular weight 60 to 120 x 10 l)
  • potassium hyaluronate derived from human umbilical cord
  • potassium hyaluronate derived from human um
  • keratan sulfate examples include Keratan sulfate sodium salt (derived from corneal cornea) manufactured by Seikagaku Corporation.
  • R is a linear or branched alkyl group having 4 to 37 carbon atoms, a cycloalkyl group having 4 to 37 carbon atoms, A alkenyl group having 4 to 37 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an aralkyl group having 8 to 20 carbon atoms having a shape or a branch.
  • alkyl or cycloalkyl group having 4 to 37 carbon atoms examples include n, i or t-butyl, n, i or t-pentyl, hexyl, and cycloalkyl.
  • alkenyl group having 4 to 37 carbon atoms examples include a butenyl group, a pentenyl group, a hexenyl group, a cholesteryl group, a geranyl group, a linaloyl group, a citronellyl group, and an oleyl group.
  • Examples of the aryl group having 6 to 14 carbon atoms or the aralkyl group having 8 to 20 carbon atoms include a phenyl group, a tolyl group, a naphthyl group, a benzyl group, a 1- or 2-indanyl group, and a triphenylmethyl group.
  • alkyl groups, cycloalkyl groups, alkenyl groups, and aryl groups may further have a substituent.
  • additional substituents include a hydroxyl group, a carboxyl group, a phenyl group, an alkyl group, and the like.
  • the alkyl group, cycloalkyl group, alkenyl group, aryl group or aralkyl group be unsubstituted in that the effect of the present invention becomes more remarkable.
  • GAG derivatives are used, they are preferably unsubstituted.
  • R is: CH 2 (CH 2 ) k CH 3 or ⁇ / Cn 2 (CH2) m-
  • R is preferably an alkyl group having 4 to 37 carbon atoms which may have a branch, more preferably a straight-chain alkyl group having 12 to 37 carbon atoms, and still more preferably 12 to 25 carbon atoms.
  • a straight-chain alkyl group is exemplified, and a straight-chain alkyl group having 12 to 18 carbon atoms is particularly preferable.
  • the first is a method in which the reducing terminal sugar moiety of glycosaminoglycan is used as a lactone, and the carbonyl group is bonded to a primary amine represented by R—NH 2 via an amide bond.
  • a suitable aqueous solvent eg, water or phosphate buffer
  • 2 to 100 equivalents, preferably 5 to 15 equivalents of iodine or bromine are added to 1 mol of GAG.
  • a suitable aqueous solvent eg, water or phosphate buffer
  • iodine or bromine are added to 1 mol of GAG.
  • add chlorine preferably iodine
  • M is an alkali metal such as potassium
  • X is an integer of 1 to 3).
  • the pH is adjusted to 8 to 14 and the oxidation reaction is performed at 0 to 100 ° C, preferably at 10 to 30 ° C.
  • the oxidized product thus formed is converted into a strongly acidic cation exchange resin, for example, Dowex 50 (trade name; manufactured by Muromachi Kagaku), Amberlite IR 120 (trade name, manufactured by Organo) and / Or Treatment with inorganic acids such as hydrochloric acid, sulfuric acid, etc., organic acids such as acetic acid, citric acid, succinic acid, or acid anhydrides of these acids to specifically lactonize the reducing end sugar moiety of GAG The obtained compound can be obtained.
  • Dowex 50 trade name; manufactured by Muromachi Kagaku
  • Amberlite IR 120 trade name, manufactured by Organo
  • inorganic acids such as hydrochloric acid, sulfuric acid, etc.
  • organic acids such as acetic acid, citric acid, succinic acid, or acid anhydrides of these acids to specifically lactonize the reducing end sugar
  • the second is to reduce with a reducing agent Schiff base resulting reacted with the reducing end sugar amino group of the aldehyde R- NH 2 of the GAG, in a method of forming a covalent bond in the form of Aminoarukiru group is there.
  • a suitable solvent water, dimethylformamide, dimethylsulfoxide, methanol, etc.
  • R—NH 2 a primary amine represented by R—NH 2 is added, and the mixture is usually heated to 0 to 100 ° C.
  • the reaction is preferably performed at 5 to 60 ° C to form a Schiff base.
  • Examples of the salts in these GAG derivatives include the same as those described in the above-mentioned examples of GAG salts.
  • GAG or a salt thereof (which may be simply abbreviated as "GAG derivative” in the present invention) in which a specific primary amine is covalently bonded to the reducing terminal sugar moiety, because its conformation is maintained.
  • GAG derivative insoluble substrates such as plastic plates or cell membranes where GAG and the substituent R bonded to it interact with each other and free GAG hardly adheres. It is considered that the GAG derivative can be properly attached, and that the physiological activity of GAG on biological tissues (particularly, smooth muscle cell proliferation inhibitory action ⁇ antithrombotic action) is enhanced.
  • the GAG derivative preferably has a structure in which the reducing terminal sugar represented by the general formula (1) is open.
  • R and GAG are the same as described above.
  • R ′ to R ′ are preferably those derived from N-acetylglucosamine or N-sulfoglucosamine as a reducing terminal sugar of heparin or heparan sulfate.
  • residues der Ru specifically, a hydrogen atom as R 1, 'one NH 2 as, -NHS 0 3 - or one NH C 0 CH 3, as R 3 is a hydrogen atom, R' R a Is a hydroxyl group, R s is a hydrogen atom, R s is a GAG residue, and R ′ is one CH 2 S 0 or CH 20 H.
  • Ri to R ′ is a case where the structure represented by the formula is a residue derived from glucuronic acid or iduronic acid of the reducing terminal sugar of heparin or heparan sulfate.
  • a R 5 is hydrogen Hara Child
  • R 3 to R 6 Only one of R 3 to R 6 represents a GAG residue, preferably R 5 or R 5 is a GAG residue. Further, in the general formula, it is preferable that L ′ is —CONHR, since the effects of the present invention become more remarkable and the safety for living bodies is enhanced.
  • L 1 is one C ONHR
  • the first method is preferable as a method for producing a GAG derivative.
