JP2005103319A - Water-insoluble porous particles of biocompatible substances and process for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a process for producing embolic substances which contain no cross-linking agent, are biologically compatible, have high elasticity, excellent embolic capacity for treating embolization, and an excellent effect of fast recanalization after treatment for embolization, and can be mass-produced and controlled in particle sizes. <P>SOLUTION: The water insoluble porous particles are constituted so as to be useful as a hemostatic substance, to contain no linking agent, to be biocompatible, and to present excellent effect of aggregating platelets as an embolic substance with excellent embolic capacity. The particles are expected to have fast recanalization and are further useful as a carrier for medicinal formulation. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a water-insoluble porous particle of a biocompatible substance useful as an embolic material for embolism treatment or a carrier for pharmaceutical preparation, and a method for producing the same.

Currently, the main therapies for hepatocellular carcinoma include therapies such as hepatectomy, transarterial embolization, and ethanol injection therapy. Among them, transarterial embolization (hereinafter sometimes abbreviated as TAE) is a therapy widely applied to multiple cases, large liver cancer, recurrent cases after resection, and the like. The therapy is performed by injecting a lipiodol suspension of an anticancer drug into a cancer tissue using a microcatheter, and then embolizing a blood vessel leading to the cancer tissue with an embolic substance suspended using a nonionic contrast agent. It is. According to this therapy, the blood supply to the cancer tissue can be cut off, and the cancer tissue can be effectively necrotized by so-called “military attack”. In addition, since the therapy is a tissue selective treatment, side effects such as normal cell necrosis can be minimized. It is known that this therapy is also effective for renal cancer.

The following patent documents 1 to 3 are known as prior arts related to an embolic material used for TAE.

To summarize, Patent Document 1 describes: a. Polysaccharides or polysaccharide derivatives such as cross-linked partially hydrolyzed potato starch (specified composition / property / function: physiologically acceptable, water-insoluble, hydrophilic, swellable, composed of glucose units with three-dimensional network structure, shared By cross-linking by a crosslink having a sexual bond, and a particle having a substitution degree such that it is decomposed into a water-soluble fraction by α-amylase in plasma by a method known per se,
b. Sieving the particles and collecting a fraction having a particle size selected based on the vessel diameter;
c. Suspending the fraction in a physiologically acceptable aqueous solution, optionally with other physiologically acceptable substances,
d. Disclosed is a method for producing a drug for intravascular administration for embolism treatment, characterized in that the suspension is filled in a container and subjected to aseptic or sterilization treatment, and epichlorohydrin crosslinked partially hydrolyzed potato starch particles based on the invention are disclosed A biodegradable temporary embolic material using ED is marketed as degradable starch microsphere (trade name: manufactured by Pharmacia, hereinafter abbreviated as DSM).
The DSM has a blood flow blocking effect that lasts only a few tens of minutes, and not only cannot be expected to have the above-mentioned “troop attack” effect, but also uses a crosslinking agent for water insolubilization.
In addition, the use of self-clotting clots, muscle fragments, metals, activated carbon particles, gelatin sponges, silicon spheres, polyvinyl alcohol sponges, cyanoacrylates, poly (lactic acid glycolic acid) microspheres, etc. have been reported so far for embolic substances used in TAE. However, at present, gelatin sponge is most commonly used around the world.

Reference 2 describes gelatin gelatin and a water-soluble solution that crosslinks with gelatin as a method for producing gelatin spherical particles in order to improve the problem that gelatin sponge mechanically crushed particles are difficult to adhere to blood vessels. It is disclosed that an aqueous solution of a compound is dispersed in a dispersion solvent obtained by dissolving ethyl cellulose that is insoluble in water in a nonpolar organic solvent that is incompatible with water to cause a crosslinking reaction.
However, the product obtained by the production method described in the publication does not have porosity and does not have the elasticity required as an embolic material for embolization treatment, but is specifically disclosed. The spherical particles are cross-linked using a cross-linking agent such as glutaraldehyde.
Not only glutaraldehyde but many crosslinking agents lack biocompatibility, and it is reported in the literature that their persistence and toxicity are a concern (van Luyn MJ., Biomaterials, 13 (14), pp. .1017-1024 (1992): van Luyn MJ., J. Biomed., Mater. Res., 26 (8), pp. 1091-1110 (1992): Huang Lee LL., J. Biomed., Mater. Res ., 24 (9), pp.1185-1201 (1990)).

Patent Document 3 discloses a vascular embolization agent made of a crosslinked gelatin spherical particle having no porosity produced by the method described in Patent Document 2, and the recanalization of the embolic artery is compared with that of a human. As a result of kidney embolization experiments in dogs that are said to be early, arterial embolism has been confirmed even after 30 days.
It has been reported in literatures and the like that an embolic material for embolization treatment enables embolization that is therapeutically effective if recanalized after 2 weeks, and there is no concern about side effects such as necrosis of normal cells ( Morio Sato, Ryusaku Yamada, Journal of Japanese Society of Medical Radiology, 43 (8), p.977-1005 (1983)).

Japanese Patent Publication No. 61-25689 (corresponding patent: US Pat. No. 4,124,705) Japanese Patent Publication No.62-33263 JP 60-2222045 (corresponding patent: European Patent No. 132983)

Therefore, it does not contain a cross-linking agent, is biocompatible, has excellent elasticity such as passing through a needle or catheter and fitting to the blood vessel wall, therapeutically effective embolization, and side effects such as necrosis of normal cells. An embolizing substance having a rapid recanalization ability after embolization treatment in which there is no concern is not known so far, and the development thereof has been demanded.
In addition, it has been necessary to develop a method for producing an embolic material that can be aseptically mass-produced and the particle diameter can be controlled.

