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WO1998003203A1 - Particules poreuses insolubles dans l'eau, constituees de substances biocompatibles et leur procede de production - Google Patents

Particules poreuses insolubles dans l'eau, constituees de substances biocompatibles et leur procede de production Download PDF

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Publication number
WO1998003203A1
WO1998003203A1 PCT/JP1997/002478 JP9702478W WO9803203A1 WO 1998003203 A1 WO1998003203 A1 WO 1998003203A1 JP 9702478 W JP9702478 W JP 9702478W WO 9803203 A1 WO9803203 A1 WO 9803203A1
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WO
WIPO (PCT)
Prior art keywords
particles
water
substance
biocompatible substance
biocompatible
Prior art date
Application number
PCT/JP1997/002478
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English (en)
Japanese (ja)
Inventor
Satoshi Izumikawa
Noboru Yamashita
Akira Takagi
Yoshinori Masuda
Akira Okada
Muneo Fukui
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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 Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU34615/97A priority Critical patent/AU3461597A/en
Priority to JP50678698A priority patent/JP3879018B2/ja
Publication of WO1998003203A1 publication Critical patent/WO1998003203A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1658—Proteins, e.g. albumin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

  • the present invention relates to water-insolubilized porous particles of a biocompatible substance useful as an embolic substance for embolization treatment or a carrier for pharmaceutical preparations, and a method for producing the same.
  • Transcatheter arterial embolization (hereinafter sometimes abbreviated as TAE) is one of the most widely used therapies for multiple cases, large-scale liver cancer, and recurrent cases after resection.
  • TAE Transcatheter arterial embolization
  • the therapy is performed by injecting a lipiodol suspension of an anticancer drug into cancer tissue using a microcatheter, and then embolizing blood vessels leading to the cancer tissue with a suspended embolic material using a nonionic contrast agent. It is something to be done.
  • the blood supply to the cancer tissue is cut off, and the cancer tissue can be effectively killed by the so-called “arms attack”.
  • this therapy is a tissue-selective therapy, side effects such as necrosis of normal cells can be minimized. It is known that the therapy is also effective for renal cancer.
  • a Polysaccharides or polysaccharide derivatives such as partially hydrolyzed potato starch (specified composition, properties, and functions: from physiologically acceptable, water-insoluble, hydrophilic, swellable, glucose units having a three-dimensional network structure)
  • a method for producing a drug for intravascular administration for the treatment of embolism is disclosed, and a biodegradable temporary embolic material using epichlorohydrin-crosslinked partially hydrolyzed potato starch particles based on the invention is degra It is marketed as Double Starch Microsphere (trade name: manufactured by Pharmacia Co., Ltd .; abbreviated as DSM).
  • the DSM only lasts for several tens of minutes, preventing the effect of the above-mentioned “weapon attack” and also uses a cross-linking agent for water insolubilization.
  • Embolic substances used in TAE have so far used autologous clots, muscle fragments, metals, activated carbon particles, gelatin sponges, silicon spheres, polyvinyl alcohol sponges, cyanoacrylates, polylactic acid dalicholate microspheres, etc.
  • gelatin sponges are currently the most commonly used in countries around the world.
  • Japanese Patent Publication No. 62-333263 discloses the manufacture of gelatin spherical particles in order to improve the problem that mechanically crushed gelatin sponges, which were actually used in clinical practice, are difficult to adhere to blood vessels.
  • a cross-linking reaction is carried out by dispersing an aqueous solution of gelatin and a water-soluble compound which undergoes a cross-linking reaction with gelatin in a dispersion solvent in which water-insoluble ethyl cellulose is dissolved in a non-polar organic solvent which is incompatible with water. It is disclosed.
  • Japanese Unexamined Patent Publication (Kokai) No. 60-222,045 discloses a non-porous crosslinked gelatin sphere prepared by the method described in the above-mentioned Japanese Patent Publication No. 62-32,263.
  • a vascular embolic agent consisting of particles is disclosed, and renal embolism in dogs, in which re-opening of the embolized artery is premature compared to humans, was confirmed as a result of a renal embolism experiment 30 days later. I have.
  • embolic material for embolic treatment can be used as a therapeutically effective embolic therapy if recanalized after 2 weeks, and that there is no concern about side effects such as necrosis of normal cells. (Morio Sato, Ryusaku Yamada, Journal of the Japanese Society of Medical Radiology, 43 (8), p. 977-1005 (1983)).
  • the present inventors studied a method for producing water-insoluble and porous particles without using a cross-linking agent.
  • the cross-linking agent was not added, the emulsion was unified when the emulsion was prepared.
  • the porous particles cannot maintain their shape and become agglomerated, and water is present in the particles when the emulsion is prepared and gelled by cooling to remove the particles from the poor solvent.
  • heated in a heated state it dissolves or agglomerates.
  • washing and removing the solvent used during production it can not be sufficiently washed to a permissible amount by stirring alone, and it increases the porosity of the surface of gel particles. Problems such as inability to produce porous particles were clarified.
  • the present inventors have conducted intensive studies to produce porous particles of a biocompatible substance that can be satisfied as an embolic material for embolization treatment.
  • Water-insolubilized porous particles having sufficient elasticity as an embolic substance and embolic ability considered to be therapeutically effective can be prepared by heating porous particles in a system substantially free of water to make them water-insoluble.
  • the water-insolubilized porous particles obtained in this way are not only excellent as embolic substances, but also various other substances such as pharmaceutical substances such as bone growth factor (BMP) and various carriers for cell immobilization or culture.
  • BMP bone growth factor
  • the inventors have found that they have excellent properties as a carrier, and have completed the present invention.