  • the antithrombotic surface treatment agent of the present invention may be in any state of a solution, a paste, a powder, or the like, and the treatment agent is contact-coated, sprayed, impregnated or coated on the surface of an insoluble substrate as described below.
  • the GAG derivative is adsorbed on the surface of the substrate by immersing and infiltrating it in the treating agent, so that sufficient antithrombotic properties can be imparted to medical devices, medical devices, etc., and can be easily removed as necessary It is.
  • the term “adsorption” refers to a state in which the GAG derivative binds to the surface of the substrate and is not easily released by washing or the like due to physical or chemical interaction between the GAG derivative and the insoluble substrate.
  • a hydrophobic bond is exemplified.
  • the method of bonding the GAG derivative to the insoluble substrate is not limited to the above-mentioned “adsorption”.
  • the functional group of the substrate and the amino group of the GAG derivative may be directly or covalently bonded via a spacer, or the ion may be ionized.
  • a method of chemically bonding such as bonding may be used.
  • the treating agent of the present invention may contain only a GAG derivative, or may use other additives in addition to the GAG derivative.
  • examples thereof include a solvent, a stabilizer, an antibacterial agent, an antifungal agent, a surfactant, Examples include a binder resin and a pH adjuster.
  • Solvents that can be used in the treatment agent of the present invention include water, saline, salt solutions such as potassium chloride, lithium chloride, and magnesium sulfate, buffers (such as Tris, acetic acid, and phosphate buffer), methanol, and the like.
  • Organic solvents such as ethanol, dimethylformamide, dimethylsulfoxide and the like may be used alone or as a mixture.
  • the content of the GAG derivative in the treatment agent of the present invention is 0.
  • 0 1 w / v% to 10 w / v% is preferred, more preferably 0.1 w / v% to 5 w / v%.
  • the treating agent of the present invention is a solid or granule, it is dissolved in the above-mentioned solvent and used for treating an insoluble base material. Therefore, if the GAG derivative is in a stable state, specific embodiments such as the content of the GAG derivative and the like are included. Is not limited.
  • medical devices and medical devices include systems such as artificial hearts, artificial lungs, artificial blood vessels, catheters, and artificial dialysis machines made of the following insoluble base materials.
  • the material of the insoluble substrate is preferably one having a hydrophobic surface, but is not limited as long as the GAG derivative is bonded.
  • Examples of the insoluble base material for artificial hearts include polyurethane and silicone rubber, and examples of the insoluble base material for artificial lungs include polyethylene, polypropylene, and polytetrafluoroethylene. Tylene terephthalate, polytetrafluoroethylene and the like. It can also be applied to medical devices and medical devices made of general-purpose polymer materials such as polyvinyl chloride, segmented polyurethane, poly (methyl methacrylate), and cellulose.
  • the method for adsorbing the GAG derivative on the insoluble substrate as described above preferably includes a method in which a solution of the GAG derivative (the above-mentioned liquid treating agent) is brought into contact with the substrate to adsorb the GAG derivative.
  • a method of infiltrating or immersing the insoluble substrate in the above-mentioned liquid treating agent for about 1 to 10 hours may be simple.
  • the amount of the GAG derivative adsorbed on the insoluble substrate may be any amount as long as a predetermined antithrombotic property can be obtained, and is, for example, 1 to 3 ng / cm 2 .
  • a method of chemically binding the GAG derivative to the surface of the insoluble substrate can be mentioned.
  • the GAG derivative adsorbed on the insoluble substrate surface as described above is preferably further subjected to a water washing treatment.
  • the GAG derivative forms a monomolecular layer on the surface of the insoluble base material, and the surface becomes smooth, and the base that comes into contact with blood is formed. Since the GAG molecules are uniformly arranged on the surface of the material, the physiological or biochemical action of the GAG derivative, such as antithrombotic properties, is further enhanced.
  • the water-washing treatment is performed to such an extent that a physiological or biochemical effect such as antithrombotic effect is imparted by forming a uniform layer of the GAG derivative on the surface of the insoluble substrate using water or an aqueous solvent.
  • Washing more specifically, flowing water or an aqueous solvent at a low speed of about 1 cm / sec for a fixed time (for example, 1 minute), or washing an insoluble substrate in water or an aqueous solvent for a certain time (for example, 5 minutes to 1 minute) (0 minutes).
  • the GAG derivative adsorbed on the surface of the insoluble substrate can be optionally removed as required.
  • the removal can be carried out by treating the surface with alcohol or a solution containing alcohol.
  • examples of the alcohol or the solution containing the alcohol include methyl alcohol, ethyl alcohol, and an aqueous solution containing 50% or more of them.
  • the insoluble base material having the GAG derivative adsorbed thereon can be removed by immersing it for a certain period of time (for example, 5 minutes to 2 hours) and infiltrating it.
  • the adsorption of a saccharide having such a hydrophobic group such as an alkyl group, an alkenyl group, a cycloalkyl group, an aralkyl group, or an aryl group to an insoluble base material is generally based on hydrophobic bonds.
  • the GAG derivative of the present invention has a specific hydrophobic group only at the reducing end, it binds to the insoluble substrate only at one point at the reducing end. In such a case, the GAG derivatives also cause aggregation and form a layered layer of the GAG derivative in some cases.However, the layered GAG derivative is washed away with an appropriate solvent such as water or a salt solution. It can be a monomolecular film.