Under such circumstances, the present inventors examined a method for producing water-insoluble and porous particles without using a cross-linking agent. When no cross-linking agent was added, the emulsion was united when the emulsion was prepared. When heated to increase the strength of the particles, the porous particles cannot keep their shape and become agglomerates, and when the particles are removed from the poor solvent by gelation by cooling after emulsion preparation, water is present in the particles. Dissolved or agglomerated when heated in a state where the solvent used at the time of production was washed away, and the agitation alone was not enough to wash below the allowable amount, and the surface porosity of the gel particles could not be increased. The problems in producing porous particles have been clarified.

Furthermore, as a result of intensive research aimed at producing porous particles of a biocompatible material that is satisfactory as an embolic material for embolism treatment, the present inventors have found that the porous particles of a biocompatible material that has been gelled or solidified are substantially reduced. It was found that water-insolubilized porous particles having sufficient elasticity as an embolic substance and embolizing ability that is therapeutically effective can be prepared by heating in a water-free system. Furthermore, the water-insolubilized porous particles obtained in this way are not only excellent as an embolizing substance, but also various kinds of substances such as pharmaceutical substances such as bone growth factor (BMP) and various cell immobilization or culture carriers. The present invention has been completed by finding that it has excellent properties as a carrier.
That is, the present invention relates to a water-insolubilized porous particle of a gel-forming or solidifying biocompatible substance substantially free of a crosslinking agent. The present invention also relates to a water-insoluble porous particle of a biocompatible substance obtained by heating a gelled or solidified porous particle of a biocompatible substance in a system substantially free of water to insolubilize the water. .

In addition, according to the present invention, a method for producing porous particles of a biocompatible material that is insolubilized by heating gelled or solidified porous particles of a biocompatible material in a system substantially free of water, A gel-forming or solidifying biocompatible substance is foamed in a good solvent solution of the substance, dispersed in a poor solvent of the biocompatible substance that is immiscible with the good solvent, and cooled to gel or solidify. Thereafter, the obtained porous particles are washed with a solvent miscible with the poor solvent of the biocompatible substance and heated in a system substantially free of water, and water-insolubilized porous particles of the biocompatible substance and A method for its manufacture is provided.

Furthermore, according to the present invention, a gel-forming or solidifying biocompatible substance in a good solvent solution, a substance that can be dissolved in a biocompatible substance in a poor solvent, or a biocompatible substance in a good solvent, and Disperse the substance that migrates to the poor solvent of the substance, further disperse the dispersion in the poor solvent of the biocompatible substance, cool it to gel or solidify, and then biopsy the resulting porous particles Provided is a water-insoluble porous particle of a biocompatible material, which is washed with a solvent miscible with a poor solvent of the active material and heated in a system substantially free of water, and a method for producing the same.
Conventionally, a soft material such as foam has an unstable shape, and even if it can be made into a block shape, it is a size that can be used as an embolic material without using a crosslinking agent, and is water-insoluble and porous. Under circumstances where it was considered extremely difficult to obtain retained particles, the gelled or solidified biocompatible substance porous particles were heated in a system substantially free of water to make the particles insoluble. It was completely unexpected that the water-insolubilized porous particles of the invention were obtained.

The present invention is described in detail below.
In the present invention, “substantially free of a crosslinking agent” means that an embodiment in which a crosslinking agent is added within a range that does not impair the object of the present invention, particularly 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 can be insolubilized by heat treatment. Among them, those in which the gel strength is increased or solidified by cooling at the time of emulsion formation in the emulsification step described later are preferable. Further, the biocompatible substance is preferably one that foams when dissolved in a good solvent for the substance. Further, by dispersing a poor solvent of a biocompatible substance in a good solvent solution of the substance, without foaming or without foaming, the dispersion is further dispersed in the poor solvent of the substance. A mode in which pores can be formed inside, or a substance that can be dissolved in a poor solvent of a biocompatible substance or a substance that is insoluble in a good solvent of a biocompatible substance and is transferred to a poor solvent of a biocompatible substance A mode in which pores can be formed in the particles by dispersing the dispersion in a poor solvent of the substance after being dispersed in a good solvent solution of the active substance is also encompassed in the present invention. Examples of 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 moves to the poor solvent of the substance include, for example, soybean oil when the biocompatible substance is gelatin Oils, organic solvents such as chloroform, 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 an amino acid or a biological compound, a derivative thereof, or a physiologically acceptable salt thereof. Examples thereof include polypeptides, derivatives thereof, proteins, derivatives thereof, polysaccharides, derivatives thereof, physiologically acceptable salts thereof, mixtures containing them, and mixtures of them with polypeptides. Specifically, proteins or polypeptides such as gelatin, collagen, atelocollagen, albumin, fibrin, protamine, derivatives thereof, or physiologically acceptable salts thereof, dulan gum, gum arabic, hyaluronic acid, alginic acid, chondroitin sulfate , Polysaccharides such as heparin, chitin and chitosan, derivatives thereof, and physiologically acceptable salts thereof. Among these, gelatin, atelocollagen, albumin, hyaluronic acid, alginic acid, derivatives thereof, or physiologically acceptable salts thereof are preferable. These biocompatible substances may be used alone or in combination. Furthermore, gelatin is preferable.

The good solvent for the biocompatible substance is not particularly limited as long as it is pharmaceutically acceptable and can dissolve the substance. For example, water, dimethyl sulfoxide, benzyl alcohol and the like can be mentioned. Of these, water is preferred. The solvent may contain a pharmaceutically acceptable additive such as a buffer, an emulsifier, and an isotonic agent. Examples of the buffer include phosphates, carbonates, and organic acid salts. Examples of the emulsifier include polysorbate, polyethylene hydrogenated castor oil, and sorbitan sesquioleate. Examples of the isotonic agent include sodium chloride, glucose, lactose, and sucrose. These additives may be used alone or in combination of two or more. When the substance is dissolved, the solution may be heated to be dissolved. The concentration of the biocompatible substance dissolved in the good solvent varies depending on the type of the biocompatible substance, but is usually about 0.01 to 50% by weight, preferably about 0.1 to 30% by weight. More preferably, it is about 1 to 20% by weight.