  • the present invention relates to water-insolubilized porous particles of a gel-forming or solidifying biocompatible substance substantially containing no crosslinking agent. Further, the present invention relates to water-insolubilized porous particles of a biocompatible substance obtained by heating gelled or solidified porous particles of a biocompatible substance in a system substantially free of water to make them water-insoluble. .
  • the gelled or solidified porous particles of a biocompatible substance are heated substantially in the presence of water, and the porous particles of the biocompatible substance are insoluble in water by heating in a system.
  • a gel-forming or solidifying biocompatible substance is foamed in a good solvent solution of the substance, dispersed in a poor solvent of a biocompatible substance that is immiscible with the good solvent, and cooled.
  • the obtained porous particles are washed with a solvent in which the poor solvent for the biocompatible substance is miscible, and heated in a system substantially free of water to make the biocompatible substance insoluble in water.
  • porous particles and a method for producing the same are provided.
  • a substance that is soluble in a poor solvent for a biocompatible substance or insoluble in a good solvent for a biocompatible substance is dissolved in a good solvent solution of a gel-forming or solidifying biocompatible substance. And dispersing the substance that migrates to the poor solvent for the substance, further dispersing the dispersion in the poor solvent for the biocompatible substance, and cooling and gelling or solidifying the resultant.
  • Water-insolubilized porous particles of a biocompatible substance obtained by washing with a solvent that is miscible with a poor solvent for a biocompatible substance and heating in a system substantially free of water are provided.
  • foams such as foam have an unstable shape, and although they can be made into blocks, they are small enough to be used as embolic substances without using a cross-linking agent, and are water-insoluble and porous. Under the circumstances that it was considered extremely difficult to make the particles holding the gel, the gelled or solidified porous particles of the biocompatible substance were heated in a substantially water-free system to make them insoluble in water. The water-insolubilized porous particles of the present invention were obtained. Was completely unexpected.
  • substantially contains no cross-linking agent means that a cross-linking agent is added within a range that does not impair the object of the present invention, in particular, within a range that does not exhibit toxicity. It means that.
  • the biocompatible substance used in the present invention is not particularly limited as long as it is pharmaceutically acceptable and biodegradable, and is water-insoluble by heat treatment. Among them, those in which the strength of the gel is increased or solidified by cooling during the formation of the emulsion in the later-described emulsion forming step are preferable. Further, it is preferable that the biocompatible substance foams when dissolved in a good solvent for the substance. Also, without foaming or foaming, after dispersing the poor solvent of the biocompatible substance in a good solvent solution of the substance, the dispersion is further dispersed in the poor solvent of the substance.
  • the present invention also encompasses an embodiment in which a substance can be dispersed in a solution of a biocompatible substance in a good solvent, and then the dispersion can be further dispersed in a poor solvent of the substance to form pores inside the particles.
  • the substance that is soluble in the poor solvent of the biocompatible substance or the substance that is insoluble in the good solvent of the biocompatible substance and migrates to the poor solvent for the substance include, for example, soybean oil when the biocompatible substance is gelatin, and so on. Oils, organic solvents such as black form, and organic compounds such as polystyrene beads.
  • the biocompatible substance of the present invention is not particularly limited as long as it is a polymer composed of amino acid or a biologically-derived compound, a derivative thereof, or a physiologically acceptable salt thereof.
  • a polypeptide, a derivative thereof, a protein, a derivative thereof, a polysaccharide, a derivative thereof, a physiologically acceptable salt thereof, a mixture containing them, or a mixture of these and a polypeptide can be given.
  • proteins or polypeptides such as gelatin, collagen, atelocollagen, albumin, fibrin, protamine, derivatives thereof, or physiologically acceptable salts thereof, juran gum, arabia gum, hyaluronic acid, alginic acid, chondroitin Polysaccharides such as sulfuric acid, heparin, chitin, chitosan, their derivatives, or their physiologically acceptable salts Is mentioned.
  • gelatin, atelocollagen, albumin, hyaluronic acid, alginic acid, derivatives thereof, or physiologically acceptable salts thereof are preferred.
  • biocompatible substances may be used alone or in combination of two or more. Further, gelatin is preferred.
  • the good solvent for the biocompatible substance is not particularly limited as long as it is pharmaceutically acceptable and can dissolve the substance.
  • the solvent may contain pharmaceutically acceptable additives such as a buffer, an emulsifier, and a tonicity agent.
  • the buffer include phosphate, carbonate, and organic acid salt.
  • the emulsifier include polysorbate, polyethylene hydrogenated castor oil, and sorbitan sesquioleate.
  • the tonicity agent include sodium chloride, glucose, lactose, and sucrose. One or more of these additives may be used.
  • the solution may be dissolved by heating.
  • the degree of dissolution of a biocompatible substance in a good solvent for the substance varies depending on the type of the biocompatible substance, but is usually about 0.01 to 50% by weight, preferably about 0. 30% by weight, more preferably about 1 to 20% by weight.
  • the poor solvent for the biocompatible substance is a pharmaceutically acceptable substance that does not dissolve the biocompatible substance, or a pharmaceutically acceptable substance that is immiscible with a good solvent for the biocompatible substance.
  • mineral oil eg, liquid paraffin
  • animal oil eg, soybean oil, sesame oil, peanut oil, cottonseed oil, camellia oil, rapeseed oil, coconut oil, eucalyptus oil, corn oil, olive oil, castor oil, etc.
  • Silicon oil fatty acids, fatty acid esters (for example, medium-chain fatty acid triglyceride (for example, trade name: Panacet, manufactured by NOF Corporation), ethyl oleate, etc.), organic solvents (for example, toluene, benzene, hexane) , Chloroform, dichloromethane, carbon tetrachloride, etc.).