  • the GAG portion can assume a free conformation in an aqueous solution such as blood, and as a result, the GAG The original activity of having is impaired It is maintained as it is, and therefore easily binds to thrombin and antithrombin III, and can suppress the formation of thrombus.
  • the medical material of the present invention is obtained by adsorbing a GAG derivative or a salt thereof on the surface of an insoluble substrate.
  • a medical material can be used as a material for the above-mentioned medical device, medical device and the like.
  • the medical material of the present invention is particularly useful as an antithrombotic medical material.
  • the insoluble substrate is polyethylene terephthalate, and the water receding contact angle of the surface (without washing or washing with water) on which the GAG derivative is adsorbed as described above is 50 ° or less. Material.
  • the insoluble substrate is polyvinyl chloride, and the water receding contact angle of the surface (no washing or washing with water) on which the GAG derivative is adsorbed as described above is 80 ° or less. It is a medical material.
  • the water receding contact angle is a well-known and commonly used physical property indicating the hydrophobic / hydrophilic property of the material surface in the technical field, for example, SCI srael et al .: AC SP olm. Prep r. 30, 328 ( It can be measured according to the known method described in 1989).
  • the GAG derivative of the present invention is useful as a medicament, particularly as a smooth muscle cell proliferation inhibitor and antithrombotic agent.
  • a GAG derivative by administering an effective amount of a GAG derivative to a subject in need of treatment or prevention with this drug, such as a patient with arteriosclerosis, the formation of thrombus is prevented, and the proliferation of smooth muscle cells on the inner wall of blood vessels is prevented. Can be suppressed, and coronary stenosis can be prevented. In addition, it can be applied to the prevention of restenosis after vascular reconstruction and the prevention of arteriosclerosis.
  • R of the GAG derivative is a straight-chain having 12 or more carbon atoms. Chain alkyl groups are preferred because they further improve antithrombotic properties.
  • the case where the covalent bond is an amide bond is preferable from the viewpoint of increasing biosafety.
  • the glycosaminoglycan of the GAG derivative may be the above-mentioned low molecular weight heparin, heparan sulfate or dermatan Sulfuric acid is preferred. Thereby, the smooth muscle cell proliferation inhibitory effect can be further improved.
  • the medicament of the present invention in particular, a smooth muscle cell proliferation inhibitor or an antithrombotic agent, is administered by oral or parenteral administration of a GAG derivative (intravenous, intramuscular, subcutaneous administration into tissues (injection), enteral administration, It can be formulated into any dosage form such as liquid preparation, solid preparation, semi-solid preparation, etc., and administered to patients by any administration method.
  • a GAG derivative intravenous, intramuscular, subcutaneous administration into tissues (injection), enteral administration
  • It can be formulated into any dosage form such as liquid preparation, solid preparation, semi-solid preparation, etc., and administered to patients by any administration method.
  • the preparation is produced in a usual manner by adding a pharmaceutically acceptable preparation auxiliary to the GAG derivative. Furthermore, a sustained-release preparation can be prepared by a known technique.
  • agent of the present invention When the agent of the present invention is used for treating patients with arteriosclerosis or the like, intramuscular injection, intravenous injection, subcutaneous injection or intraperitoneal injection is preferred.
  • GAG derivatives are water-soluble and can easily produce liquid preparations.
  • an emulsifier lecithin, polysorbate 80, polyoxyethylene hydrogenated castor oil, etc.
  • GAG derivatives and excipients lactose, starch, crystalline cellulose, etc.
  • binders starch, crystalline cellulose, etc.
  • disintegrants carboxymethylcellulose, etc.
  • lubricants magnesium stearate, talc, etc.
  • Solid preparations for powder application such as powders, granules, capsules, tablets, etc., or sweeteners (sucrose, sorbitol, etc.), water, essential oils, ethanol, etc. It can also be used as a liquid preparation for oral administration such as syrup.
  • a suppository base such as mono-, di- or triglycerides of cocoa fatty acid, polyethylene glycol, etc.
  • a suppository base such as mono-, di- or triglycerides of cocoa fatty acid, polyethylene glycol, etc.
  • it can be obtained by dissolving a GAG derivative in polyethylene glycol, soybean oil, or the like, and coating with a gelatin film.
  • the GAG derivative can be added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol and the like to prepare an ointment or, if necessary, heated and kneaded to obtain an external preparation for skin.
  • the tape agent can be obtained by kneading a GAG derivative with an adhesive such as rosin or acrylate polymer, and spreading this on a nonwoven fabric or the like.
  • the inhalant can be obtained, for example, by dissolving or dispersing the GAG derivative in a propellant such as a pharmaceutically acceptable inert gas, and filling this into a pressure-resistant container.
  • a propellant such as a pharmaceutically acceptable inert gas
  • the content of the GAG derivative in the above drugs varies depending on the dosage form, administration method, number of administrations, etc., but usually about 0.1 to 10% by weight for injections, and about It is about 1 to 80% by weight, and about 0.1 to 10% by weight for external preparations.