  The poor solvent for the biocompatible substance is not particularly limited as long as it is pharmaceutically acceptable and does not dissolve the biocompatible substance, or is pharmaceutically acceptable and does not mix with the good solvent for the biocompatible substance. Not. For example, mineral oil (such as liquid paraffin), animal oil, vegetable oil (such as soybean oil, sesame oil, peanut oil, cottonseed oil, coconut oil, rapeseed oil, coconut oil, eucalyptus oil, corn oil, olive oil, castor oil), silicon oil , Fatty acids, fatty acid esters (for example, medium chain fatty acid triglycerides (for example, trade name: panacet, manufactured by NOF Corporation), ethyl oleate, etc.), organic solvents (for example, toluene, benzene, hexane, chloroform, dichloromethane, tetrachloride) Carbon, etc.). Among these, vegetable oils such as soybean oil, sesame oil, peanut oil, cottonseed oil, coconut oil, rapeseed oil, coconut oil, eucalyptus oil, corn oil, olive oil, and fatty acid esters such as medium chain fatty acid triglyceride and ethyl oleate are preferable. You may use the poor solvent of these biocompatible substances 1 type or in mixture of 2 or more types. Of these, 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 these, a honeycomb-shaped one is preferable. In addition, a drug or a compound may be contained or immobilized in the particles. Inclusion or immobilization of a drug or compound can be performed 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 later. In addition, generally pharmaceutically acceptable additives such as excipients, stabilizers, buffers, dispersants, and coating agents may be used together with the particles. Examples of the excipient include lactose, crystalline cellulose, dextran and the like. Examples of the stabilizer include lactose, trehalose, polyethylene glycol and the like. Examples of the buffer include phosphates, carbonates, and organic acid salts. Examples of the dispersant include carboxymethyl cellulose, glycerin, soybean oil and the like. Examples of the coating agent include acrylic acid polymers and polylactic acid glycolic acid copolymers. These additives may be used alone or in combination of two or more.

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 / ml, preferably 0.005 to 0.9 g / ml, and more preferably 0.005 to 0.2 g / ml. It is. The specific gravity can be calculated, for example, by taking a fixed volume (ml) with a graduated cylinder, measuring the weight (g) at that time, and dividing the weight by the volume.
The particle diameter of the water-insolubilized porous particles of the present invention is not particularly limited, but is usually 0.01 to 10 mm, preferably 0.1 to 7 mm. In addition, when used for TAE, the particle size is not particularly limited as long as the side effects are not a concern. However, the particle size can be usually applied to an injection needle or a catheter or to a blood vessel selected for embolization treatment. Preferably it is 0.5-10 mm, More preferably, it is 0.5-7 mm. In addition, the particle diameter as used in the field of this invention means an average particle diameter.

The water-insolubilized porous particles of the present invention have elasticity that can pass through an injection needle or a catheter, and elasticity that allows particles to freely deform and embolize blood vessels that are selected for embolization treatment. When used in TAE, for example, particles having a particle diameter of 0.5 to 1.5 mm are swollen in a solvent such as water and passed through a microcatheter (standard 3 French (outer diameter 1 mm)) or a corresponding channel. What is possible is preferred.
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 rate is determined by, for example, immersing particles of a constant volume (abbreviated as V ₁ ) in water, physiological saline, various electrolyte solutions, medical infusions, oils, contrast agents, or therapeutic pharmaceutical solutions, after 1 hour. The swelling volume (abbreviated as V ₂ ) is measured using a graduated cylinder or the like, and can be calculated by V ₂ / V ₁ .

Next, the manufacturing method of this invention is demonstrated (refer FIG. 1).
In the present invention, “substantially no water” means that the water is present within a range that does not impair the object of the present invention, in particular, within a range where particles are not dissolved or aggregated during heat treatment. Included in the invention. In particular, “substantially no water” means a state in which the particles are washed with a good solvent for the biocompatible substance and a solvent in which the poor solvent for the substance is miscible in the washing and dehydration process described below. Alternatively, it means a state in which the particles are dried by a drying means such as ventilation drying, vacuum drying or freeze drying.

Regarding the method for producing water-insolubilized porous particles comprising the biocompatible substance of the present invention, a good solvent (abbreviated as S) solution (abbreviated as S1) of a biocompatible substance (abbreviated as M) is stirred, for example. The foaming step for foaming, the foam obtained in this step is put into a poor solvent of M (abbreviated as S2), and for example, the emulsification step for stirring to form an emulsion, the emulsion obtained in this step is, for example, Gelling step of cooling to below the gelation temperature of M to gel (or solidify) to form gel particles, for example, sieving the gel particles obtained in this step and removing S2 by removing from S2. In the step of removing the poor solvent (S2), the gel particles obtained in the step are washed with a solvent (S3) miscible with S2, for example, and dried (dehydrated) to form porous particles. The resulting porous particles are substantially The heat treatment step of heat treatment in the absence system of water and water-insoluble porous particles, and the step of washing with water if necessary lyophilization. In addition, about each said process, although it divides for convenience, in order to demonstrate this invention in detail, since one part process can also serve as another process, this invention is not restrained by these processes. .