  • fatty acid esters such as medium-chain fatty acid triglyceride and ethyl oleate are preferred.
  • the solvents for these biocompatible substances may be used alone or as a mixture of two or more.
  • fatty acid esters are preferred.
  • the porous particles of the present invention are not particularly limited as long as they are spherical or amorphous particles and have one or more pores on the surface and inside and are insoluble in water. Among them, a honeycomb shape is preferable.
  • a drug or compound may be contained or immobilized in the particles.
  • the drug or compound can be contained or immobilized by a method known per se. Examples of the method include a method in which a drug or a compound is added or mixed to contain or immobilize in each step of the production method described below.
  • generally pharmaceutically acceptable additives such as excipients, stabilizers, buffers, dispersants, and coating agents may be used together with the particles.
  • excipients include lactose, crystalline phenolic cellulose, dextran and the like.
  • examples of the stabilizer include lactose, trehalose, polyethylene dalicol and the like.
  • the buffer include phosphate, carbonate, and organic acid salt.
  • the dispersant include carboxymethyl cellulose, glycerin, and soybean oil.
  • the coating agent include atalylic acid polymer and polylactic acid / glycolic acid copolymer. One or more of these additives may be used.
  • the specific gravity of the water-insolubilized porous particles of the present invention is not particularly limited, but is usually 0.001 to 1 g / w, preferably 0.005 to 0.9 gm, more preferably 0.005 to 0.2 gZm. It is.
  • the specific gravity can be calculated, for example, by taking a fixed volume (ml) with a measuring cylinder, measuring the weight (g) at that time, and dividing the weight by the volume.
  • the particle size of the water-insolubilized porous particles of the present invention is not particularly limited, but is usually 0.01 to 1 Omm, and preferably 0.1 to 7 mm.
  • the particle size is not particularly limited as long as the particle size does not cause a side effect.
  • it can be applied to a normal injection needle or a force table and to a blood vessel selected for embolization treatment.
  • it is 0.5 to 10 mm, more preferably 0.5 to 7 mm.
  • the particle diameter in the present invention means an average particle diameter.
  • the water-insolubilized porous particles of the present invention have elasticity that can pass through an injection or a catheter or the like, and also have elasticity that particles can freely deform and embolize a blood vessel or the like selected for embolization treatment.
  • a microcatheter standard 3
  • a microcatheter standard 3
  • a material capable of passing through a flow path corresponding thereto is preferable.
  • the swelling ratio of the water-insolubilized porous particles of the present invention is not particularly limited, but is usually about 0.1 to 100 times, preferably about 0.1 to 10 times, and more preferably about 1 to 5 times. .
  • the swelling ratio can be determined, for example, by immersing particles of a certain volume (abbreviated as V) in water, saline, various electrolyte solutions, medical infusions, oils, contrast agents, or therapeutic drugs.
  • V 2 The volume of S Peng Jun (abbreviated as V 2) can be measured using a measuring cylinder or the like, and can be calculated by V 2 ZV.
  • substantially free of water refers to an embodiment in which water is present within a range that does not impair the object of the present invention, in particular, within a range in which particles are not dissolved or aggregated during heat treatment. Included in the present invention. More specifically, “substantially free of water” means that the particles have been washed in a washing / dehydration step described below with a solvent in which a good solvent for the biocompatible substance and a poor solvent for the substance are miscible. Alternatively, it means that the particles have been dried by a drying means such as through-air drying, vacuum drying, or freeze-drying.
  • a foaming step in which foaming is performed by stirring an foaming step in which the foam obtained in the step is poured into a poor solvent of M (abbreviated as S2), and stirring is performed, for example, to form an emulsion.
  • a gelation step in which the emulsion obtained in the step is cooled to, for example, a gelling temperature of M or lower to gel (or solidify) to form gel particles, and the gel particles obtained in the step are sieved, for example, by sieving.
  • the above steps are separated for the sake of convenience in order to explain the present invention in detail, but the present invention is not limited to these steps because some steps can also serve as other steps. .
  • each step will be described in detail.
  • a good solvent (S) solution (S1) of the biocompatible substance (M) is foamed.
  • S1 good solvent
  • M biocompatible substance
  • the method includes, for example, a homogenizer
  • the emulsification step is not particularly limited as long as the foam obtained in the above step can be added to the poor solvent (S 2) of M to form an emulsion.
  • a stirrer such as a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.), a stirring motor with a paddle (MAZELA Z, manufactured by EYLA), and a magnetic stirrer (MAG MIXER, manufactured by Yamato Scientific Co., Ltd.) are used.
  • a stirrer such as a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.), a stirring motor with a paddle (MAZELA Z, manufactured by EYLA), and a magnetic stirrer (MAG MIXER, manufactured by Yamato Scientific Co., Ltd.) are used.
  • the ratio of adding the foam obtained in the above step to the poor solvent (S 2) of M is not particularly limited as long as the emulsion can be formed, but is usually 1.0 or less.
  • the conditions such as the number of rotations of the machine and the size of the container may be any conditions as long as defoaming or fusion between emulsion particles does not occur. Even if foaming is not performed or foaming is performed, the poor solvent of the biocompatible substance is dispersed in a good solvent solution of the substance, and this dispersion is further dispersed in the poor solvent of the substance.
  • a pore can be formed inside the particle, or a substance that is soluble in a poor solvent for a biocompatible substance or a substance that is insoluble in a good solvent for a biocompatible substance and migrates to a poor solvent for the substance
  • the foaming step is omitted.
  • 32 is dispersed in 1 (82/31)
  • the dispersion is further dispersed in S 2, and when an S 2 ZS 1 / S 2 emulsion is formed, this step can also serve as the foaming step .