  • the dose of the GAG derivative varies depending on the patient's age, symptoms, body weight, and administration method, and cannot be specified unconditionally. However, in the case of intra-organ administration (injection), the daily dose is 1 to 1,000 mg / day. It is preferable to administer in several divided doses.
  • 50% lethal dose (LD50) of heparin in mice (male, female) in acute toxicity test is 500 Omg / kg or more by oral administration, 2500 mg / kg or more by dermal or intraperitoneal administration, and intravenous injection. It is known to be over 1,000 mg / kg, and is currently commonly used as a drug (anticoagulant), so its safety has already been proven. Therefore, the GAG derivative of the present invention, which is synthesized using heparin as GAG and whose physiological activity is heparin, seems to have the same safety as heparin.
  • the fluorescently labeled glycosaminoglycan derivative or a salt thereof of the present invention is obtained by labeling the above-mentioned GAG derivative with a fluorescent substance.
  • This fluorescent-labeled GAG derivative is used for analysis of the distribution of the GAG derivative adsorbed on the surface of the insoluble base material, and for examining the retention, adsorption state, distribution, etc. of the GAG derivative administered in vivo. Useful as reagents, diagnostics, etc.
  • the fluorescent-labeled GAG derivative can be reacted with the fluorescent substance and the GAG derivative while stirring in a solution, and can be purified if necessary.
  • the reaction temperature is usually room temperature (5 to 35 ° C), and the reaction time is usually 1 hour to 30 hours.
  • Examples of the fluorescent substance include those that easily react with the GAG derivative.
  • a fluorescent probe selected from fluorescein, dansyl, fluorescamine, rhodamine B, tetramethyl rhodamine, and an isoindole derivative is used.
  • the amount of the fluorescent substance introduced into the GAG derivative is preferably from 1 to 15 per molecule of the GAG derivative, more preferably from 1 to 10 and still more preferably. Is 1-3. Confirmation of the introduced amount can be calculated by a UV / VIS spectrum in a borate buffer.
  • FIG. 1 is a view showing the results of ESC A measurement of the heparin derivative-coated PET surface of the present invention.
  • FIG. 2, FIG. 3, and FIG. 4 are diagrams showing the measurement results of the water contact angle on the PET surface coated with the heparin derivative of the present invention.
  • Fig. 5 is a schematic diagram created based on a scanning electron micrograph of the heparin derivative-coated PET of the present invention after washing with water and then incubating at 37 ° C for 30 minutes in a suspension of platelets washed with PBS.
  • FIG. 5 is a schematic diagram created based on a scanning electron micrograph of the heparin derivative-coated PET of the present invention after washing with water and then incubating at 37 ° C for 30 minutes in a suspension of platelets washed with PBS.
  • FIG. 6 is a graph showing the inhibitory effect of smooth muscle cell proliferation on different concentrations of heparin and the heparin derivative of the present invention.
  • FIG. 7 is a graph showing the temporal inhibitory effect on smooth muscle cell proliferation when heparin and 500 g / ml of the heparin derivative of the present invention are added.
  • FIG. 8 is a graph showing the inhibitory effect of smooth muscle cell proliferation upon culturing for 5 days after the addition of heparin and 500 g / ml of heparin derivative.
  • FIG. 9 is a graph showing the adhesion of smooth muscle cells to a glass surface in the presence of heparin and a heparin derivative.
  • FIGS. 10 and 11 are diagrams showing the thrombin-capturing ability when heparin or a heparin derivative is added to a culture solution when culturing smooth muscle cells or fibroblasts, respectively.
  • FIG. 12 is a diagram showing the thrombin-capturing ability of alkylated heparin of various alkyl chain lengths bound to a glass surface.
  • FIGS. 13 and 14 are diagrams showing the degree of accumulation of heparin and heparin derivatives in the injured blood vessel wall (in vivo).
  • N, N-dimethylformamide (hereinafter, DMF, 50 ml) was added to remove the solvent.
  • DMF dimethylformamide
  • tri-n-butylamine (0.55 ml) and octadecylamine (lmmol) were added, and the mixture was stirred at room temperature for 12 hours.
  • the solvent was removed under reduced pressure at 60 ° C to 25 ml, water (5 ml), saturated sodium acetate solution (2 ml), and ethanol (300 ml) were added.
  • the C-18 alkylated heparan sulfate was synthesized in the same manner as described above, except that heparan sulfate (manufactured by Seikagaku Corporation) was used instead of heparin sodium salt.
  • heparin sodium salt (4.0 g, molecular weight 12,000) in water (80.0 ml) and elute after treatment with an ion exchange column (Dowex 50WX8 [H +], Muromachi Chemical) The solution was dialyzed and freeze-dried to obtain heparin (3.8 g).
  • O click evening Desi Ruamin dissolved in black port Holm 33. 7 mg, was added dropwise a 1. 3 X 1 0 4 mol
  • the reaction solution was concentrated, dissolved in water, treated with an ion exchange column (Dowex 50WX8 [H + ]) to remove the amine, and the eluate was dialyzed and freeze-dried.
  • the obtained powder was washed with a black hole form to remove unreacted octyl decylamine.
  • the residue was lyophilized and dissolved in water to give the O-click evening de acylation heparin (1 34. 8 mg ⁇ 1. 1 X 1 0 ⁇ 5 ⁇ 1 ).
  • the amount of DTAF introduced per heparin sodium molecule for this DTAF-Hep was calculated by a UV / VIS spectrum in a borate buffer (pH 9.18), and as a result, heparin (average molecular weight 12000 The amount introduced per molecule was 2.7.
  • the amount of DTAF introduced per molecule of C- 18 alkylated heparin was measured using a UV / VIS spectrum in a borate buffer (pH 9.18).
  • the introduction amount per molecule of C-18 alkylated heparin was 2.7.