Hereinafter, each process will be described in detail.
The foaming step is not particularly limited as long as it is a method of foaming a good solvent (S) solution (S1) of the biocompatible substance (M). Examples of the method include foaming using a stirrer such as a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.), a paddle stirring motor (MAZELA Z, manufactured by EEYLA), a magnetic stirrer (manufactured by Yamato Kagaku Co., Ltd.), oxygen, and the like. , Carbon dioxide, nitrogen, air and the like, and a method of foaming. When foaming using a stirrer, conditions such as the rotational speed of the machine and the size of the container may be any conditions as long as air can be embraced. Moreover, when foaming by sending in gas, any conditions may be used as long as S1 can be foamed. For example, a method of sending nitrogen gas through a porous glass filter in S1 can be mentioned. When preparing S1, if M is difficult to dissolve, M may be dissolved by heating S1.

The emulsification step is not particularly limited as long as it is a method capable of forming the emulsion by adding the foam obtained in the above step to M poor solvent (S2). Examples of the method include emulsion using a stirrer such as a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.), a stirring motor with a paddle (MAZELA Z, manufactured by EYELA), a magnetic stirrer (MAG MIXER, manufactured by Yamato Kagaku Co., Ltd.). And the like. At this time, the ratio (foam / S2) of adding the foam obtained in the above step to the poor solvent (S2) of M is not particularly limited as long as it is a ratio capable of forming an emulsion, but is usually 1.0 or less, preferably Is 0.8 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 is not performed. In addition, even if it does not foam or does not foam, after dispersing the poor solvent of the biocompatible substance in the good solvent solution of the substance, the dispersion is further dispersed in the poor solvent of the substance, whereby the particles Or a substance that is soluble in a poor solvent of the biocompatible substance or a substance that is insoluble in the good solvent of the biocompatible substance and moves to the poor solvent of the substance. In the case where pores can be formed inside the particles by further dispersing the dispersion in a poor solvent of the substance after being dispersed in a good solvent solution, the foaming step is omitted. For example, S1 and S2 Is dispersed (S2 / S1), and when the dispersion is further dispersed in S2 to form an S2 / S1 / S2 emulsion, this step can also serve as the foaming step. In this case, the ratio of S2 / S1 is not particularly limited as long as an emulsion is formed, but is usually 1.0 or less, preferably 0.8 or less. Further, the ratio of (S2 / S1) / S2 is not particularly limited as described above, but 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 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 by washing with a poor solvent of the substance. When the emulsion is gelled (or solidified), easy-to-handle particles can be obtained. The gelation temperature of the biocompatible substance can be appropriately selected according to the composition of the normal biocompatible substance, the concentration of the good solvent solution of the substance, or the holding time (time for maintaining a certain temperature). For example, when a 4% gelatin aqueous solution is rapidly cooled, it can be gelled at about 18 ° C. However, when gelled particles are washed with alcohols in the washing step described below, an exothermic reaction occurs, so preferable. In the case of a biocompatible substance other than gelatin, it can be solidified by washing with a poor solvent for the substance.

About the removal process of the poor solvent (it abbreviates as S2) of a biocompatible substance, if it is the method of removing S2 by taking out the particle | grains obtained at the said process from S2, it will not restrict | limit in particular. Examples of the method include sieving, filtration, and centrifugation. In this step, it is preferable to cool the system below the gelation temperature of the biocompatible substance in order to stably maintain the shape of the particles. In this step, 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 (S3) in which S and S2 are miscible. In this step, for example, the particles are taken out on the mesh and washed in S3, or the particles are put in a beaker and washed with stirring under reduced pressure in S3, and returned to normal pressure, or the particles and S3 are put in a beaker. Wash by sonication. You may repeat the process of this pressure reduction, a normal pressure, and an ultrasonic wave. By this step, holes are further generated on the surface and inside, and S2 remaining inside is efficiently cleaned. S3 is not particularly limited as long as it is pharmaceutically acceptable and miscible with S and S2, and is a poor solvent for M. Examples of S3 include alcohols (for example, methanol, ethanol, isopropanol, etc.), acetone, dioxane, hexane, halogen-based organic solvents, and the like. Of these, alcohols such as methanol, ethanol and isopropanol are preferred. These may be used alone or in combination of two or more. In this step, it is preferable to cool the system below the gelation temperature of the biocompatible substance in order to stably maintain the shape of the particles. In this step, an aggregation inhibitor may be added. Examples of the aggregation inhibitor include lactose, D-sorbitol, crystalline cellulose and the like. Furthermore, steps such as ventilation drying, vacuum drying, and freeze drying can be performed before and after the step.

The heat treatment step is not particularly limited as long as it is treated in a system substantially free of water at a temperature and time conditions at which the particles obtained in the step are insoluble in water. In addition, the process may be performed under any conditions as long as the biocompatible substance has a temperature and time for causing intermolecular crosslinking. The time condition in the method is determined depending on the temperature condition, and examples include a temperature of 110 ° C. to 220 ° C. for 10 minutes to 120 hours. Preferably they are 135 degreeC-200 degreeC, and are 10 minutes or more and 120 hours or less, More preferably, they are 145 degreeC-190 degreeC for 1 hour or more and 6 hours or less. Moreover, you may perform this process under pressure reduction. The said process can serve as a sterilization process. Further, after the step, if necessary, the particles may be washed with water to remove water-soluble components.

The sterilization treatment may be performed by the high-pressure steam method (Japanese Pharmacopoeia) or the like after the particles of the present invention are filled and sealed in a medical packaging container (for example, vial, ampoule, prefilled syringe, etc.).
The particles of the present invention can be further subjected to a dehydration step by a method known per se after filling into a medical packaging container (for example, vial, ampoule, prefilled syringe, etc.). As this process, drying methods, such as ventilation drying, vacuum drying, and freeze-drying, are mentioned, for example.
When the porous particles of the present invention are used as an embolic material for embolization treatment, the dose can be adjusted as appropriate depending on the thickness of the blood vessel 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 physiologically acceptable liquids (physiological saline, iodized poppy oil fatty acid ethyl ester, etc.) and the like.