  • the ratio of S 2 ZS 1 is not particularly limited as long as it is a ratio at which an emulsion is formed, but is usually 1.0 or less, preferably 0.8 or less. Furthermore, as for the ratio of (S 2 / S 1) ZS 2, Although not limited, it is 1.0 or less, preferably 0.8 or less.
  • the gelation (or solidification) step is not particularly limited as long as the emulsion obtained in the above step is gelled (or solidified).
  • Examples of the method include a method of cooling the system below the gelation (or solidification) temperature of the biocompatible substance, and a method of solidifying the substance by washing it with a poor solvent. When the emulsion gels (or solidifies), particles that can be easily handled can be obtained.
  • the gelation temperature of the biocompatible substance can be appropriately selected depending on the composition of the biocompatible substance, the concentration of the substance in a good solvent solution, or the retention time (time for maintaining a certain temperature).
  • the substance when quenching a 4% gelatin aqueous solution, it is possible to gel at about 18 ° C; when washing gelled particles with alcohols in the washing step described below, an exothermic reaction occurs. It is preferably at most 16 ° C.
  • the substance can be solidified by washing with a poor solvent for the substance.
  • the step of removing the poor solvent (abbreviated as S2) of the biocompatible substance is not particularly limited as long as it is a method of removing S2 by removing the particles obtained in the above step from S2. Examples of the method include sieving, filtration, and centrifugation.
  • the system is preferably cooled to a temperature lower than the gelation temperature of the biocompatible substance in order to maintain the shape of the particles stably.
  • the particles may be classified according to the purpose of use.
  • the washing / dehydrating step is not particularly limited as long as S and S2 are washed from the particles obtained in the above step.
  • Examples of the method include a method of washing with a solvent (S 3) in which S and S 2 are miscible.
  • S 3) a solvent
  • the particles are taken out on a mesh and washed with S3, or the particles are put into a beaker, washed while being stirred under reduced pressure with S3, and returned to normal pressure, or the particles and S3 are mixed in a beaker. And wash the whole beaker by ultrasonic irradiation.
  • the steps of reduced pressure, normal pressure and ultrasonic waves may be repeated. By this step, pores are further formed on the surface and inside, and S 2 remaining inside is efficiently cleaned.
  • S3 is pharmaceutically acceptable, is miscible with S and S2, and is not particularly limited as long as it is a poor solvent for M.
  • S3 include alcohols (eg, methanol, ethanol, isopropanol, etc.), acetone, dioxane, hexane, and halogen-based organic solvents. Above all, methano Alcohols such as ethanol, ethanol and isopropanol are preferred. These may be used alone or in combination of two or more.
  • an anti-agglomeration agent may be added.
  • the agglomeration inhibitor include lactose, D-sorbitol, and crystalline cellulose. Further, before and after this step, steps such as ventilation drying, vacuum drying, and freeze drying can be performed.
  • the heat treatment step is not particularly limited as long as the particles are substantially insoluble in water and the system is treated under the conditions of temperature and time at which the particles obtained in the step become insoluble in water.
  • any conditions may be used for this step as long as the temperature and the time at which the biocompatible substance causes intermolecular crosslinking.
  • the time conditions in the method are determined by the temperature conditions, and include, for example, 110 minutes to 220 degrees and 10 minutes or more and 120 hours or less.
  • the temperature is from 135 minutes to 120 hours at 135 T, more preferably from 1 hour to 6 hours at 144 to 190 ° C.
  • this step may be performed under reduced pressure. This step can also serve as a sterilization treatment.
  • the particles may be washed with water to remove water-soluble components.
  • the sterilization treatment may be performed by filling the particles of the present invention in a medical packaging container (for example, a vial, an ampoule, a prefilled syringe, etc.), and then using a high-pressure steam method (Japanese Pharmacopoeia) or the like.
  • a medical packaging container for example, a vial, an ampoule, a prefilled syringe, etc.
  • a high-pressure steam method Japanese Pharmacopoeia
  • a dehydration step can be further carried out by a method known per se.
  • drying methods such as ventilation drying, vacuum drying, and freeze drying.
  • the dose can be appropriately adjusted depending on the thickness of blood vessels selected for embolization treatment, the spread of tumor tissue, or the instrument used. Usually, it is 1 g or less, preferably 0.5 g or less. In this case, it may be used as a pharmaceutical composition together with a physiologically acceptable liquid (physiological saline solution, iodinated poppy oil fatty acid ethyl ester, etc.).
  • a physiologically acceptable liquid physiological saline solution, iodinated poppy oil fatty acid ethyl ester, etc.
  • the porous particles of the present invention are used as an embolic substance in TAE and the like, and also used as a hemostatic substance in medical procedures such as biopsy.
  • the particle It may be used as a pharmaceutical composition together with a liquid alone or a physiologically acceptable liquid (such as physiological saline). It is also used as a carrier for various cell immobilization or culture. In this case, it may be used as a pharmaceutical composition together with a physiologically acceptable liquid (such as physiological saline).
  • a wound protectant a disintegrant for oral preparations, a drug adsorbent (for example, a bitterness inhibitor), a carrier for sustained release preparations, and a material for preventing breakage during transportation.
  • porous particles of the present invention can also contain or mix a pharmaceutical substance such as a diagnostic drug or a therapeutic drug. That is, in this case, a pharmaceutical composition containing the porous particles of the present invention is provided.
  • Examples of the diagnostic agent include X-ray contrast agents and radioisotopes as contrast agents.
  • Examples of the X-ray contrast agent include amide trizoic acid, iotharamic acid, omidamide, metrizonic acid, or a physiologically acceptable salt thereof as a triode compound, adipiodone, ixoxagluate, and a triode dimer compound.