  • Synthesis and purification were performed in the same manner as in Synthesis Example 12 except that butylated heparin (100 mg) obtained in Synthesis Example 10 was used instead of octadecylated heparin.
  • DTAF-Hep-C4 (12.6 mg) was obtained.
  • the amount of DTAF introduced per molecule of C-4 alkylated heparin for this D TAF-HepC4 was calculated by a UV / VIS spectrum in borate buffer (pH 9.18).
  • the amount of C-4 alkylated heparin (average molecular weight 12,000) was 2.7 per molecule.
  • N / C and S / C shown on the vertical axis represent the ratios of nitrogen-binding carbon / carbon-binding carbon and io-bonding carbon / carbon-binding carbon, respectively.
  • 1, 2, 3, and 4 on the horizontal axis represent the washing steps after the PET film was soaked in each derivative solution, 1 was not washed, 2 was washed with water, 3 was washed with 30% ethanol, and 4 was washed with 70% ethanol. Show the later state.
  • the contact angle with water droplets was measured. Measured at 2 x 10' ⁇ (8kV, 20mA) at room temperature with a Mg anode (Mg K radiation) using Shimadzu ES CA750, and the obtained results are shown in Figs. 2 and 3. .
  • the vertical axis represents the contact angle with water
  • the numerical value shown on the horizontal axis represents the cleaning stage as in FIG. 1
  • 0 represents the untreated PET surface
  • 1 represents no cleaning
  • 2 represents water. Washing
  • 3 shows the state after washing with 30% ethanol
  • 4 shows the state after washing with 70% ethanol (washing was performed in the same manner as in Example 1).
  • the contact angle with water droplets was measured using the above polyvinyl chloride (PVC) film instead of the PET film.
  • PVC polyvinyl chloride
  • a PET plate coated with each derivative obtained in Synthesis Examples 1 to 3 was washed with water in the same manner as described above, and then added to a platelet solution (250000) washed with Dulbecco's phosphate buffered saline (PBS). Was injected at 37 ° C. for 30 minutes. The cells were fixed with 1.25% glutaraldehyde, freeze-dried, and observed with a scanning electron microscope. Figure 5 shows the results.
  • Smooth muscle cells were prepared from the egret aorta using collagenase and elastase. 1 in 15% Dulbecco's modified Eagle's medium (DMEM, Gibco Laboratories Inc., Grand Island, NY), 15% fetal bovine serum (FBS, Gibco Lab. Inc.), 501 U / ml streptomycin (Flow Lab., Irvine, Scotland) and 2. Amphotericin B (ICN Biomedicals INC., Aurora Ohio)
  • the above smooth muscle cells were seeded (5 ⁇ 10 3 cells / ell) in a DMEM serum-free medium in a 24-well class evening plate (Sumitomo Bakelite Co., Ltd.). After culturing for 3 days, the cells were washed with phosphate buffered saline (PBS, manufactured by Nissui Pharmaceutical), and then replaced with the culture solution of the DMEM serum-supplemented medium. Heparin, C-18 alkyl at each concentration Heparin was added thereto and cultured for 5 days, and the number of cells was measured and compared with the number of cells in the non-added group (control).
  • PBS phosphate buffered saline
  • the cell number was measured using Cell Counting Kit-8 (manufactured by Dojindo Laboratories) and the absorbance at 45 Onm was measured.
  • Fig. 6 shows the inhibitory effect on smooth muscle cell proliferation after 5 days of culture.
  • Fig. 7 shows the temporal suppression effect of the above.
  • the vertical axis represents the smooth muscle cell density indicated by 0 D at 45 Onm
  • the horizontal axis represents the concentration of heparin and C-18 alkylated heparin.
  • the white bars in each bar graph indicate the non-added group (control)
  • the shaded lines indicate the heparin 500 ⁇ g / m1 added group
  • the black painted group indicates the C-18 alkylated heparin added group (500g / ml).
  • the numerical value on the horizontal axis represents the number of days of culture, and the vertical axis represents the smooth muscle cell density indicated by an OD of 45 Onm.
  • a circular glass plate (15mm0, Matsunami Glass Industry Co., Ltd., Osaka) was placed in the bottom of a 24-hole plate (Iwaki Glass Co. Ltd., Chiba, Japan) and fixed with a stainless steel ring.
  • 1 ml of a suspension (1 ⁇ 10 4 cells / ml) of a smooth muscle cell (using the same cells as described in “Cell culture” in Example 4) was seeded.
  • the supernatant was fluorescently labeled with alkylated heparin (synthesized in Synthesis Example 12).
  • the medium was replaced with a culture solution (100-500 g / ml) containing DT AF-Hep-C18) After a predetermined time (5 days), the cells were washed three times with PBS (-), and then washed 10 times. After fixation with a neutral formalin solution at 488 nm, observation was performed with a confocal laser scanning microscope (Bio-Rad Lab., Hercules, CA) at an excitation wavelength of 488 nm, and C- 18 alkylated heparin inside the cells was observed. Was examined.
  • a culture solution containing neither heparin nor C-18 alkylated heparin was used as a control.
  • a circular glass plate (15 mm 0, Matsunami Glass Industry Co., Ltd., Osaka) was placed in the bottom of a 24-hole plate (Iwaki Glass Co. Ltd., Chiba, Japan) and fixed with a stainless steel ring.
  • the same smooth muscle cell suspension (1 ⁇ 10 4 cells / ml) as described above was inoculated into each well in a volume of 1 ml.
  • Incubator one (3 7 ° C, 9 5 % air, 5% C 0 2) in a 1 2-hr cultured after cell adhesion, culture solution containing heparin heparin or C one 1 8 alkylation f supernatant ( 100 to 500 g / m1).
  • the cells were washed three times with PBS (-) and fixed with a 10% neutral formalin solution.
  • PBS (-) was used for the buffer.
  • 0.1 M Tri-HC1 buffer was used for Alkaline phosphatase substrate kit.
  • the working temperature with the reagent was 4 ° C, and the working time was 30 minutes. After each operation, washing with PBS (-) was performed.
  • an antithrombin III solution (1 unit / ml, Sigma Chemical Co, USA) is allowed to act, followed by a thrombin solution ( (10 units / ml, Sigma Chemical Co, USA) to form heparin or C118 alkylated heparin-antithrombin III-thrombin complex on the substrate.