The porous particles of the present invention are used as an embolic material for TAE and the like, and are also used as a hemostatic material in medical practice such as biopsy. In this case, the particles may be used alone or in combination with a physiologically acceptable liquid (such as physiological saline) as a pharmaceutical composition. Moreover, it is 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). Furthermore, it is also used as a wound protective agent, a disintegrant for oral preparations, a drug adsorbent (for example, bitterness preventive agent), a carrier for sustained-release preparations, a material for preventing damage during transportation.
The porous particles of the present invention can also be used by containing or mixing 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 an X-ray contrast agent and a radioisotope as a contrast agent. Examples of the X-ray contrast agent include amidotrizoic acid, iotalamic acid, iodamide, metrizoic acid as a triiodo compound, or physiologically acceptable salts thereof, and adipiodone, oxaglic acid, iotroxic acid, iodoxamic acid as a triiododimer compound. , Iocarmic acid, or physiologically acceptable salts thereof, iotrolane, iopamidol, iohexol, iohersol, iomeprol, metrizamide as nonionic compounds, iodinated poppy oil fatty acid ethyl ester as iodinated oil (trade name: Lipiodol Ultrafluid ) And the like.
The diagnostic agent may be a radioactive substance, for example. The material may be in solution or particulate form. The fine particles are generally the same size or smaller than the particles of the present invention. Contains radioactive isotopes such as indium, thallium, iodine, technetium, gallium, cerium, rubidium, chromic acid, iron, tin, xenon, carbon, oxygen, nitrogen, fluorine or their physiologically acceptable salts It may be a substance. These may use one or two 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 drug include an antitumor drug or a similar radioactive substance. Examples of the antitumor agents include mitomycin C, actinomycin D, bleomycin-based drugs (such as bleomycin hydrochloride), anthracycline-based antibiotics (such as aclarubicin hydrochloride, epirubicin hydrochloride, doxorubicin hydrochloride), and neocartino as antitumor antibiotics. Statin, dinostatin styramer (SMANCS), etc., methotrexate, tegafur, fluorouracil, etc. as antimetabolites, cyclophosphamide as alkylating agents, nimustine hydrochloride, ranimustine, etc., irinotecan hydrochloride, vinblastine sulfate as antitumor plant component drugs, Other tumor drugs such as etoposide include carboplatin, 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 (for example, α, β, γ), interleukin (for example, IL-1 to IL-18), tumor necrosis factor (TNF), and the like. Examples of the hematopoietic factor include erythropoietin (EPO), granulocyte colony stimulating factor (G-CSF), macrophage colony stimulating factor (M-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), thrombopoietin (TPO), Examples include platelet growth factor and stem cell growth factor (SCF). Various growth factors include, for example, basic or acidic fibroblast growth factor (FGF) or a family thereof, nerve cell growth factor (NGF) or a family thereof, insulin-like growth factor (IGF), osteogenic factor (for example, BMP1 to BMP12) or a transforming growth factor (TGF-β) superfamily, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and the like. Examples of various hormones include insulin, calcitonin, glucagon, human growth factor (hGH), parathyroid hormone (PTH) and the like. Examples of the enzyme include L-asparaginase, superoxide dismutase (SOD), tissue plasminogen activator (t-PA), and the like. These biological agents may be naturally occurring sequence structures or modified versions thereof. Moreover, those modifications (for example, the chemical modification by polyethyleneglycol etc.) may be sufficient. These may be used as monomers or as homo or hetero multimers.

The therapeutic agent may be a substance involved in the expression of proteins and peptides (for example, nucleic acids such as DNA and RNA, or low and high molecular transcription regulators and inhibitors thereof).
Furthermore, as therapeutic agents, for example, substances that act on blood vessels (vasodilators, vasoconstrictors, etc.), substances that act on coagulation, substances that act on the formation or dissolution of thrombus, antibacterial substances, anti-inflammatory substances An anesthetic, a substance exhibiting a hormonal effect, a bone resorption inhibitor (for example, bisphosphonates), various vitamins, an antiparasitic substance and the like.
Two or more of these therapeutic agents or diagnostic agents may be used in combination. Further, they may be diluted with a physiologically acceptable liquid (such as physiological saline).

The water-insolubilized porous particles made of the biocompatible substance of the present invention do not contain a cross-linking agent, are biocompatible, have excellent elasticity such as passing through an injection needle or catheter and fitting to the blood vessel wall surface. It is expected to have rapid recanalization after embolization treatment because it has effective embolic ability and is porous and does not cause side effects such as necrosis of normal cells. It can be used for transarterial embolization therapy.
The porous particles of the present invention can be used for the therapy, for example, biopsy hemostatic substances, various cell immobilization or culture carriers, wound protection agents, disintegrators for oral preparations, drug adsorbents (bitter taste). (Inhibitors), carriers for sustained-release preparations, and materials for preventing damage during transportation.
Furthermore, according to the present invention, there is provided an embolic material for embolism treatment or a pharmaceutical substance containing water-insolubilized porous particles of a biocompatible substance substantially free of a crosslinking agent, and a pharmaceutical composition containing the particles. .
Furthermore, according to the present invention, there is provided a method for producing porous particles that can be mass-produced, control the particle diameter, and have the above characteristics.

  Below, based on a comparative example, an Example, and a test example, although this invention is demonstrated in detail, this invention is not limited by these Examples.

Comparative Example 1
20 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. 200 ml of this solution is put into 1 liter of Panacet 800 (manufactured by NOF Corporation) and stirred at 200 rpm using a stirrer (MAZELA Z, manufactured by Tokyo Rika Kikai Co., Ltd.) equipped with a Teflon (registered trademark) paddle to form an emulsion. It was. This emulsion was cooled and gelled to obtain gel particles. Under cooling, the gel particles were taken out using a mesh (250 μm) and washed with isopropyl alcohol (IPA). Next, IPA was removed using a glass filter, and particles were taken out. This was vacuum dried and then heated at 155 ° C. for 4 hours to obtain particles. The obtained particles had no pores on the surface, and the inside was not porous (honeycomb-like).