  • Iotroxic acid eodoxamic acid, iocarmic acid, or a physiologically acceptable salt thereof, as a non-ionic compound, iotrolan, iopamidol, iohexol, iohersole, iomeprol, metrazamide, or Examples of monodized oils include oxidized poppy oil and fatty acid ethyl ester (trade name: Lipiodol Penoletraphnolide).
  • the diagnostic agent may be, for example, a radioactive substance.
  • the substance may be in the form of a solution or microparticles.
  • the fine particles are generally the same size or smaller than the particles of the present invention.
  • Contains radioisotopes such as indium, thallium, iodine, technetium, gallium, cerium, norebidium, chromate, iron, tin, xenon, carbon, oxygen, nitrogen, fluorine or their physiologically acceptable salts It may be a substance that does. These may use one or more different radioisotopes.
  • the concentration and radioactivity of the radioactive substance are not particularly limited as long as they can be diagnosed.
  • Examples of the therapeutic agent include an antitumor agent or a similar radioactive substance.
  • Examples of the antitumor drug include mitomycin C, actinomycin D, bleomycin (bleomycin hydrochloride, etc.), Lacyclin antibiotics (acralubicin hydrochloride, epirubicin hydrochloride, doxorubicin hydrochloride, etc.), neocarzinostatin, dinostatin stylamer (SMANCS), etc.
  • Examples of antitumor plant component drugs include irinotecan hydrochloride, vinblastine sulfate, etoposide, etc., and other tumor drugs include carpoplatin, cisplatin, pentostatin, lentinan and the like.
  • examples of the therapeutic agent include biological agents such as cytokines, hematopoietic factors, various growth factors, and enzymes.
  • examples of the cytokine include interferon (eg, ⁇ , ⁇ , y), interleukin (eg, IL-1 to IL-18), tumor necrosis factor (TNF), and the like.
  • hematopoietic factor examples include erythropoietin ( ⁇ - ⁇ ), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM- CSF), thrombopoietin (II), platelet growth factor, stem cell growth factor (SCF) and the like.
  • growth factors examples include basic or acidic fibroblast growth factor (FGF) or their families, nerve cell growth factor (NGF) or their families, insulin-like growth factor (IGF), bone Form factors (eg BMP 1-2) or transforming growth factors (TGF-), superfamily, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), epithelial cell growth factor (EGF ).
  • FGF basic or acidic fibroblast growth factor
  • NGF nerve cell growth factor
  • IGF insulin-like growth factor
  • TGF- transforming growth factors
  • HGF hepatocyte growth factor
  • PDGF platelet-derived growth factor
  • EGF epithelial cell growth factor
  • Various hormones include insulin, calcitonin, glucagon, human growth factor (hGH), parathyroid hormone (PTH), and the like.
  • the enzyme include L-asparaginase, superoxide dismutase (SOD), and tissue plasminogen activator (t-PA).
  • Therapeutic agents are substances involved in the expression of proteins and peptides (for example, nucleic acids such as DNA and RNA, or low- and high-molecular transcriptional regulators and their inhibitors). Agent).
  • therapeutic agents include, for example, substances acting on blood vessels (vasodilators, vasoconstrictors, etc.), substances acting on coagulation, substances acting on the formation or dissolution of thrombus, antibacterial substances, anti-inflammation Substances, anesthetics, substances that exhibit hormonal effects, bone resorption inhibitors (for example, bisphosphonates), various vitamins, and antiparasitic substances.
  • therapeutic agents or diagnostic agents may be used as a mixture of two or more. Further, they may be used by diluting them with a physiologically acceptable liquid (eg, physiological saline).
  • FIG. 1 shows a production method for producing the water-insolubilized porous particles of the present invention. A detailed description is given in the section of the disclosure of the invention.
  • FIG. 2 shows the mechanism of action (from administration to recanalization) of embolization therapy when the water-insolubilized porous particles of the present invention are used for transarterial embolization therapy.
  • the mechanism is as follows: (1) Particles selectively administered to a target blood vessel by a catheter physically emboli the blood vessel; (2) Platelet adheres to the particle and Z or is brought into contact with the particle to induce platelet aggregation. Clots are formed (the embolism becomes strong). 3The embolus causes necrosis of a malignant tumor whose nutrient supply is cut off.
  • the concentration of the anticancer drug at the tumor site is also high.
  • particles are degraded by enzymes in the living body, and blood vessels are re-communicated.
  • Necrotic areas or surrounding tissues are restored to normal.
  • the features of the porous particles of the present invention in the mechanism are considered as follows. That is, (1) Regarding the above mechanism (1), since the particles of the present invention are porous, the particle surface area is large, and the particles have excellent elasticity, so that they can be freely adjusted according to the blood vessel wall and the thickness of the blood vessel. By being deformable, particles can be formed in a state where the particles are close to each other in an embolus position and denser.
  • the particles of the present invention can be deformed even in a microcatheter used for TAE or the like, it is possible to administer particles having a particle size larger than that of non-porous' ft particles. An embolic effect is expected. In addition, usually, when a micro catheter is used, a considerable force is required. When the particles of the present invention are used, the physical burden on the practitioner may be reduced for the reasons described above. Be expected. (2) It is generally said that platelet aggregation is induced by contact of platelets with, for example, collagen. Regarding the mechanism (1), for example, a case is considered where gelatin obtained by decomposing collagen is used as a base for an embolic substance.
  • the specific surface area of the particles of the present invention is large because of their porosity, and platelet aggregation is likely to occur because of their large contact surface area with platelets.
  • the particles of the present invention are porous, platelets can infiltrate between the particles, so that the platelet aggregation effect is further enhanced, and the embolization ability is thought to be enhanced accordingly.
  • turbulence is likely to occur in blood vessels due to the effects of particle irregularities, and that platelet aggregation is likely to occur due to the shearing pressure exerted on platelets.
  • the mechanism (1) it is considered that the particle of the present invention is degraded from the inside of the particle due to its porosity in the decomposition by the in-vivo enzyme, so the disappearance rate is high.
  • Figure 3 shows the mechanism of action (from administration to recanalization) when non-porous particles are used in the therapy. Since the particles are not porous, it can be considered that the particle size that can be administered is poorer than the porous particles of the present invention in terms of the embolic property and the re-penetrating ability based on the platelet aggregation action.
  • FIG. 4 shows the results of a platelet aggregation test on the particles of the present invention prepared from Example 16 and the non-porous particles obtained from Comparative Examples 3 to 6. (Beagle A blood)
  • FIG. 5 shows the results of the platelet aggregation test as in FIG. (Blood of Beagle Dog B) Best Mode for Carrying Out the Invention
  • Gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) (20 g) was placed in purified water (500 zo) and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (1000 rpm, 10 minutes) to foam. This foam (400 ⁇ ) is put into Panacet 800 (Nippon Oil & Fats Co., Ltd.) 1/200, and stirred at 200 rpm using a stirrer (MAZELA Z, Tokyo Rika Instruments) equipped with a Teflon paddle. To form an emulsion. When this emulsion was taken out using a mesh at room temperature without gelling, the emulsion was coalesced and could not be taken out as particles.
  • a homogenizer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • MAZELA Z Tokyo Rika Instruments
  • the gel particles were taken out using a mesh (250 ⁇ m) and washed with isopropyl alcohol (IPA). After washing, ⁇ PA was removed using a glass filter, and gel particles were taken out. This was vacuum-dried and heated at 155 ° C for 4 hours to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • each particle 1 j 1 before and after the heat treatment was placed in a 1-oz Spitz tube, and water was added thereto to make 1 z, and the residual gel volume after shaking for a certain period of time with a shaker was used.
  • the structure retention ability was compared by measuring.
  • the particles subjected to the heat treatment immediately swelled and maintained their structures, whereas the particles not heat-treated dissolved the gel with time and could not maintain the structure. Therefore, the book It was suggested that the inventive particles were water-insoluble and had a moderate strength considered to be applicable to embolization therapy.
  • the porous particles produced using darthal aldehyde as a cross-linking agent As a result, with respect to the porous particles produced using darthal aldehyde as a cross-linking agent, a tendency to suppress cell growth was observed. In contrast, the porous particles of the present invention tended to promote cell growth. Therefore, it was suggested that the particles of the present invention are more excellent in cell proliferation and safety than particles crosslinked with glutaraldehyde.
  • Gelatin (CP-2, manufactured by Takashiro Chemical Co., Ltd.) (50 g) was placed in purified water (500 ⁇ ) and heated to dissolve. The solution is returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo). (10 () 00 rpm, 10 minutes). The foam was added to soybean oil (manufactured by Kanto Kagaku) 1 /, and the same operation as in Example 1 was carried out to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • Gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) (50 g) was placed in purified water (500 /) and heated to dissolve. The solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (lOOOOOrpm, 10 minutes) to foam. The foam (400 m) was put into sesame oil (manufactured by Kanto Kagaku) 1 /, and the same operation as in Example 1 was carried out to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • ⁇ serum albumin (BS S, manufactured by Sigma) was placed in 100 ⁇ of purified water, and dissolved by stirring with a magnetic stirrer. This solution was stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (lOOOOOrpm, 10 minutes) to foam. 20 zo of this foam was put into 1 zo of Panaceto 800 (manufactured by NOF CORPORATION), and the same operation as in Example 1 was carried out to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • BS S manufactured by Sigma
  • alginic acid manufactured by Sigma
  • 20 g of alginic acid was placed in purified water 100/77 and stirred and dissolved with a magnetic stirrer.
  • the solution was stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (lOOOOORpm, 10 minutes) to foam.
  • 20 bubbles of this foam were put in 1 panaceto 800 (manufactured by NOF CORPORATION), and the same operation as in Example 1 was carried out to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • Gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) (50 g) was placed in purified water (50 zo), and dissolved by heating. The solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (100,000 rpm, 10 minutes) to foam. This bubble 40 ⁇ / ⁇ 15 (manufactured by Kao Corporation) was added to 1/100/1 (manufactured by NOF CORPORATION) 1 / containing 1%, and the same operation as in Example 1 was carried out to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • Example 1 50 g of hydrolyzed gelatin (trade name; Nippi High Grade Gelatin, manufactured by Nippi) was placed in 500 777 of purified water, and heated to dissolve. The solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (100 rpm, 10 minutes) to foam. 400/77 of this foam was put into Panasate 800 (manufactured by NOF Corporation), and stirred at 400 rpm using a stirrer (MAZELA Z, manufactured by EYELA) equipped with a Teflon paddle. To form an emulsion. Thereafter, the same operation as in Example 1 was performed to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • a homogenizer manufactured by Tokushu Kika Kogyo Co., Ltd.
  • Gelatin (CP-2, manufactured by Takashiro Chemical Co., Ltd.) (4 g) was placed in purified water (100 / dilute) and heated to dissolve. The solution was returned to room temperature, added with 20/77 / of panacet, and stirred with a homogenizer to form an emulsion. The emulsion was added in a panasate 800 (manufactured by NOF Corporation) 400/77, and the same operation as in Example 1 was carried out to obtain particles of the present invention. The obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • Example 1 1 In the same manner as in Example 1, the obtained gel particles were vacuum-dried and then heated at 190 ° C for 1 hour to obtain particles of the present invention.
  • the obtained particles had pores on the surface, and the upper part was porous (honeycomb). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.
  • the gel particles obtained were dried under vacuum in the same manner as in Example I, and then heated at 170 ° C for 2 hours to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • the gel particles obtained were dried in a vacuum in the same manner as in Example 1 and then heated at 160 ° C. for 4 hours to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • the gel particles obtained were dried in vacuo in the same manner as in Example 1 and then heated at 145 ° C. for 5 hours to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • the obtained gel particles were lyophilized, and then heated at 145 ° C for 5 hours to obtain particles of the present invention.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • the gel particles were taken out using a mesh (300 / xm) and washed with cooled isopropyl alcohol (IPA). After washing, the IPA was removed using a mesh, and the gel particles were taken out. Put the gel particles and IPA into a beaker, reduce the pressure using a water jet pump, and stir with a magnetic stirrer. While washing, the gel particles were washed. Further, the pressure was returned to normal pressure, the whole beaker was transferred to an ultrasonic cleaner, and the gel particles were irradiated with ultrasonic waves. The gel particles were classified using a mesh, and the gel particles were taken out using a filter. This was vacuum-dried and heated at 155 ° C for 4 hours to obtain particles of the present invention.
  • IPA isopropyl alcohol
  • the particles were further washed with water and freeze-dried to obtain particles.
  • the obtained particles had pores on the surface and were porous (honeycomb) inside. When dispersed in water, they swelled while maintaining the shape of spherical particles.
  • a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, 6 g of ethylcell mouth (49% containing an ethoxy group) was dissolved, and this solution was fitted with a cooling tube and a Teflon paddle. Ezo was placed in a separable flask. The stirring speed was 400 rpm, and the temperature was 70 ° C.
  • gelatin was added to water at a concentration of 30% by weight, and 40 g of an aqueous solution obtained by dissolving at 60 ° C was added.4 g of a 50% aqueous dartal aldehyde solution (1 equivalent of the amino group of gelatin, (4 equivalents of Daltar aldehyde) and reacted for 5 minutes to obtain brownish particles. This was washed with ethyl acetate, further washed with acetone, and sieved to collect particles of 0.5 to 1.0 mm, and dried with a vacuum drier to obtain particles. Observation of the particles with an electron microscope revealed that the surface was smooth and had no pores inside.
  • the total amount was set to 4, and this was transferred to a blood collection bottle, 40 mg of each particle was added, and the number of platelets over time was measured using an animal blood cell measuring device (Celltack ⁇ , manufactured by Nihon Kohden).
  • Celltack ⁇ manufactured by Nihon Kohden
  • collagen (mg Z 72 zo, poma tendon collagen, manufactured by Hormon Chemie) was added (the collagen concentration in the blood was reduced). 33.3 ⁇ g / m).
  • a blank test was performed using sodium citrate-containing blood.
  • the water-insolubilized porous particles made of the biocompatible substance of the present invention are biocompatible without containing a crosslinker, and have excellent elasticity such as passing through an injection needle or a catheter and fitting to the wall of a blood vessel.
  • embolic potential that is considered therapeutically effective, and because of its porous nature, it is expected to have a rapid re-penetrating ability after embolic treatment without concern about side effects such as necrosis of normal cells.
  • it can be used for transarterial embolization therapy such as hepatocellular carcinoma.
  • porous particles of the present invention can be used for the therapy, etc., for example, a biopsy hemostatic substance, various carriers for immobilizing or culturing cells, a wound protecting agent, disintegration of oral preparations, and the like.
  • an embolic material for treating emboli containing water-insolubilized porous particles of a biocompatible substance substantially free of a cross-linking agent, and a pharmaceutical substance and a pharmaceutical composition containing the particles is provided.

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Abstract

L'invention concerne des particules poreuses insolubles dans l'eau, qui ne contiennent pas d'agent de réticulation, sont biologiquement compatibles et poreuses, présentent un degré d'élasticité élevé, un excellent effet embolique pour traiter l'embole et un excellent effet d'agrégation plaquettaire, et sont donc utiles en tant que substance hémostatique. Du fait de leur porosité, ces particules permettent une recanalisation dans les vaisseaux sanguins après le traitement de l'embole. On produit ces particules en chauffant des particules poreuses constituées d'une substance biocompatible se présentant sous forme de gel ou de solide dans un système sensiblement exempt d'humidité de sorte qu'elles soient insolubles dans l'eau. Ces particules sont également utiles en tant qu'excipient de préparation médicinale.
PCT/JP1997/002478 1996-07-19 1997-07-17 Particules poreuses insolubles dans l'eau, constituees de substances biocompatibles et leur procede de production WO1998003203A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU34615/97A AU3461597A (en) 1996-07-19 1997-07-17 Water-insoluble porous particles of biocompatible substances and process for producing the same
JP50678698A JP3879018B2 (ja) 1996-07-19 1997-07-17 生体適合性物質の水不溶化多孔性粒子及びその製造法

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JP8/190878 1996-07-19
JP19087896 1996-07-19

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WO1998003203A1 true WO1998003203A1 (fr) 1998-01-29

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003013552A1 (fr) * 2001-08-04 2003-02-20 Sang-Mun Han Matières d'embolisation contenant de la chitine et du chitosane et méthode de préparation associée
JP2003508565A (ja) * 1999-08-27 2003-03-04 エルテーエス ローマン テラピー−ジステーメ アーゲー 急速に崩壊するキトサンを原料とするペレット
WO2003063922A1 (fr) * 2002-01-31 2003-08-07 Aesculap Ag & Co. Kg Agent hemostatique contenant de l'alcool polyvinylique et sa mise a disposition pour la medecine
WO2007004484A1 (fr) 2005-07-01 2007-01-11 The Nippon Synthetic Chemical Industry Co., Ltd. Particules de pva destinées à être utilisées lors de l'embolisation temporaire d'un vaisseau sanguin, procédé pour la production de celles-ci et agent d'embolisation temporaire pour un vaisseau sanguin
JP2008520563A (ja) * 2004-11-16 2008-06-19 バイオアバイラビリティ，インク． 栄養学的に使用するための高濃度自己マイクロエマルジョン化コエンザイムｑ１０調製物
EP1772483A4 (fr) * 2004-07-23 2008-12-24 San Ei Gen Ffi Inc Composition contenant un composant hydrogel dérivé de gomme arabique
JP2010162063A (ja) * 2009-01-13 2010-07-29 Japan Health Science Foundation 塞栓材
JP2010227050A (ja) * 2009-03-27 2010-10-14 Nitta Gelatin Inc 食品素材、その製造方法およびその用途
WO2010150715A1 (fr) 2009-06-26 2010-12-29 日本合成化学工業株式会社 Modèle animal non humain d'infarctus du myocarde et procédé pour le construire
JP2013064009A (ja) * 2012-12-07 2013-04-11 Bioavailability Inc 栄養学的に使用するための高濃度自己マイクロエマルジョン化コエンザイムｑ１０調製物
JP2013540723A (ja) * 2010-09-08 2013-11-07 上海市腫瘤研究所 腫瘍治療のための医薬品徐放血管塞栓ゲル化剤及びその調製方法
JP2024513861A (ja) * 2021-04-28 2024-03-27 ネクストバイオメディカル カンパニー リミテッド 分解時間調節が可能な塞栓用水和ゲル及びその製造方法

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JP5307490B2 (ja) 2008-09-25 2013-10-02 日東電工株式会社 ゼラチン粒子の製造方法
US20140079794A1 (en) * 2012-09-18 2014-03-20 Nitto Denko Corporation Gelatin particle and use thereof, and device for administration of physiologically active substance
CA2849472A1 (fr) 2013-04-22 2014-10-22 Nitto Denko Corporation Soutien de gelatine reticule et soutien pour liberation controlee d'une substance physiologiquement active utilisant celui-ci

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JPH04327528A (ja) * 1991-04-23 1992-11-17 Lion Corp 経口用固形製剤

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JPH0441437A (ja) * 1990-06-04 1992-02-12 Dainippon Pharmaceut Co Ltd 液体浮遊性中空材料
JPH04327528A (ja) * 1991-04-23 1992-11-17 Lion Corp 経口用固形製剤

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003508565A (ja) * 1999-08-27 2003-03-04 エルテーエス ローマン テラピー−ジステーメ アーゲー 急速に崩壊するキトサンを原料とするペレット
WO2003013552A1 (fr) * 2001-08-04 2003-02-20 Sang-Mun Han Matières d'embolisation contenant de la chitine et du chitosane et méthode de préparation associée
KR100478227B1 (ko) * 2001-08-04 2005-03-21 한상문 키틴 및/또는 키토산으로 구성되는 혈관 색전 물질의 제조방법
WO2003063922A1 (fr) * 2002-01-31 2003-08-07 Aesculap Ag & Co. Kg Agent hemostatique contenant de l'alcool polyvinylique et sa mise a disposition pour la medecine
EP1772483A4 (fr) * 2004-07-23 2008-12-24 San Ei Gen Ffi Inc Composition contenant un composant hydrogel dérivé de gomme arabique
JP2008520563A (ja) * 2004-11-16 2008-06-19 バイオアバイラビリティ，インク． 栄養学的に使用するための高濃度自己マイクロエマルジョン化コエンザイムｑ１０調製物
WO2007004484A1 (fr) 2005-07-01 2007-01-11 The Nippon Synthetic Chemical Industry Co., Ltd. Particules de pva destinées à être utilisées lors de l'embolisation temporaire d'un vaisseau sanguin, procédé pour la production de celles-ci et agent d'embolisation temporaire pour un vaisseau sanguin
US8361454B2 (en) 2005-07-01 2013-01-29 The Nippon Synthetic Chemical Industry Co., Ltd. PVA particle for temporary embolic material and production process thereof, and temporary embolic material
JP2010162063A (ja) * 2009-01-13 2010-07-29 Japan Health Science Foundation 塞栓材
JP2010227050A (ja) * 2009-03-27 2010-10-14 Nitta Gelatin Inc 食品素材、その製造方法およびその用途
WO2010150715A1 (fr) 2009-06-26 2010-12-29 日本合成化学工業株式会社 Modèle animal non humain d'infarctus du myocarde et procédé pour le construire
JP2013540723A (ja) * 2010-09-08 2013-11-07 上海市腫瘤研究所 腫瘍治療のための医薬品徐放血管塞栓ゲル化剤及びその調製方法
JP2013064009A (ja) * 2012-12-07 2013-04-11 Bioavailability Inc 栄養学的に使用するための高濃度自己マイクロエマルジョン化コエンザイムｑ１０調製物
JP2024513861A (ja) * 2021-04-28 2024-03-27 ネクストバイオメディカル カンパニー リミテッド 分解時間調節が可能な塞栓用水和ゲル及びその製造方法
JP7679491B2 (ja) 2021-04-28 2025-05-19 ネクストバイオメディカル カンパニー リミテッド 分解時間調節が可能な塞栓用水和ゲル及びその製造方法

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