  • the complex was detected using a Vactastain ABC-AP sheep IgG kit (Vector Laboratories, Inc. Burlingame). The procedure was performed according to the kit.
  • FIG. 10 and FIG. 11 the relative fluorescence intensity on the cell surface when the fluorescence intensity per cell in the case of the control is set to 1 is shown.
  • Example 8 Thrombin Capturing Ability on Alkylated Heparin-Adsorbed Surface
  • a PET film was soaked in a 1% (w / v) aqueous solution of each heparin derivative of the present invention synthesized in Synthesis Examples 1 to 4 for 3 hours.
  • alkylated heparin C-4, C-18, C-12, C-18 alkylated heparin
  • the ability to form a bimolecular or trimolecular complex with thrombin was measured by a confocal laser scanning fluorescence microscope using a chromogenic substrate in the same manner as described above.
  • Figure 12 shows the results.
  • Example 9 Localized delivery and accumulation of heparin using a multifunctional balloon catheter for PTCA
  • a multifunctional PTCA (percutaneous coronary angioplasty) catheter that allows the balloon to be inflated and infused with the drug while perfusing the blood continues to deliver the fluorescently labeled alkylated heparin to the vascular site.
  • the accumulation on the injured vessel wall was examined.
  • fluorescently labeled alkylated heparin and heparin were delivered to the left and right common carotid arteries of the same dog, respectively, and the extent of accumulation was compared 24 hours later.
  • the measurement results of the contact angles shown in FIGS. 2, 3 and 4 show that the contact angle after coating the heparin derivative of the present invention is smaller than that of the untreated plastic plate. This indicates that the water wettability is improved as compared with, indicating that the biocompatibility is improved. Also, the difference between the advancing angle and the receding angle after water washing was smaller than that without washing, indicating that the surface layer of the plastic plate was smoother, and a more uniform coating film was formed. This indicates that it exhibits more antithrombotic properties.
  • the platelets adhering to the untreated PET surface not only had a large number, but also extended pseudopodia and violently extended, whereas the heparin derivative of the present invention was coated. Platelets adhered to the surface However, it remained almost spherical, indicating that platelet activation was significantly suppressed.
  • the above R preferably has 12 or more carbon atoms.
  • the heparin derivative of the present invention inhibited the growth of smooth muscle cells in a dose-dependent manner and completely inhibited the proliferation at a concentration of 400 g / ml or more.
  • the proliferation was significantly inhibited against 500 ⁇ g / ml heparin as a control.
  • the heparin derivative of the present invention has an activity equivalent to that of the control / 500 / g / ml heparin at a concentration of 300 zg / ml at a concentration of 300 zg / ml. .
  • FIG. 7 which shows the time course of the growth inhibitory effect
  • the difference between the heparin derivative of the present invention and heparin is more remarkable, and the cell density increases over time in the heparin-added group, and On the other hand, the growth was completely suppressed by day 5 in the heparin derivative-added group of the present invention.
  • the heparin derivative having an alkyl having 3 carbon atoms has a growth inhibitory effect that is rather inferior to that of heparin.
  • the heparin derivative is more effective than heparin, and the C-118 alkylated heparin derivative has a remarkably superior effect on inhibiting smooth muscle cell proliferation.
  • the GAG derivative of the present invention is adsorbed and enters the cells through a lipid-rich (hydrophobic) extracellular matrix, and supports the high retention property when administered to a living body. It is thought that this has a direct effect on cell function.
  • the heparin derivative of the present invention has a higher thrombin-capturing ability on smooth muscle cells or fibroblasts than heparin.
  • the fluorescence intensity increases with increasing alkyl chain length, and alkylated heparin with alkyl chain lengths of C18 and C12 has high adsorption stability and thrombin trapping ability. It turned out that.
  • the fluorescence intensity of the untreated PET surface was set to 1, and the relative fluorescence intensity of each was shown. Since the relative fluorescence intensity increases in the order of heparin C4, C8, C12, and CI8, it is considered that alkylated heparin exhibits stronger thrombin-capturing ability as the alkyl chain increases.
  • Fig. 13 which is a schematic diagram created based on a fluorescence micrograph
  • alkylated heparin showed fluorescence emission in all delivered blood vessels and all around the intima side. It was found that it was specifically attached. In contrast, heparin only showed fluorescence emission in a part of the inner membrane.
  • the alkylated heparin was higher in luminance than heparin and accumulated to deeper parts of the media.
  • alkylated heparin accumulates sufficiently in the vascular region up to 24 hours after delivery even in vivo (in vivo). Phosphorus has been experimentally demonstrated to accumulate to deeper parts of the vascular media. Industrial applicability
  • the GAG derivative of the present invention when administered to a warm-blooded animal containing humans, adheres to the endothelium of the blood vessel and stays there.
  • the effect of inhibiting the proliferation of muscle cells can be expected at a clinically useful level.
  • using the GAG derivative of the present invention it is possible to easily cover the surface of artificial materials for medical devices, medical devices, etc., and to give the medical devices, medical devices, etc. sufficient antithrombotic properties for a long period of time. Can be.