Comparative Example 2
20 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam is put into 1 liter of Panacet 800 (manufactured by NOF Corporation) and stirred at 200 rpm using a stirrer (MAZELA Z, manufactured by Tokyo Rika Kikai Co., Ltd.) equipped with a Teflon (registered trademark) paddle to form an emulsion. It was. When this emulsion was taken out using a mesh at room temperature without gelling, the emulsion was united and could not be taken out as particles.

20 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam is put into 1 liter of Panacet 800 (manufactured by NOF Corporation) and stirred at 200 rpm using a stirrer (MAZELA Z, manufactured by Tokyo Rika Kikai Co., Ltd.) equipped with a Teflon (registered trademark) paddle to form an emulsion. It was. This emulsion was cooled and gelled to obtain gel particles. Under cooling, the gel particles were taken out using a mesh (250 μm) and washed with isopropyl alcohol (IPA). After washing, IPA was removed using a glass filter, and gel particles were taken out. This was vacuum-dried and then heated at 155 ° C. for 4 hours to obtain particles of the present invention. The obtained particles had pores on the surface, and the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

Test example 1
For the porous particles prepared in Example 1, 1 ml of each particle before and after heat treatment was added to a 10 ml Spitz tube to add water to 10 ml, and the residual gel volume after shaking for a certain period of time was measured with a shaker. The structure maintenance ability was compared.
As a result, the heat-treated particles immediately swelled and maintained their structure, whereas the particles not subjected to the heat treatment were unable to maintain the structure because the gel dissolved over time. Therefore, it was suggested that the particles of the present invention are water-insoluble and have an appropriate strength considered to be applicable to embolization therapy.

Test example 2
1 g of the uncrosslinked porous particles obtained in the intermediate step of Example 1 was dispersed in 300 ml of cold water, and a 10% glutaraldehyde aqueous solution was added dropwise so as to be 1% and reacted for 30 minutes. After washing with water to remove uncrosslinked glutaraldehyde, it was autoclaved at 121 ° C. for 20 minutes, and freeze-dried to obtain a comparative sample.
Cell proliferation experiments were performed on the sample obtained in Example 1 and the comparative sample.
200 μl of 5 × 10 ⁴ cells / ml W20 cells (mouse bone marrow stromal cells) per well were added to a microplate and cultured overnight in a CO ₂ incubator. Thereafter, bone morphogenetic factor (BMP-2) was added at 41.8 U / well. The medium was exchanged with ml and cultured for another 24 hours. A constant volume of about 10 μl was added to the sample and the comparative sample when BMP-2 was added. The number of proliferated cells was evaluated by a color reaction using intracellular alkaline phosphatase activity after freeze-thawing of the cells.
As a result, a tendency to suppress cell growth was observed for porous particles produced using glutaraldehyde as a crosslinking agent. On the other hand, the cell growth promotion tendency was recognized about this invention porous particle. Therefore, it was suggested that the particles of the present invention are superior in cell growth and safety to particles cross-linked with glutaraldehyde.

20 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of soybean oil (manufactured by Kanto Chemical Co., Inc.), and the same operation as in Example 1 was followed to obtain particles of the present invention. The obtained particles had pores on the surface, and the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  50 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of soybean oil (manufactured by Kanto Chemical Co., Inc.), and the same operation as in Example 1 was followed to obtain particles of the present invention. The obtained particles had pores on the surface, and the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  50 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of sesame oil (manufactured by Kanto Chemical Co., Inc.), and the same operation as in Example 1 was followed to obtain particles of the present invention. The obtained particles had pores on the surface, and the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  20 g of bovine serum albumin (BSA, manufactured by Sigma) was put into 100 ml 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.) (10000 rpm, 10 minutes) to cause foaming. 200 ml of this foam was put into 1 liter of Panacet 800 (manufactured by NOF Corporation), and 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  20 g of alginic acid (manufactured by Sigma) was placed in 100 ml 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.) (10000 rpm, 10 minutes) to cause foaming. 200 ml of this foam was put into 1 liter of Panacet 800 (manufactured by NOF Corporation), and 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  50 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of Panacet 800 (manufactured by Nippon Oil & Fats Co., Ltd.) containing 1% of Leodor AO-15 (manufactured by Kao Corporation), and 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  50 g of hydrolyzed gelatin (trade name; Nippi High Grade Gelatin, manufactured by Nippi) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of Panacet 800 (manufactured by NOF Corporation), and stirred at 400 rpm using a stirrer (MAZELA Z, manufactured by EYELA) equipped with a Teflon (registered trademark) 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  20 g of acid-treated gelatin (G-0785P, Nitta Gelatin Co., Ltd.) was placed in 500 ml of purified water and dissolved by heating. This solution was returned to room temperature and stirred with a homogenizer (manufactured by Tokushu Kika Kogyo Co., Ltd.) (10000 rpm, 10 minutes) to cause foaming. 400 ml of this foam was put into 1 liter of Panacet 800 (manufactured by NOF Corporation), and 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  4 g of gelatin (CP-2, manufactured by Miyagi Chemical Co., Ltd.) was placed in 100 ml of purified water and dissolved by heating. This solution was returned to room temperature, 20 ml of panacet was added, and the mixture was stirred with a homogenizer to form an emulsion. This emulsion was put into 400 ml of Panacet 800 (manufactured by NOF Corporation), and 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  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 inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  In the same manner as in Example 1, the obtained gel particles were vacuum-dried 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  In the same manner as in Example 1, the obtained gel particles were vacuum dried 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  In the same manner as in Example 1, the obtained gel particles were vacuum-dried 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

In the same manner as in Example 1, the obtained gel particles were freeze-dried 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 the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

  105 g of gelatin (GGG, manufactured by Nitta Gelatin Co., Ltd.) was placed in purified water to make 3 l, and heated to dissolve. This solution was returned to room temperature and stirred with a stirrer (manufactured by EYELA) (1200 rpm, 20 minutes) to cause foaming. 6 l of this foam was put into 8 l of Panacet 800 (manufactured by NOF Corporation) and stirred at 170 rpm using a stirrer (MAZELA Z, manufactured by EYELA) equipped with a Teflon (registered trademark) paddle to form an emulsion. This emulsion was cooled and gelled to obtain gel particles. Under cooling, the gel particles were taken out using a mesh (300 μm) and washed with cooled isopropyl alcohol (IPA). After washing, IPA was removed using a mesh, and gel particles were taken out. The gel particles and IPA were put into a beaker, the pressure was reduced using a water pump, and the gel particles were washed while stirring with a magnetic stirrer. Furthermore, the pressure was returned to normal pressure, the 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 then heated at 155 ° C. for 4 hours to obtain the particles of the present invention. Next, the particles were further washed with water and freeze-dried to obtain particles. The obtained particles had pores on the surface, and the inside was porous (honeycomb-like). When dispersed in water, the particles swelled while maintaining the shape of spherical particles.

Comparative Example 3
In a dispersion medium consisting of 150 g of cyclohexane and 50 g of toluene, 6 g of ethyl cellulose (49% containing ethoxy group) was dissolved, and this solution was put into a 500 ml separable flask equipped with a condenser and a Teflon (registered trademark) paddle. The stirring speed was 400 rpm and the temperature was 70 ° C. 40 g of an aqueous solution obtained by adding gelatin to water at a concentration of 30% by weight and dissolving at 60 ° C. was added thereto, and 4 g of a 50% glutaraldehyde aqueous solution (4 equivalents of glutaraldehyde per 1 equivalent of amino groups of gelatin) was added. After 5 minutes of reaction, brown particles were obtained. This was washed with ethyl acetate, further washed with acetone, sieved to collect particles of 0.5 to 1.0 mm, and dried by a vacuum dryer to obtain particles. When the particles were observed with an electron microscope, the surface was smooth and there were no pores inside.

Comparative Example 4
The same operation as in Comparative Example 3 was performed. However, the addition amount of glutaraldehyde was 0.15 g (0.15 equivalent of glutaraldehyde with respect to 1 equivalent of amino group of gelatin).

Comparative Example 5
The same operation as in Comparative Example 3 was performed. The cross-linking agent was changed from glutaraldehyde to polyglycerol polyglycidyl ether (trade name Denacol EX512, manufactured by Nagase Kasei Co., Ltd.), and 5 g (4 equivalents of epoxy group to 1 equivalent of amino group of gelatin) was added and the reaction time was 70. Particles were obtained by the same operation at 5 ° C. for 5 hours.

Comparative Example 6
The same operation as in Comparative Example 3 was performed. However, the gelatin concentration was 5% by weight.

Test example 3
The particles of the present invention produced by sieving out particles of 0.5-1.0 mm from the heat-treated particles (155 ° C., 4 hours) produced in Example 16 and dispersing them in water. About the particle | grains manufactured by Comparative Examples 3-6, the platelet aggregation effect | action of each particle | grain was measured. In the test, 0.4 ml of a sodium citrate test solution (trade name: Chitrate, manufactured by Midori Cross) was added to a 5 ml syringe (made by Terumo), and blood collected from two beagle dogs (A and B) was added to make a total volume of 4 ml. This was transferred to a blood collection bottle, 40 mg of each particle was added, and this was carried out by measuring the number of platelets over time using an animal blood cell measurement device (Celltac α, manufactured by Nihon Kohden Co., Ltd.). In order to confirm the blood coagulation action, 0.1378 ml of collagen (1 mg / ml, equine tendon collagen, manufactured by Hormon-Chemie) was added (the collagen concentration in the blood was 33.3 μg / ml). Moreover, in order to evaluate the validity of the blood used for the test, a blank test was performed using sodium citrate-containing blood.
The results of using two bloods of beagle dog A and beagle dog B are shown in FIGS. 4 and 5, respectively. About the particle | grains manufactured by Comparative Examples 3-6, the relative ratio of the number of platelets (residual rate of the number of blood platelets) which made the initial value 100 was hardly changed like the blank. In contrast, for the particles of the present invention, a significant decrease in the relative ratio of platelet count based on platelet aggregation was observed. Therefore, platelet aggregation occurs around the embolic material, so that a stronger embolization can be expected in embolization therapy. In addition, a decrease in the number of platelets based on platelet aggregation was observed 5 minutes after the addition of collagen, and the validity of the blood used for the measurement was confirmed.

The manufacturing method which manufactures the water insolubilization porous particle of this invention is shown. A detailed description is given in the disclosure section of the invention.

When the water-insolubilized porous particles of the present invention are used in a transarterial embolization treatment method, the mechanism of action of embolization treatment (from administration to recanalization) is shown. The mechanism is as follows: (i) particles selectively administered to a target blood vessel by a catheter physically embolize the blood vessel; (ii) platelet aggregation occurs due to platelet adhesion and / or contact with the particles. Induced, clots are formed (embolization becomes stronger), (iii) The embolization necroses a malignant tumor whose nutrition has been cut off (when used in combination with an anticancer agent, the anticancer agent at the tumor site) It is considered that the concentration is increased and further therapeutic effect is expected), (iv) particles are degraded by enzymes in the body and blood vessels are recanalized, and (v) necrotic parts 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 mechanism (i), since the particles of the present invention are porous, the surface area of the particles is large and the elasticity of the particles is excellent. By being able to do so, it is possible to form a state in which the particles are more closely packed at the embolization site. In addition, since the particles of the present invention can be deformed even in a microcatheter used for TAE and the like, it is possible to administer particles having a larger particle diameter than non-porous particles, and a good embolization effect can be obtained. Be expected. In general, when a microcatheter is used, a considerable force is required. However, when the particles of the present invention are used, it is expected that the physical burden on the practitioner is reduced for the reason described above. (2) It is generally said that platelet aggregation is induced when platelets come into contact with, for example, collagen. Regarding the mechanism (ii), for example, a case where gelatin obtained by degrading collagen is used as a base of an embolic substance is considered. The specific surface area of the particles of the present invention is large because it is porous, and platelet aggregation tends to occur because the contact surface area with platelets is large. In addition, since the particles of the present invention are porous, platelets can enter between the particles, so that the platelet aggregation effect is further enhanced, and the embolization ability is also enhanced accordingly. Furthermore, it can be expected that turbulent flow is easily generated in the blood vessel due to the unevenness of the particles, and platelet aggregation is likely to occur due to the shear deformation pressure applied to the platelets. (3) Regarding the mechanism (iv), it is considered that the rate of disappearance is high because the particles of the present invention are decomposed from the inside of the particles due to the porous nature in the degradation by the enzyme in the living body.

It 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 is considered to be inferior in embolizability and recanalization ability based on the administrable particle diameter and platelet aggregation action as compared with the porous particles of the present invention.

The platelet aggregation test result is shown about this invention particle prepared from Example 16, and the nonporous particle | grains obtained from Comparative Examples 3-6. (Beagle dog A blood)

The platelet aggregation test results are shown as in FIG. (Beegle dog B blood)

Claims (16)

A gel-forming or solidifying biocompatible substance substantially free of cross-linking agent (from one or more selected from the group consisting of gelatin and their derivatives, and physiologically acceptable salts thereof) Water-insolubilized porous particles comprising a biocompatible substance. 2. The biocompatible substance is one or more selected from the group consisting of a polypeptide, a derivative thereof, a protein, a derivative thereof, a polysaccharide, a derivative thereof, and a physiologically acceptable salt thereof. The described particles. Biocompatible substances are from collagen, atelocollagen, albumin, fibrin, protamine, duran gum, gum arabic, hyaluronic acid, alginic acid, chondroitin sulfate, heparin, chitin, chitosan and their derivatives, and physiologically acceptable salts thereof. The particle according to claim 2, which is one type or two or more types selected from the group consisting of: The particle according to claim 3, wherein the biocompatible substance is one or more selected from the group consisting of atelocollagen, albumin, hyaluronic acid, alginic acid and derivatives thereof, and physiologically acceptable salts thereof. . The particle according to any one of claims 1 to 4, which has a particle diameter of 0.01 to 10 mm. The particle according to any one of claims 1 to 5, having a specific gravity of 0.001 g / ml to 1 g / ml. A pharmaceutical composition comprising water-insolubilized porous particles of a biocompatible substance substantially free of a crosslinking agent according to any one of claims 1 to 6. The pharmaceutical composition according to claim 7, which is used as an embolic material for embolism treatment. The pharmaceutical composition according to claim 7, which is used as a hemostatic substance. The porosity of gelled or solidified biocompatible materials (excluding one or more biocompatible materials selected from the group consisting of gelatin and derivatives thereof and physiologically acceptable salts thereof) Water-insolubilized porous particles of a biocompatible material obtained by heating water-soluble particles in a system substantially free of water to insolubilize them. A gel-forming or solidifying biocompatible substance is foamed in a good solvent solution of the substance, dispersed in a poor solvent of the biocompatible substance that is immiscible with the good solvent, and cooled to gel or solidify. 11. The particle according to claim 10, wherein the obtained porous particle is washed with a solvent miscible with a poor biocompatible substance and heated in a system substantially free of water to insolubilize the particle. The porosity of gelled or solidified biocompatible materials (excluding one or more biocompatible materials selected from the group consisting of gelatin and derivatives thereof and physiologically acceptable salts thereof) A method for producing water-insoluble porous particles of a biocompatible material, wherein the water-insoluble particles are heated by a system substantially free of water to insolubilize the particles. A gel-forming or solidifying biocompatible substance is foamed in a good solvent solution of the substance, dispersed in a poor solvent of the biocompatible substance that is immiscible with the good solvent, and cooled to gel or solidify. The method for producing particles according to claim 12, wherein the obtained porous particles are washed with a solvent miscible with a poor solvent of the biocompatible substance and heated in a system substantially free of water to insolubilize the particles. . A poor solvent of the substance is dispersed in a good solvent solution of the gel-forming or solidifying biocompatible substance, the dispersion is further dispersed in the poor solvent of the biocompatible substance, and this is cooled to be gelated or 13. The method for producing particles according to claim 12, wherein after the solidification, the obtained porous particles are washed with a solvent miscible with a poor solvent of the biocompatible substance and heated in a system substantially free of water to be insoluble in water. Law. Disperse in a good solvent solution of a biocompatible substance a substance that is soluble in a poor solvent of a gel-forming or solidifying biocompatible substance or that is insoluble in a good solvent of the biocompatible substance and moves to the poor solvent of the biocompatible substance The dispersion is further dispersed in a poor biocompatible substance solvent, and after cooling and gelling or solidifying, the obtained porous particles are mixed with a poor biocompatible substance solvent. The method for producing particles according to claim 12, wherein the particles are washed and heated in a system substantially free of water to be insolubilized. The method for producing particles according to any one of claims 12 to 15, wherein the water-insolubilized porous particles obtained by the production method of claims 12 to 15 are further dispersed in water and then freeze-dried.

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