Landscapes

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

Abstract

La présente invention concerne des dérivés de glycosaminoglycane ou des sels de ceux-ci qui permettent d'effectuer des traitements de surface antithrombotiques sur des instruments médicaux à structure complexe ou des systèmes complets devant être mis en contact avec le sang. Lorsqu'ils sont administrés à des patients souffrant d'artériosclérose, ces dérivés peuvent empêcher la prolifération des cellules du muscle vasculaire lisse tel que l'artère coronaire. En outre, cette invention concerne l'utilisation efficace de ces dérivés. Par ailleurs, ces dérivés de glycosaminoglycane sont caractérisés en ce que un amine primaire R-NH2 (dans lequel R représente éventuellement C4-37 alkyle ramifié, C4-37 cycloalkyle, éventuellement C4-37 alcényle ramifié, C6-14 aryle ou C8-20 aralkyle) est lié par covalence à la fraction de sucre de réduction terminale de glycosaminoglycane.
PCT/JP2000/005337 1999-08-10 2000-08-09 Derives de glycosaminoglycane et leur utilisation WO2001012675A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU64729/00A AU6472900A (en) 1999-08-10 2000-08-09 Glycosaminoglycan derivatives and utilization thereof
JP2001517573A JP4754137B2 (ja) 1999-08-10 2000-08-09 グリコサミノグリカン誘導体およびその使用

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP22668899 1999-08-10
JP11/226688 1999-08-10

Publications (1)

Publication Number Publication Date
WO2001012675A1 true WO2001012675A1 (fr) 2001-02-22

Family

ID=16849107

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2000/005337 WO2001012675A1 (fr) 1999-08-10 2000-08-09 Derives de glycosaminoglycane et leur utilisation

Country Status (3)

Country Link
JP (1) JP4754137B2 (fr)
AU (1) AU6472900A (fr)
WO (1) WO2001012675A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006022087A (ja) * 2004-06-08 2006-01-26 Rohto Pharmaceut Co Ltd 眼科用清涼組成物
JP2008266225A (ja) * 2007-04-23 2008-11-06 Toyobo Co Ltd 抗血栓性抗菌性組成物および医療用具

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092928A1 (fr) * 1982-04-22 1983-11-02 Woodroof Laboratories Incorporated Matériaux bio compatibles et hémocompatibles et méthodes
DE4217916A1 (de) * 1992-05-30 1993-12-02 Job Prof Dr Med Harenberg N-Alkylamin- und N-Arylalkylaminderivate von Heparin, Verfahren zu ihrer Herstellung und ihrer Verwendung
US5464942A (en) * 1990-07-24 1995-11-07 Seikagaku Kogyo Kabushiki Kaisha Phospholipid- or lipid-linked glycosaminoglycan and process for producing the same

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2041377B (en) * 1979-01-22 1983-09-28 Woodroof Lab Inc Bio compatible and blood compatible materials and methods
US4945086A (en) * 1988-05-03 1990-07-31 The Board Of Trustees Of The Leland Stanford Junior University Smooth muscle cell growth inhibitor
JP2667441B2 (ja) * 1988-05-18 1997-10-27 生化学工業株式会社 血管内皮細胞増殖抑制剤
US5250519A (en) * 1991-03-29 1993-10-05 Glycomed Incorporated Non-anticoagulant heparin derivatives
ATE190619T1 (de) * 1993-09-01 2000-04-15 Akzo Nobel Nv Biskonjugate, die zwei saccharide und einen spacer enthalten
JPH07179349A (ja) * 1993-12-24 1995-07-18 Terumo Corp コンドロイチン硫酸のアシル誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0092928A1 (fr) * 1982-04-22 1983-11-02 Woodroof Laboratories Incorporated Matériaux bio compatibles et hémocompatibles et méthodes
US5464942A (en) * 1990-07-24 1995-11-07 Seikagaku Kogyo Kabushiki Kaisha Phospholipid- or lipid-linked glycosaminoglycan and process for producing the same
DE4217916A1 (de) * 1992-05-30 1993-12-02 Job Prof Dr Med Harenberg N-Alkylamin- und N-Arylalkylaminderivate von Heparin, Verfahren zu ihrer Herstellung und ihrer Verwendung

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006022087A (ja) * 2004-06-08 2006-01-26 Rohto Pharmaceut Co Ltd 眼科用清涼組成物
JP2008266225A (ja) * 2007-04-23 2008-11-06 Toyobo Co Ltd 抗血栓性抗菌性組成物および医療用具

Also Published As

Publication number Publication date
JP4754137B2 (ja) 2011-08-24
AU6472900A (en) 2001-03-13

Similar Documents

Publication Publication Date Title
JP5165298B2 (ja) 新規なヘパリン様硫酸化多糖類
JP4278716B2 (ja) Ｎ−硫酸化ヒアルロン酸化合物、その誘導体および製造方法
EP1117695B1 (fr) Polymeres biocompatibles, les compositions les contenant et leur utilisation pour la préparation de médicaments
JP4993465B2 (ja) 変性された高分子ならびにその製造方法および使用方法
AU2003243885B8 (en) Medical products comprising a haemocompatible coating, production and use thereof
AU692389B2 (en) Cyclodextrin compounds and methods of making and use thereof
DE60104703T2 (de) Neue vernetzte derivate der hyaluronsäure.
US7041657B2 (en) Compositions and methods for modulation of vascular structure and/or function
JP5059787B2 (ja) セルロース誘導体およびその製造方法
DE69733493T2 (de) Dermatandisulfat,ein hemmer von thrombinerzeugung und komplementaktivierung
JPH0672893A (ja) 抗リウマチ剤
US20080183282A1 (en) Use of lipid conjugates for the coating of stents and catheters
US7345117B1 (en) Sulphated hyaluronic acid and sulphated derivatives thereof covalently bound to polyurethanes, and the process for their preparation
JP2003335801A (ja) 脂質結合グリコサミノグリカンの製造法
EP1166788B1 (fr) Medicaments contre les affections articulaires
DE10261986A1 (de) Hämokompatibel beschichtete Oberflächen
JP2997018B2 (ja) 燐脂質又は脂質結合グリコサミノグリカン
WO2001012675A1 (fr) Derives de glycosaminoglycane et leur utilisation
Gupta et al. Recent advances in the design and immobilization of heparin for biomedical application: A review
JP3032824B1 (ja) 骨誘導促進剤
WO2004004794A1 (fr) Resine compatible avec le liquide organique et le tissu vivant
RU2792001C2 (ru) Функционализированная гиалуроновая кислота или ее производное для лечения воспалительных состояний
Malhotra et al. Biomedical Applications of Chitosan and Its Derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase