JP5027591B2 - Crosslinked polymer particles and process for producing the same - Google Patents

Description

  The present invention is useful as an adsorbent / treatment material for treating a liquid containing physiological substances and / or cells, and is particularly useful as an adsorbent / treatment material for treating a pathogenic substance in blood. The present invention relates to a crosslinked polymer particle having a lower ratio on the particle surface than the ratio of a polymerized unit containing nitrogen to the total weight of the particle, and a method for producing the same.

  In recent years, extracorporeal circulation therapy has been widely used as a treatment method for various intractable diseases that cannot be sufficiently improved by administration of drugs. As a method for this, blood purification adsorption therapy that actively removes pathogenic substances present in the blood of patients has been actively attempted, and its effect has been recognized for many intractable diseases. There are two types of blood purification adsorption therapy: plasma perfusion and direct blood perfusion. The plasma perfusion type blood purification adsorption therapy is a two-stage system of plasma separation means and blood purification means, requiring a dedicated device for safe operation, increasing the treatment cost, and requiring complicated operation. On the other hand, the blood purification adsorption therapy of the direct blood perfusion method is easy to operate because it is a one-stage system that directly perfuses blood to the adsorber, and it is possible to reduce the burden on the patient with a small amount of circulating fluid. However, since blood and adsorbent are in direct contact, it is essential that blood components such as platelets do not adhere.

Typical examples of products currently on the market for direct blood perfusion adsorbers include: (See Non-Patent Document 1)
One of them is an adsorber for removing β2 microglobulin (molecular weight: about 12000) from Kaneka Corporation. The use is applied to amyloidosis accompanied by joint pain, and is used in hemodialysis. The adsorbent used in this adsorber (see Non-Patent Document 2) is obtained by immobilizing a ligand having affinity for a causative substance on porous cellulose beads having a particle size of about 500 μm with good blood compatibility. However, in order to produce this adsorbent, a process for immobilizing the ligand on the carrier is required, and the production process becomes complicated.

  The other is Kuraray Medical Co., Ltd.'s adsorbable blood purifier for renal assistance. The use is used to remove uremic toxin-causing substances (molecular weight: about 100 to 2000) as renal aids. The adsorbent used in this adsorber (see Non-Patent Document 2) has a particle size of 400 to 900 μm, and is used as an adsorbent for blood perfusion directly, so that it is a poly HEMA with good blood compatibility on the activated carbon surface. Coating is applied. Since the pathogenic substance is adsorbed on the activated carbon, a step of immobilizing the ligand is not necessary. However, since the activated carbon coating is required to produce this adsorbent, the production process becomes complicated.

  From the above, in order to achieve both the ability of adsorbing the causative agent and blood compatibility, the above-mentioned commercial product is manufactured by a complicated process for direct blood perfusion. Since these complicated processes are required, the manufacturing cost of the product is also increased. Thus, an adsorbent for direct blood perfusion that can be easily obtained without the need for a facility for immobilizing a ligand or a facility for coating is desired.

In addition, as a direct blood perfusion adsorbent, patents (see Patent Documents 1 to 4) for balancing both the ability to adsorb pathogens and blood compatibility have also been disclosed, but graft polymerization, coating and Complicated processes and equipment such as injection molding are required.
Japan Medical Equipment Manufacturers Association, Specified Insurance Medical Materials Guidebook, p175-, 2003 Artificial organ, Vol. 23, no. 2, p439-, 1994 Special table 2001-525200 Special table 2002-541928 Special table 2003-506111 JP 2004-121857 A

  The object of the present invention is useful as an adsorbent / treatment material for treating liquids containing physiological substances and / or cells, etc., and particularly as an adsorbent for direct blood perfusion, it has both the ability to adsorb pathogens and blood compatibility. An object of the present invention is to provide a crosslinked polymer particle having a ratio of the polymerized unit containing nitrogen to the total polymerized unit, which is lower than that of the total weight of the particle, and a method for producing the same.

  As a result of intensive studies to solve the problems of the conventional adsorbents described above, the present inventors surprisingly, by using the crosslinked polymer particles of the present invention, surprisingly, with a simple manufacturing method, It has been found that an adsorbent having both the ability to absorb pathogenic substances and blood compatibility can be achieved as an adsorbent for direct blood perfusion.

  That is, the present invention is a crosslinked polymer particle containing vinyl alcohol units and polymerized units containing nitrogen as constituent elements, and the surface nitrogen concentration specified by X-ray photoelectron spectroscopy analysis on the particle surface is 3.0 to 9. The present invention relates to crosslinked polymer particles having a nitrogen content of 10.0 to 18.0% by weight with respect to the total weight of the particles at a dry weight specified by elemental analysis.

  Further, the present invention is a crosslinked polymer particle comprising a synthetic polymer containing vinyl alcohol units and nitrogen-containing polymerized units as constituent elements, wherein the ratio of the polymerized units containing nitrogen on the surface of the crosslinked polymer particles is 20.0. It is related with the crosslinked polymer particle which is 55.0 weight% and the ratio of the polymerization unit containing nitrogen with respect to all the polymerization units which comprise crosslinked polymer particle is 60.0-95.0 weight%.

  In the present invention, the ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles is lower than the ratio to the total weight of the particles, and the ratio on the particle surface is low. 3. The crosslinked polymer particle according to claim 1, wherein a difference between the unit ratio and the ratio on the particle surface is 10.0 to 75.0% by weight.

  Further, a part of the carboxylic acid vinyl ester unit of the crosslinked polymer containing a carboxylic acid vinyl ester unit obtained by polymerization of a monomer mixture containing a vinyl alcohol unit and a vinyl compound having a carboxylic acid vinyl ester and a triazine ring, or The present invention relates to the crosslinked polymer particles formed by the entire hydrolysis and / or transesterification.

  The present invention also relates to the above-mentioned crosslinked polymer particles, wherein the polymerization conversion of the carboxylic acid vinyl ester in the polymerization of the monomer mixture containing the carboxylic acid vinyl ester and the vinyl compound having a triazine ring is 10 to 80%.

  In the present invention, the crosslinked polymer particles have a volume average particle size of 50 to 3000 μm, and 80% by volume or more of the particles have a volume average particle size of 0.8 to 1.2 times the volume average particle size. To the crosslinked polymer particles.

  The present invention also relates to the above-mentioned crosslinked polymer particle having a volume average particle diameter of 150 to 3000 μm and a particle diameter of less than 100 μm of 5% by volume or less.

  In addition, after forming droplets of the monomer mixture in the dispersion medium and polymerizing the droplets to obtain core particles, the dispersion is different from the monomer mixture in the dispersion medium containing the core particles. The present invention relates to the above-mentioned crosslinked polymer particles obtained by introducing a monomer mixture, polymerizing to form core / shell particles, processing and modifying the particles.

  In the present invention, the liquid column of the monomer mixture ejected from the nozzle hole into the dispersion medium is regularly vibrated to form droplets having a uniform diameter in the dispersion medium. The present invention relates to the above-mentioned crosslinked polymer particles obtained by polymerizing under the conditions that do not cause coalescence or additional dispersion to obtain core particles.

  The present invention also relates to a body fluid treatment material comprising the aforementioned crosslinked polymer particles.

  The present invention also includes forming droplets of a monomer mixture in a dispersion medium, polymerizing the droplets to obtain core particles, and then the monomer mixture in the dispersion medium containing the core particles. The present invention relates to a method for producing the crosslinked polymer particles, comprising introducing a monomer mixture different from the above and polymerizing the mixture so as to form core / shell particles.

  In the present invention, the liquid column of the monomer mixture ejected from the nozzle hole into the dispersion medium is regularly vibrated to form droplets having a uniform diameter in the dispersion medium. The present invention relates to a method for producing the crosslinked polymer particles, comprising polymerizing the core particles under conditions that do not cause coalescence or additional dispersion.

  The object of the present invention is useful as an adsorbent / treatment material for treating liquids containing physiological substances and / or cells, etc., and particularly as an adsorbent for direct blood perfusion, it has both the ability to adsorb pathogens and blood compatibility. Provided is a crosslinked polymer particle in which the ratio of the polymerized unit containing nitrogen to the total polymerized unit is lower than the ratio to the total weight of the particle and the ratio on the particle surface is low, and a process for producing the crosslinked polymer particle.

  In the crosslinked polymer particle containing the vinyl alcohol unit and nitrogen-containing polymer unit of the present invention as constituent elements, the surface nitrogen concentration specified by X-ray photoelectron spectroscopy (XPS) is 3.0 to 9.5 at%. Preferably, it is 5.0 to 8.0 at%.

  In the crosslinked polymer particles, the nitrogen content in the dry weight specified by elemental analysis is 10.0 to 18.0% by weight, preferably 12.0 to 18.0% by weight.

  In the crosslinked polymer particle of the present invention, when the polymerized unit containing nitrogen is a polymerized unit having a triazine ring, the ability to adsorb pathogens in blood is particularly large.

  In the crosslinked polymer particle comprising the vinyl alcohol unit and nitrogen-containing polymer unit of the present invention as constituent elements, the ratio of the polymer unit containing nitrogen on the particle surface is 20.0 to 55.0% by weight, preferably Is 30.0 to 50.0% by weight.

  In the crosslinked polymer particles, the ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles is 60.0 to 95.0% by weight, preferably 70.0 to 95.0% by weight. is there.

  Here, when the surface nitrogen concentration specified by XPS is less than 3.0 at%, or when the ratio of the polymerized unit containing nitrogen on the particle surface is less than 20.0 wt%, the complement system and leukocytes This is not preferable because it tends to cause activation. On the other hand, when the nitrogen content in the dry weight specified by elemental analysis is less than 10.0% by weight, the ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles is 60.0% by weight. If it is less than%, the adsorption ability of the pathogenic substance in the blood becomes small, which is not preferable. When the surface nitrogen concentration specified by XPS exceeds 9.0 at%, or when the ratio of polymerized units containing nitrogen on the particle surface exceeds 55.0% by weight, platelet adhesion increases, The loss of useful components due to specific adsorption tends to increase, which is not preferable. On the other hand, when the nitrogen content in the dry weight specified by elemental analysis exceeds 18.0 wt%, the ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles is 95.0 wt% If it exceeds 1, the crosslinked polymer particles become brittle, which is not preferable.

  The ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles and the ratio of the polymerized units containing nitrogen on the surface of the crosslinked polymer particles are within the preferred range, and constitute the crosslinked polymer particles. The ratio of the polymerized unit containing nitrogen to the total polymerized unit is larger than the ratio of the polymerized unit containing nitrogen on the surface of the crosslinked polymer particle, and the ratio of the polymerized unit containing nitrogen to the total polymerized unit constituting the crosslinked polymer particle. However, the difference from the nitrogen-containing polymerized units on the surface of the crosslinked polymer particles is preferably 10.0 to 75.0% by weight. In this case, it is possible to obtain crosslinked polymer particles that have a large ability to adsorb pathogenic substances in blood and extremely little platelet adhesion.

  Although the crosslinked polymer particles of the present invention are usually used in an aqueous medium, the surface nitrogen concentration specified by X-ray photoelectron spectroscopy (XPS) referred to in the present invention is the t-butyl alcohol freeze-drying method, etc. Is the nitrogen concentration on the surface of the crosslinked polymer particles identified by conducting surface elemental analysis by XPS on the crosslinked polymer particles substantially completely dried while maintaining the particle structure in water.

  In the crosslinked polymer particle of the present invention, when the polymerized unit constituting the crosslinked polymer particle is known, nitrogen on the surface of the crosslinked polymer particle is contained from the surface nitrogen concentration specified by the surface element analysis by XPS. It is possible to calculate the proportion of polymerized units.

  In the present invention, the nitrogen content in the dry weight specified by elemental analysis means that the cross-linked polymer particles that have been sufficiently washed are substantially completely dried by vacuum drying or the like, and then the element is obtained by a CHN coder or the like. It is the nitrogen content in the dry weight of the crosslinked polymer particle specified by performing the analysis. Synthetic polymers containing vinyl alcohol units are water-absorbing and moisture-absorbing and require attention to water content, but the presence or absence of water content in the sample can be confirmed by the Karl Fischer method or the like.

  In the crosslinked polymer particle of the present invention, when the polymerized unit constituting the crosslinked polymer particle is known, the total polymerization constituting the crosslinked polymer particle is determined from the nitrogen content in the dry weight specified by elemental analysis. It is possible to calculate the ratio of polymerized units containing nitrogen to units.

  For example, even when a certain polymerization unit is introduced by copolymerization, the composition of the copolymer to be produced does not necessarily match the charged composition of the monomer when the polymerization conversion is less than 100%. Therefore, it is necessary to determine the nitrogen content or the proportion of polymerized units containing nitrogen for those actually used as the adsorbent / treatment material.

  As described above, in the adsorbent for direct blood perfusion, complicated processes and equipment are required to achieve both the ability to adsorb the causative agent and blood compatibility. The droplets of the body mixture are formed in a dispersion medium, and the droplets are polymerized to obtain core particles. Then, the shell mixture is formed in the dispersion medium containing the core particles for shell formation different from the monomer mixture. By introducing a monomer mixture and polymerizing to form core / shell particles, nitrogen is present in a specific ratio in the core part and the shell part, or a polymer containing unit containing nitrogen exists in a specific ratio By doing so, it is considered that both the ability to adsorb pathogens and blood compatibility can be achieved.

  That is, the problem is achieved by causing the core portion and the shell portion of the crosslinked polymer particle of the present invention to have nitrogen in a specific ratio in each molecule, or by causing a nitrogen-containing polymer unit to exist in a specific ratio. It has been done. In addition, the production process is achieved only by the polymerization process, and the equipment can also use a normal polymerization equipment. The production process of the adsorbent that has been studied so far, for example, “support production process + ligand immobilization process” “activated carbon This is simpler than the “manufacturing process + coating process”.

  The cross-linked polymer particles of the present invention are obtained by polymerizing a monomer mixture containing at least a monomer that gives a vinyl alcohol unit and a monomer containing nitrogen to form a cross-linked polymer, and then a single amount that gives a vinyl alcohol unit. From the viewpoint of the design of polymer particles, crosslinked polymer particles in which a part or all of the body units are vinyl alcohol units by a chemical reaction or the like are preferable. However, the monomer mixture for the shell portion does not necessarily include a monomer containing nitrogen. The monomer mixture may contain other monomers, a non-polymerizable liquid, a linear polymer, a polymerization initiator and the like as necessary.

  Preferred examples of the monomer that gives a vinyl alcohol unit include carboxylic acid vinyl esters. Examples of carboxylic acid vinyl esters preferably used in the present invention include aliphatic carboxylic acid vinyl ester compounds such as vinyl acetate, vinyl propionate, vinyl butyrate, vinyl valerate, vinyl caproate, and divinyl adipate, vinyl benzoate, and phthalate. Examples thereof include aromatic carboxylic acid vinyl ester compounds such as vinyl acid. Of these, aliphatic carboxylic acid vinyl ester compounds such as vinyl acetate and vinyl propionate are more preferable, and vinyl acetate is most preferable from the viewpoint of ease of polymerization and saponification / ester exchange reaction and economical efficiency. One type of carboxylic acid vinyl ester may be used, or two or more types may be used in combination.

  As the nitrogen-containing monomer of the present invention, a monomer having a triazine ring is particularly preferable because of its high ability to adsorb pathogenic substances in blood. Preferable examples of the nitrogen-containing monomer include vinyl compounds having a triazine ring such as triallyl cyanurate, triallyl isocyanurate, and trimethallyl isocyanurate. From the viewpoint of good physical or chemical stability. Isocyanurates such as triallyl isocyanurate and trimethallyl isocyanurate are particularly preferred, and triallyl isocyanurate is most preferred from the viewpoint of ease of handling. One type of monomer containing nitrogen may be used, or two or more types may be used in combination.

  As the monomer other than the monomer used in the present invention, a monomer that can be directly or indirectly copolymerized with the monomer can be used, and may be used as necessary. It is not necessary to use it.

  Such monomers include acrylic acid, methyl acrylate, ethyl acrylate, butyl acrylate, alkyl acrylate, methoxyethyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, polyoxyethylene Acrylic acid such as monoacrylate and polyoxypropylene monoacrylate and esters thereof, methacrylic acid, methyl methacrylate, butyl methacrylate, alkyl methacrylate, t-butyl methacrylate, methoxyethyl methacrylate, cyclohexyl methacrylate, benzyl methacrylate, 2-ethylhexyl methacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, glycidyl methacrylate, glycerol monomethacrylate, polyethylene glycol Methacrylic acid and its esters such as nonmethacrylate and tetrahydrofurfuryl methacrylate, aromatic vinyl compounds such as styrene, methylstyrene, ethylstyrene and styrenesulfonate, and vinyl compounds such as vinyl cyanide compounds such as acrylonitrile and methacrylonitrile. can give. And / or a polyfunctional vinyl compound such as the following can be used. These monomers can be used alone or in combination of two or more as required.

  The crosslinked structure in the crosslinked polymer particle of the present invention can be obtained, for example, by copolymerizing a polyfunctional vinyl compound. Examples of the polyfunctional vinyl compound include ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, polyethylene glycol diacrylate, polyalkylene glycol diacrylate, polyalkylene glycol dimethacrylate, 1.3-butylene glycol dimethacrylate, 1 .6-Hexanediol diacrylate, glycerol dimethacrylate, trimethylolpropane triacrylate, trimethylolpropane trimethacrylate, acrylates and methacrylates such as pentaerythritol triacrylate, dipentaerythritol hexaacrylate, butanediol divinyl ether, diethylene glycol divinyl ether Divinyl A Le ethers, divinyl benzene, aromatics such as divinyl naphthalene, allyl methacrylate, triallyl cyanurate, triallyl isocyanurate, allyl compounds such as diallyl phthalate and the like. Among them, trimethylolpropane trimethacrylate, trimethylolpropane triacrylate, pentaerythritol triacrylate, triallyl cyanurate, triallyl isocyanurate, trimethallyl isocyanurate are easy to obtain high mechanical strength and dense pore structure. A compound having a trifunctional or higher functional crosslinkable vinyl group such as the above is more preferable. Furthermore, when the crosslinked structure in the crosslinked polymer particle of the present invention is formed from polymerized units containing nitrogen, it is particularly preferable because of its large ability to adsorb pathogenic substances in blood. Therefore, as described above, polyfunctional vinyl compounds having a triazine ring such as triallyl cyanurate, triallyl isocyanurate, and trimethallyl isocyanurate are particularly preferred, and triallyl isocyanurate is most preferred. One kind of these crosslinkable monomers may be used, or two or more kinds may be used in combination.

  In the copolymerization reaction, when the polymerization conversion rate is sufficiently high, the average composition of the finally obtained copolymer matches the charged monomer composition. On the other hand, it is known that the composition of the copolymer produced at a certain point of time is affected by the difference in the monomer composition at that point of time and the reactivity of each monomer with a certain radical. Therefore, the composition of the copolymer produced at a certain point in time does not necessarily match the charged monomer composition. That is, the composition and composition distribution of the copolymer obtained by completing the polymerization at a relatively low polymerization conversion rate are greatly different from those of the copolymer obtained at a high polymerization conversion rate that is generally performed in ordinary copolymerization. May be different. In the crosslinked polymer particles of the present invention, it is possible to make characteristics such as composition distribution of the crosslinked polymer particles more favorable for affinity with physiological substances by adjusting the combination of monomers and the polymerization conversion rate. .

  That is, in the crosslinked polymer particle of the present invention, when polymerizing a monomer mixture containing at least a carboxylic acid vinyl ester and a vinyl compound having a triazine ring, the polymerization conversion of the carboxylic acid vinyl ester is between 10% and 80%. To form a cross-linked polymer having a carboxylic acid vinyl ester unit as one of the constituent elements, and then performing saponification and / or transesterification to convert a part or all of the carboxylic acid vinyl ester unit into a vinyl alcohol unit. In the case of the cross-linked polymer particles, blood compatibility is much better and more preferable.

  A more preferable polymerization conversion rate of the carboxylic acid vinyl ester is 10 to 70%, and more preferably 15 to 65%.

  Here, when the polymerization conversion rate of the carboxylic acid vinyl ester is less than 10%, it is difficult to obtain sufficient particle strength. On the other hand, when the polymerization conversion of the carboxylic acid vinyl ester exceeds 80%, activation of the complement system and leukocytes tends to increase, which is not preferable.

In polymerizing a monomer mixture containing at least a carboxylic acid vinyl ester and a vinyl compound having a triazine ring, vinyl compounds having a triazine ring are used for forming core particles with respect to 100 parts by weight of the carboxylic acid vinyl ester. It is preferable to use parts by weight. More preferably, it is 50-150 weight part. When the amount of the vinyl compound having a triazine ring is less than 40 parts by weight with respect to 100 parts by weight of the carboxylic acid vinyl ester for forming the core particles, the ability to adsorb the pathogenic substance becomes small, which is not preferable. On the other hand, when the amount of the vinyl compound having a triazine ring exceeds 200 parts by weight, the particles become brittle, which is not preferable. For shell formation, it is preferable to use 0 to 40 parts by weight of a vinyl compound having a triazine ring. More preferably, it is 0-30 weight part. When the amount of vinyl compound having a triazine ring for shell formation exceeds 40 parts by weight, non-specific adsorption and platelet adhesion tend to increase. As the polymerization initiator used in the present invention, for example, 2,2 ′ -Azobis (isobutyronitrile), 2,2'-azobis (2,4-dimethylvaleronitrile), 2,2'-azobis (2-methylbutyronitrile), 2,2'-azobis (2-methyl) Azo compounds such as propionamidin) dihydrochloride, benzoyl peroxide, lauroyl peroxide, t-butyl perbenzoate, t-butyl perpivalate, t-butyl peroxyisopropyl carbonate, t-butyl peroxyacetate, t -Organic peroxides such as butylperoxy-3,3,5-trimethylcyclohexane DOO but can, but it is not limited to the above. A polymerization initiator that is soluble in the monomer mixture is preferable because the polymerization reaction proceeds smoothly. In addition, those that are insoluble in the dispersion medium or have low solubility in the dispersion medium are preferable because they produce less fine particles.

  Here, the polymerization initiator is designed so as to obtain a predetermined polymerization conversion rate in consideration of the characteristics as a polymerization initiator such as reactivity with the monomer and the decomposition rate, and reaction conditions such as polymerization time and polymerization temperature. The amount and type of use are preferably selected for the core and shell portions, and can be used alone or as a mixture of two or more. The polymerization temperature is preferably in the range of 0 to 180 ° C., more preferably 20 to 120 ° C., further preferably 40 to 90 ° C., and most preferably 50 to 70 ° C. from the viewpoint of control of the polymerization reaction. is there. It is preferable to select a polymerization temperature suitable for the core particle formation and the shell formation.

  The crosslinked polymer particles of the present invention can adopt a porous structure. Due to the porous structure, the contact area with the liquid to be treated can be greatly increased, and the target substance can be treated more efficiently. Bulk specific gravity can be used as a porous index, and the bulk specific gravity is preferably 0.05 to 0.40 g / mL, and more preferably 0.10 to 0.30 g / mL. Specifically, the measurement of bulk specific gravity is the dry solid weight per 1 mL of sedimentation volume of particles that are uniformly settled in water by tapping or the like.

  In the crosslinked polymer particles of the present invention, a non-polymerizable liquid can be used in the monomer mixture for introducing a porous structure. In order to obtain a uniform porous structure, the non-polymerizable liquid is preferably soluble in the monomer mixture and insoluble or hardly soluble in the dispersion medium. Specific examples include aromatic hydrocarbons such as toluene, xylene and benzene, aliphatic hydrocarbons such as hexane, heptane, pentane and octane, ester compounds such as ethyl acetate, n-butyl acetate and n-hexyl acetate, dibutyl ether and the like Ethers, alcohols such as n-heptanol and amyl alcohol, ketones such as methyl isobutyl ketone, and the like, but are not limited thereto.

  As the polymerization proceeds, the non-polymerizable liquid and the residual monomer are phase-separated from the generated crosslinked polymer and particles to form pores. Therefore, the structure and size of the pores are greatly affected by the amount of non-polymerizable liquid used and the difference in affinity between the non-polymerizable liquid and the resulting crosslinked polymer. For example, if a non-polymerizable liquid having a lower affinity with the produced polymer is selected, the porous structure formed in the crosslinked polymer particles has a larger pore size. One type of non-polymerizable liquid may be used, or two or more different types may be mixed, and the affinity with the produced polymer is changed depending on the type and mixing ratio, and the porous structure such as pore diameter is adjusted. It is possible. Furthermore, it is possible to adjust the porous structure such as the pore volume by changing the amount of the non-polymerizable liquid used.

  The preferred amount of non-polymerizable liquid used is 50 to 400 parts by weight for forming core particles, more preferably 100 to 300 parts by weight or less, and 0 to 400 parts by weight for forming shells. More preferably, it is 0 to 300 parts by weight or less. For the formation of core particles, the strength tends to be insufficient when the amount of the non-polymerizable liquid used exceeds 400 parts by weight, and when it is less than 50 parts by weight, it is difficult to become porous.

  In addition, a linear polymer can be used for the crosslinked polymer particles of the present invention in order to introduce a porous structure. The linear polymer referred to in the present invention refers to a polymer that is substantially non-crosslinked, may contain a branched structure, and may contain some crosslinked structure as long as it is soluble in a solvent. The linear polymer used in the present invention is an important component that determines the structure of the pore portion along with the non-polymerizable liquid. For example, the pore diameter of the crosslinked polymer particles obtained by increasing the amount of the linear polymer used increases, and the pore diameter of the crosslinked polymer particles obtained by increasing the average degree of polymerization of the linear polymer increases. By using a combination of a non-polymerizable liquid and a linear polymer, it becomes easier to control the porous structure of the crosslinked polymer particles.

  Specific examples of the linear polymer include ester resins such as polyvinyl acetate, acrylic resins such as polymethyl methacrylate and polyacrylonitrile, aromatic resins such as polystyrene, halogen resins such as polyvinyl chloride, and polybutadiene. Examples thereof include diene resins, and copolymers and blends thereof, but there are no particular restrictions as long as they are soluble in the monomer mixture, and polymers other than these can also be used.

  The preferred use amount of the linear polymer is 1 to 100 parts by weight, more preferably 2 to 40 parts by weight for forming the core particles, and more preferably 0 to 100 parts by weight for forming the shell. Is 0 to 40 parts by weight.

  Moreover, the preferable average degree of polymerization of a linear polymer is 100-5000, More preferably, it is 150-3000, Especially preferably, it is 200-1500, Most preferably, it is 300-1000.

  When the amount of the linear polymer used exceeds 100 parts by weight or when the average degree of polymerization exceeds 5000, the viscosity of the monomer mixture increases and handling becomes difficult. In addition, agglomerates are easily formed during the polymerization.

  The crosslinked polymer particles of the present invention are crosslinked polymer particles having a volume average particle diameter of 50 to 3000 μm, and 80% by volume or more of the particles are in the range of 0.8 to 1.2 times the volume average particle diameter. Preferably there is.

  A more preferable volume average particle diameter of the particles is 100 μm or more. In addition, when the liquid to be treated, such as blood, contains a cell component or has a high viscosity, it is more preferably 300 μm or more. Moreover, the more preferable volume average particle diameter of the crosslinked polymer particles of the present invention is 2000 μm or less, and more preferably 1000 μm or less.

  If the volume average particle diameter is less than 50 μm, the particle gap that becomes the flow path of the liquid to be treated becomes narrow, pressure loss increases, cells are easily activated non-specifically, and the cell permeability is low. There is a tendency to decrease or to easily cause column clogging. On the other hand, when the volume average particle diameter is larger than 3000 μm, the particle gap serving as the flow path of the liquid to be processed is widened, the pressure loss is kept low, and it is advantageous for the passage property. Tends to be less efficient.

  In addition, when the liquid to be treated, such as blood, contains a cell component or has a high viscosity, it is preferable that the particle size of less than 100 μm is 5% by volume or less. More preferably, the particles having a size of less than 100 μm are 1% by volume or less.

  When particles of 100 μm or less are present in excess of 5% by volume, small particles block the particle gap, resulting in increased pressure loss, non-specific cell activation, and decreased cell permeability. Or column clogging may occur. In addition, there is a growing concern that fine particles will flow out during use.

  For the formation of the core particle of the crosslinked polymer particle of the present invention, general suspension polymerization can be used. In suspension polymerization, droplets of the monomer mixture are dispersed by mechanical stirring using a stirring blade or the like. At this time, the droplets are divided by stirring and become smaller or become larger together with other droplets. Therefore, the obtained polymer particles have a wide particle size distribution including a large amount of large particles and small particles. The particles having a wide particle size distribution obtained by suspension polymerization or the like are preferably used by removing large particles and small particles by classification operation such as sieving.

  More preferably, after droplets of a uniform diameter of the monomer mixture are formed in the dispersion medium, the droplets are polymerized under conditions that do not cause coalescence or additional dispersion, and are processed, modified, and modified. The crosslinked polymer particles obtained by polishing.

  In the present invention, the conditions that do not cause coalescence or additional dispersion are the case where the droplets of the monomer mixture merge with other droplets to form larger droplets, or vice versa. It means a condition that does not generally occur such that it is divided into smaller droplets.

  The uniform diameter referred to in the present invention means that most of the particles have substantially the same diameter as follows and do not contain a large amount of large particles and small particles.

  That is, the polymer particle of the present invention is the above polymer particle in which 80% by volume or more of the particle is in the range of 0.8 to 1.2 times the volume average particle diameter. Here, 80% by volume or more of the particles are preferably in the range of 0.9 to 1.1 times the volume average particle diameter, and 90% by volume or more of the particles have a volume average particle diameter of the particle diameter. More preferably, it is in the range of 0.9 to 1.1 times, and 95% by volume or more of the particles are in the range of 0.9 to 1.1 times the volume average particle size of the particle size. Is particularly preferred, and most preferably has a substantially single particle size.

  When the particle size distribution is wide and small particles less than 0.8 times the volume average particle size or large particles exceeding 1.2 times exceed 20% by volume, even if the volume average particle size is the same There is a tendency that the particle gap that becomes the flow path of the liquid to be treated becomes narrow, and the pressure loss during liquid passage increases. Further, when the liquid to be treated contains a cell component, the cell is likely to be activated non-specifically, the permeability of the cell is lowered, or the column is likely to be clogged.

  The crosslinked polymer particles of the present invention having such a uniform diameter are liquids for forming core particles having a uniform diameter by giving regular vibration disturbance to the liquid column of the monomer mixture ejected from the nozzle holes into the dispersion medium. After the droplets are formed in the dispersion medium, the core particles can be obtained by polymerizing the droplets under conditions that do not substantially cause coalescence or additional dispersion. Next, the monomer mixture for shell formation is put into a dispersion medium containing core particles and polymerized as core-shell particles, whereby the crosslinked polymer particles having a uniform diameter, which were difficult to obtain by the conventional method, are obtained. It becomes possible to obtain. The crosslinked polymer particles thus obtained have the advantage that the number of large particles and small particles is extremely small and the classification loss can be greatly reduced.

  Here, the first step is a step for forming core particles of the crosslinked polymer particles of the present invention. First, uniform-sized droplets for forming core particles are generated in a dispersion medium. As an example of a droplet generator, a nozzle that ejects a monomer mixture is inserted into a column filled with a dispersion medium, and at least one small hole is arranged in the nozzle, and a mechanism for transmitting vibration is installed. Etc. An introduction pipe for supplying a dispersion medium from a dispersion medium tank can be connected to the column, and an introduction pipe for supplying a monomer mixture from a monomer mixture tank can be connected to the nozzle. In order to produce uniform droplets, it is preferable to use a metering pump with as little pulsation as possible to supply the monomer mixture.

  The particle size of the droplet is determined by the nozzle pore size, the nozzle passing speed of the monomer mixture, the viscosity of the monomer mixture and the dispersion medium, and the vibration disturbance applied to the liquid column generated by the monomer mixture passing through the nozzle. It is determined by factors such as type, frequency, and amplitude, and droplets having a desired particle size can be obtained by these factors or a combination thereof. Moreover, the droplet group which has desired particle diameter distribution can be obtained by changing combining one or more of these.

  The nozzle that can be used for droplet formation is not particularly limited, and for example, an orifice having at least one small hole can be used. Such nozzles can be used alone or in combination. As a method of giving vibration disturbance, a method of ejecting the monomer mixture from the nozzle while applying mechanical vibration to the monomer mixture, a method of ejecting the monomer mixture from the nozzle while applying mechanical vibration to the dispersion medium, Although the method etc. which apply mechanical vibration to the nozzle which a monomer mixture ejects can be illustrated, it is not limited to this.

  This is a step of polymerizing the formed droplets of uniform diameter under conditions that do not cause coalescence or additional dispersion. Here, the condition that does not cause coalescence or additional dispersion means that the droplets of the monomer mixture formed by jetting into the dispersion medium from the nozzle holes and being subjected to vibrational disturbance are the other droplets. It means a condition in which it does not substantially occur that the droplets are combined to form a larger droplet, or conversely divided into smaller droplets.

  As a method for polymerizing the droplets for forming the core particles, for example, a method of introducing the previous droplets into the reactor and performing a polymerization reaction while gently stirring the dispersion medium containing the droplets is adopted. You can also. However, if the stirring is insufficient, the droplets are likely to coalesce. Conversely, if the stirring is excessive, additional dispersion is likely to occur. Therefore, the stirring method and conditions need to be appropriately set. For example, when stirring is performed using a stirring blade, it is preferable to select a relatively low shear and high discharge type and adjust the stirring speed. In order to reduce the coalescence and additional dispersion of the droplets, it is preferable to introduce the droplet group into a dispersion medium preliminarily existing in the polymerization reactor, and the droplet generator is used as the polymerization reactor. It is more preferable to connect to the lower part of this through an introduction pipe or the like.

  The second step is a step of obtaining the crosslinked polymer particle of the present invention which is a core-shell particle in which a shell portion is formed on the core particle. As a method for carrying out the polymerization for forming the core / shell particles, for example, to sufficiently refine the monomer mixture for shell formation to be introduced after the core particles formed in the first step are sufficiently formed. It is also possible to employ a method in which the stirring speed is sufficiently increased, and then the shell-forming monomer mixture is introduced into the reactor after the second step and the polymerization reaction is performed as core-shell particles. . The monomer mixture for shell formation may be introduced once from the top of the reactor or continuously. The amount of the monomer mixture for forming the shell is preferably 5 to 50%, more preferably 10 to 30%, based on the amount of the monomer mixture for the core particles. When the ratio of the input amount is less than 5%, blood compatibility is deteriorated, which is not preferable. When the ratio of the input amount exceeds 50%, it is not preferable because the ability of adsorbing the pathogenic substance is reduced or the particles are aggregated.

  A dispersion medium that forms a continuous phase is not miscible with a monomer mixture that forms droplets, and an aqueous medium is preferably used in terms of safety, economy, and environment. The dispersion medium can contain a dispersion stabilizer. The dispersion stabilizer is not particularly limited, and those commonly used in suspension polymerization can be used. For example, a dispersion stabilizer soluble in a dispersion medium, a fine solid dispersion stabilizer, an interface, and the like. An activator or the like can be used. These may be used alone, but a greater effect can be obtained by using them in combination. Moreover, you may use an adjuvant together. In addition, if dispersion stability is insufficient, droplet coalescence tends to occur, and conversely, if dispersion stability is excessive, additional dispersion is likely to occur. It is necessary to pay attention to the usage. A more preferable method is to form a droplet group of the monomer mixture in the dispersion medium in the presence of a dispersion stabilizer soluble in the dispersion medium. In this method, a fine particle solid dispersion stabilizer is added and / or the droplet group is polymerized in the presence of a salt.

  As the dispersion stabilizer soluble in the dispersion medium, a polymer protective colloid is preferably used. Specific examples include water-soluble synthetic polymers such as polyvinyl alcohol, polyacrylamide, polyvinyl pyrrolidone, and sodium polyacrylate, water-soluble cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, and hydroxyethyl cellulose, and water-soluble natural polymers such as starch and gelatin. Can give. These may be used alone or in combination of two or more. A preferable amount of the dispersion stabilizer soluble in the dispersion medium is 0.001 to 10% by weight, more preferably 0.005 to 5% by weight, based on the dispersion medium. When the amount of the dispersion stabilizer soluble in the dispersion medium exceeds 10% by weight, it is not preferable because additional dispersion of droplets is likely to occur or new particles are formed by emulsion polymerization or the like.

  Examples of the particulate solid dispersion stabilizer include sparingly soluble inorganic substances such as calcium phosphate, calcium carbonate, and magnesium pyrophosphate, and tertiary calcium phosphate is particularly effective. These may be used alone or in combination of two or more. A preferable amount of the fine particle solid dispersion stabilizer is 0.01 to 20% by weight, more preferably 0.05 to 10% by weight, based on the dispersion medium. By using an appropriate amount of the fine particle solid dispersion stabilizer, the effect of preventing secondary aggregation of the polymer particles is increased.

  Nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene alkyl allyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene derivative, sorbitan fatty acid ester, glycerin fatty acid ester Agents, alkyl sulfate salts, alkylbenzene sulfonates, alkyl naphthalene sulfonates, alpha olefin sulfonates, dialkyl sulfosuccinates, alkyl diphenyl ether disulfonates, alkyl phosphates, polyoxyethylene alkyl phosphates, poly Anionic surfactants such as oxyethylene alkyl sulfate salts and polyoxyethylene alkyl allyl sulfate salts can be exemplified.These surfactants may be used alone or in combination of two or more. Dispersion stability can be further improved by using these surfactants together with the dispersion stabilizer. In particular, when a particulate solid dispersion stabilizer is used, it is effective to use an anionic surfactant in combination. A preferred amount of the surfactant used is 0.0001 to 5% by weight, more preferably 0.0005 to 0.5% by weight, based on the dispersion medium. When the amount of the surfactant used exceeds 5% by weight, it is not preferable because additional dispersion of droplets is likely to occur or new particles are easily formed by emulsion polymerization or the like.

  Examples of the salt include chlorides such as sodium chloride and potassium chloride, sulfates such as sodium sulfate and magnesium sulfate, and phosphates such as sodium dihydrogen phosphate and disodium hydrogen phosphate.

  Furthermore, the formation of fine particles can be suppressed by performing the above-described polymerization in the presence of a polymerization inhibitor soluble in the dispersion medium. Examples of the polymerization inhibitor soluble in the dispersion medium include nitrites such as sodium nitrite, hydroquinone, and p-diaminophenylene. A preferable concentration of the polymerization inhibitor is 0.0001 to 1% by weight, more preferably 0.0005 to 0.5% by weight, based on the dispersion medium. If the amount of the polymerization inhibitor used exceeds 1% by weight, the polymerization reaction is difficult to proceed smoothly, which is not preferable.

  The crosslinked polymer particles of the present invention can be used after being treated and modified as necessary. Treatment and modification are performed for the purpose of hydrophilicity, biocompatibility, improvement of physical and chemical properties of polymer particles, improvement of mechanical strength, addition of functions as treatment materials, reduction of eluate, and sterilization. Is called. Examples of treatment and modification include saponification, washing, high temperature treatment and high pressure treatment, radiation treatment, plasma treatment, and other chemical and / or physical treatments and modification. Or after polymerization.

  The crosslinked polymer particle of the present invention can be used as an adsorbent or a treatment material as it is. Representative of pathogenic substances in the blood are inflammatory cytokines causing inflammation, β2 microglobulin causing dialysis amyloidosis, lipoprotein causing arteriosclerosis, rheumatoid factor causing autoimmune disease, immunity Globulin and the like.

  The polymer particles of the present invention can be used, for example, by a method of mixing and contacting the liquid to be treated in a container and then separating the liquid to be treated from the polymer particles by filtration or centrifugation. More preferably, the polymer particles of the present invention are filled in a container having an inlet and an outlet such as a column, the liquid to be treated is introduced from the inlet, the liquid to be treated is brought into contact with the polymer particles in the container, and the liquid is coated from the outlet. It can be used in such a manner as to cause the processing liquid to flow out. The container may be provided with a mechanism such as a mesh that does not allow the polymer particles to pass but allows the liquid to be processed to pass.

Example 1
A 2 L separable flask having a stirring blade was charged with 378.3 g of water, 1.75 g of a 3 wt% aqueous solution of sodium alpha olefin sulfonate, and 120.0 g of a 10 wt% slurry of particulate calcium triphosphate, and stirred gently. I was allowed to.

  As a droplet generator, a nozzle for ejecting a monomer mixture is inserted into a column filled with a dispersion medium, the upper end of the nozzle is made of an orifice plate having 12 small holes with a hole diameter of 0.17 mm, and the lower end is vibrated. A transmitting diaphragm was installed, and a diaphragm connected to a vibrator was used. The column was connected to an introduction pipe for supplying a dispersion medium from a dispersion medium tank, and the nozzle was connected to an introduction pipe for supplying a monomer mixture from a monomer mixture tank for core particle formation. A double plunger pump with high quantitativeness and little pulsation was used to supply the monomer mixture.

From the monomer mixture tank for core particle formation, 100 parts by weight of vinyl acetate, 70 parts by weight of TAIC, 182 parts by weight of ethyl acetate, 35 parts by weight of heptane, 3.6 parts by weight of polyvinyl acetate (average polymerization degree 400), V 361.7 g of a monomer mixture consisting of 5.7 parts by weight of -65 was supplied to the nozzle at a rate of 27.6 mL / min, and charged into a separable flask via a droplet generator. At the same time, 500.0 g of a dispersion medium consisting of 133 g of 3 wt% PVA aqueous solution, 7.39 g of 6 wt% NaNO ₂ aqueous solution and 3859 g of water is supplied to the column from the dispersion medium tank, and is separable via a droplet generator. The flask was charged.

  At this time, the monomer mixture was subjected to mechanical vibration with a constant frequency (500 Hz) and an intensity of 0.14 G by a vibrator. The liquid column of the monomer mixture ejected from the nozzle hole is divided by the mechanical vibration to form droplets of uniform diameter in the dispersion medium in the column, and into the separable flask together with the dispersion medium supplied at the same time. Sent. The contents of the separable flask were held at 65 ° C. for 5 hours under a nitrogen atmosphere to polymerize the droplets. Next, the stirring speed was increased and the mixture was vigorously stirred, and 100 parts by weight of vinyl acetate as a monomer mixture for shell formation, 11 parts by weight of TAIC, 111 parts by weight of ethyl acetate, 30 parts by weight of heptane, polyvinyl acetate (average polymerization) Degree 400) 138.2 g of a monomer mixture consisting of 2.7 parts by weight and 4.2 parts by weight of V-65 was introduced from the upper nozzle of the separable flask. The polymerization was further continued for 8 hours after charging by holding at 65 ° C. in a nitrogen atmosphere. The contents of the separable flask were then cooled to room temperature.

  Samples were taken at the column outlet, before and after polymerization, and observed with the OMRON 3D Digital Finescope VC1000. All of the droplets maintained a uniform diameter, resulting in coalescence or additional dispersion. It was confirmed that the polymerization was performed without any problems.

  Next, hydrochloric acid was added to the contents of the separable flask to adjust the pH to 2 or less to dissolve the tribasic calcium phosphate, and then washed well with water. After confirming that the pH of the cleaning liquid was close to neutral, water was replaced with acetone, and the polymer was thoroughly washed with acetone. Next, acetone was replaced with water, and then an amount of sodium hydroxide (NaOH) of the following formula was added as an aqueous solution so as to be an excess amount with respect to the vinyl acetate unit.

NaOH (solid weight) = particle dry weight / 86.09 × 40 × 1.5
The amount of water was adjusted so that the NaOH concentration relative to water was 4% by weight. This was saponified with stirring at a reaction temperature of 40 ° C. for 6 hours. Then, it washed with water until pH of the washing | cleaning liquid became neutrality, and also wash | cleaned fully with 80 degreeC warm water. Next, autoclaving at 121 ° C. for 20 minutes is performed to obtain crosslinked polymer particles having a uniform particle diameter of about 450 μm in which 80% by volume or more of the particles are in the range of 0.9 to 1.1 times the volume average particle diameter. It was.

  The obtained polymer particles were subjected to the following evaluations, except for large particles on a sieve having an opening of 710 μm and small particles having an opening of 300 μm. In addition, the particle | grains which become a classification loss under the sieve of 710 micrometers of openings and the sieve of 300 micrometers of openings were few.

  In order to observe the obtained crosslinked polymer particles with a scanning electron microscope (SEM) while maintaining the pore structure in water, the water contained in the particles is replaced with t-butyl alcohol and freeze-dried to prepare a sample. did. As a precaution, it was confirmed with the OMRON 3D digital fine scope VC1000 that there was no noticeable shrinkage or expansion of the crosslinked polymer particles during sample preparation. When the surface and cross section of the particles were observed with an SEM, it was confirmed that a large number of fine pores of micron order or less existed in the entire crosslinked polymer particles obtained.

The crosslinked polymer particles were sufficiently vacuum-dried and then subjected to elemental analysis (CHN analysis) using a J Science Lab Microcoder JM10 type to determine the nitrogen (N) content in the dry weight. It was 3% by weight. The ratio of triallyl isocyanurate (TAIC) units to the total polymerized units constituting the crosslinked polymer particles was calculated from the elemental analysis value according to the following formula, and found to be 61.3% by weight.

TAIC content = N content × TAIC molecular weight / (N atomic weight × N atom number in TAIC)

After sufficiently additionally drying the sample prepared by t-butyl alcohol freeze-drying method for SEM observation as described above, Phi Quantum 2000 was used as an apparatus, X-ray intensity AIKα / 15 kV · 25 W, X-ray beam diameter 100 μmφ The particle surface was subjected to X-ray photoelectron spectroscopy (XPS) at a pass energy of 187.85 eV (wide spectrum) and 58.70 eV (narrow spectrum). The surface nitrogen (N) concentration (atomic percent: at%) was determined to be 8.5 at%. Also, from the surface N concentration, the ratio of triallyl isocyanurate (TAIC) units on the surface of the crosslinked polymer particles was calculated from the formula (1), and converted to wt% (weight percent: wt%) from the formula (2). It was 49.5% by weight.

Surface TAIC = 1 − {(1-6 × Surface N) / (1-5 × Surface N)} (1) Formula Surface TAIC (weight) = 249.27 × Surface TAIC /
{249.27 × surface TAIC + 44.05 × (1-surface TAIC)} (2) Formula

A column with a mesh diameter of 150 μm at the inlet and outlet is filled with 6.5 mL of the particles whose water content has been replaced with physiological saline in a sedimentation volume, and 55 mL of heparin-added physiological saline is circulated to perform the priming operation. went. 200 mL of fresh blood of a healthy person to which heparin was added was placed in a 37 ° C. water bath, and this was used as a blood pool to allow blood to pass through the column for 25 minutes at a rate of 1.3 mL / min. During that time, there was no clogging of the column or a decrease in flow rate. A small amount of blood was sampled from the column inlet side and the outlet side, and the number of blood cells was measured using a blood cell counter. As a result, the permeability of red blood cells, white blood cells and platelets was good. In addition, clear thrombus or the like was not observed in the column after blood passing.

  On the other hand, in a batch experiment, the particles were 0.5 mL in sedimentation volume, and 5.5 mL of an initial concentration of 659 pg / mL by adding IL-6, which is one of inflammatory cytokines, to human serum was stirred at 37 ° C. with stirring. When the adsorption rate was determined by contact for a time, it was 54.7%. In order to examine non-specific adsorption, the adsorption rate of albumin from human plasma of albumin having an initial concentration of 2.9 g / dL was 0.0% under the conditions of a batch experiment of IL-6.

  The adsorption rate was calculated from (“initial amount of IL-6 / albumin” − “IL-6 / albumin amount after contact”) / “initial amount of IL-6 / albumin”.

(Example 2)
A 2 L separable flask having a stirring blade was charged with 378.3 g of water, 1.75 g of a 3 wt% aqueous solution of sodium alpha olefin sulfonate, and 120.0 g of a 10 wt% slurry of particulate calcium triphosphate, and stirred gently. I was allowed to.

Production of droplets for forming core particles was carried out in the same manner as in Example 1. From the monomer mixture tank for core particle formation, 100 parts by weight of vinyl acetate, 100 parts by weight of TAIC, 197 parts by weight of ethyl acetate, 35 parts by weight of heptane, 4.3 parts by weight of polyvinyl acetate (average polymerization degree 400), V- 652.8 parts by weight of a monomer mixture of 352.8 g was supplied to the nozzle at a rate of 27.6 mL / min, and charged into a separable flask via a droplet generator. At the same time, 500.0 g of a dispersion medium consisting of 133 g of 3 wt% PVA aqueous solution, 7.39 g of 6 wt% NaNO ₂ aqueous solution and 3859 g of water is supplied to the column from the dispersion medium tank, and is separable via a droplet generator. The flask was charged.

  At this time, the monomer mixture was subjected to mechanical vibration with a constant frequency (500 Hz) and an intensity of 0.18 G by a vibrator. The liquid column of the monomer mixture ejected from the nozzle hole is divided by the mechanical vibration to form droplets of uniform diameter in the dispersion medium in the column, and into the separable flask together with the dispersion medium supplied at the same time. Sent. Next, the contents of the separable flask were kept at 65 ° C. for 5 hours under a nitrogen atmosphere to polymerize the droplets. Next, the stirring speed was increased and the mixture was vigorously stirred, and 100 parts by weight of vinyl acetate as a monomer mixture for shell formation, 0 part by weight of TAIC, 53 parts by weight of ethyl acetate, 35 parts by weight of heptane, polyvinyl acetate (average polymerization) Degree 400) A monomer mixture 147 g consisting of 4.3 parts by weight and V-65 3.8 parts by weight was charged from the upper nozzle of the separable flask. Polymerization was further carried out by maintaining at 65 ° C. under a nitrogen atmosphere for 5 hours after the addition.

  The contents of the separable flask were then cooled to room temperature.

  Samples were taken at the column outlet, before and after polymerization, and observed with the OMRON 3D Digital Finescope VC1000. All of the droplets maintained a uniform diameter, resulting in coalescence or additional dispersion. It was confirmed that the polymerization was performed without any problems.

  Thereafter, the same operation as in Example 1 was performed to obtain crosslinked polymer particles having a uniform particle size of about 450 μm, in which 80% by volume or more of the particles were in the range of 0.9 to 1.1 times the volume average particle size. .

  Elemental analysis was performed in the same manner as in Example 1, and the N content in the dry weight of the crosslinked polymer particles was determined to be 11.2% by weight. Further, the ratio of TAIC units to the total polymerization units constituting the crosslinked polymer particles was calculated to be 66.0% by weight.

  XPS analysis was performed in the same manner as in Example 1, and the surface N concentration was determined to be 7.2 at%. The ratio of TAIC units on the crosslinked polymer particle surface was 52.5% by weight.

  A column with a mesh diameter of 150 μm at the inlet and outlet is filled with 7.3 mL of the particles whose water content has been replaced with physiological saline in a 10 mm inner diameter column, and 55 mL of heparin-added physiological saline is circulated to perform the priming operation. went. 200 mL of fresh blood of a healthy person to which heparin was added was placed in a 37 ° C. water bath, and this was used as a blood pool to allow blood to pass through the column at a rate of 1.0 mL / min for 25 minutes in one pass. During that time, there was no clogging of the column or a decrease in flow rate. A small amount of blood was sampled from the column inlet side and the outlet side, and the number of blood cells was measured using a blood cell counter. As a result, the red blood cell, white blood cell and platelet permeability were good. In addition, clear thrombus or the like was not observed in the column after blood passing.

  On the other hand, in a batch experiment, the particles were precipitated at a volume of 0.5 mL, and human serum was added with IL-6, which is one of inflammatory cytokines, to an initial concentration of 743 pg / mL. It was 64% when the adsorption rate was calculated by contact for a period of time. In order to examine non-specific adsorption, the adsorption rate of albumin from human plasma of albumin having an initial concentration of 3.4 g / dL was 0.0% under the conditions of IL-6 batch experiments.

(Comparative Example 1)
In a 2 L separable flask equipped with a stirring blade, 378.25 g of water, 1.75 g of a 3 wt% aqueous solution of sodium alpha olefin sulfonate, and 120.0 g of a 10 wt% slurry of fine particulate calcium triphosphate were stirred gently. I was allowed to.

Production of droplets for forming core particles was carried out in the same manner as in Example 1. From the monomer mixture tank for forming core particles, 100 parts by weight of vinyl acetate, 31 parts by weight of TAIC, 132 parts by weight of ethyl acetate, 36 parts by weight of heptane, 3.2 parts by weight of polyvinyl acetate (average polymerization degree 400), V -65 50 g of a monomer mixture consisting of 5.0 parts by weight was supplied to the nozzle at a rate of 27.6 mL / min, and charged into a separable flask via a droplet generator. At the same time, 500.0 g of a dispersion medium consisting of 133 g of 3 wt% PVA aqueous solution, 7.39 g of 6 wt% NaNO ₂ aqueous solution and 3859 g of water is supplied to the column from the dispersion medium tank, and is separable via a droplet generator. The flask was charged.

  At this time, the monomer mixture was subjected to mechanical vibration with a constant frequency (500 Hz) and an intensity of 0.14 G by a vibrator. The liquid column of the monomer mixture ejected from the nozzle hole is divided by the mechanical vibration to form droplets of uniform diameter in the dispersion medium in the column, and into the separable flask together with the dispersion medium supplied at the same time. Sent. The contents of the separable flask were held at 65 ° C. for 5 hours under a nitrogen atmosphere to polymerize the droplets. The contents of the separable flask were cooled to room temperature without charging the monomer mixture for shell formation.

  Thereafter, the same operation as in Example 1 was performed to obtain crosslinked polymer particles having a uniform particle size of about 600 μm in which 80% by volume or more of the particles were in the range of 0.9 to 1.1 times the volume average particle size. .

  Hereinafter, evaluation of the obtained crosslinked polymer particles was performed in the same manner as in Example 1.

  Elemental analysis was performed in the same manner as in Example 1, and the N content in the dry weight of the crosslinked polymer particles was determined to be 8.4% by weight. The ratio of TAIC units to the total polymer units constituting the crosslinked polymer particles was calculated to be 49.6% by weight.

  XPS analysis was performed in the same manner as in Example 1, and the surface N concentration was determined to be 7.3 at%. Further, the ratio of TAIC units on the surface of the crosslinked polymer particles was determined to be 42.4% by weight.

  A column with a mesh diameter of 150 μm at the inlet and outlet is filled with 7.3 mL of the particles whose water content has been replaced with physiological saline in a 10 mm inner diameter column, and 55 mL of heparin-added physiological saline is circulated to perform the priming operation. went. 200 mL of fresh blood of a healthy person to which heparin was added was placed in a 37 ° C. water bath, and this was used as a blood pool to allow blood to pass through the column at a rate of 1.0 mL / min for 25 minutes in one pass. During that time, there was no clogging of the column or a decrease in flow rate. A small amount of blood was sampled from the column inlet side and the outlet side, and the number of blood cells was measured using a blood cell counter. As a result, the permeability of red blood cells, white blood cells and platelets was good. In addition, clear thrombus or the like was not observed in the column after blood passing.

  On the other hand, in a batch experiment, the particles were 0.5 mL in sedimentation volume, and IL-6, which is one of inflammatory cytokines, was added to human serum to obtain an initial concentration of 859 pg / mL. It was 0% when the adsorption rate was obtained by contact for a period of time. In order to examine non-specific adsorption, the adsorption rate of albumin from human plasma having an initial concentration of 3.0 g / dL under the conditions of IL-6 batch experiment was 0.0%.

(Comparative Example 2)
In a 2 L separable flask equipped with a stirring blade, 378.25 g of water, 1.75 g of a 3 wt% aqueous solution of sodium alpha olefin sulfonate, and 120.0 g of a 10 wt% slurry of fine particulate calcium triphosphate were stirred gently. I was allowed to.

Production of droplets for forming core particles was carried out in the same manner as in Example 1. From the monomer mixture tank for forming core particles, 100 parts by weight of vinyl acetate, 50 parts by weight of TAIC, 158 parts by weight of ethyl acetate, 30 parts by weight of heptane, 3.2 parts by weight of polyvinyl acetate (average polymerization degree 400), V -65 50 g of a monomer mixture consisting of 5.0 parts by weight was supplied to the nozzle at a rate of 27.6 mL / min, and charged into a separable flask via a droplet generator. At the same time, 500.0 g of a dispersion medium consisting of 133 g of 3 wt% PVA aqueous solution, 7.39 g of 6 wt% NaNO ₂ aqueous solution and 3859 g of water is supplied to the column from the dispersion medium tank, and is separable via a droplet generator. The flask was charged.

  At this time, the monomer mixture was subjected to mechanical vibration with a constant frequency (500 Hz) and an intensity of 0.14 G by a vibrator. The liquid column of the monomer mixture ejected from the nozzle hole is divided by the mechanical vibration to form droplets of uniform diameter in the dispersion medium in the column, and into the separable flask together with the dispersion medium supplied at the same time. Sent. The contents of the separable flask were held at 65 ° C. for 7 hours under a nitrogen atmosphere to polymerize the droplets. The contents of the separable flask were cooled to room temperature without charging the monomer mixture for shell formation.

  Thereafter, the same operation as in Example 1 was performed to obtain crosslinked polymer particles having a uniform particle size of about 600 μm in which 80% by volume or more of the particles were in the range of 0.9 to 1.1 times the volume average particle size. .

  Hereinafter, evaluation of the obtained crosslinked polymer particles was performed in the same manner as in Example 1.

  Elemental analysis was performed in the same manner as in Example 1, and the N content in the dry weight of the crosslinked polymer particles was determined to be 11.0% by weight. Further, the ratio of TAIC units to the total polymerization units constituting the crosslinked polymer particles was calculated to be 65.2% by weight.

  XPS analysis was performed in the same manner as in Example 1, and the surface N concentration was determined to be 10.5 at%. Further, when the ratio of TAIC units on the surface of the crosslinked polymer particles was determined, it was 61.6% by weight.

  A column with a mesh diameter of 150 μm at the inlet and outlet is filled with 7.3 mL of the particles whose water content has been replaced with physiological saline in a 10 mm inner diameter column, and 55 mL of heparin-added physiological saline is circulated to perform the priming operation. went. 200 mL of fresh blood of a healthy person to which heparin was added was placed in a 37 ° C. water bath, and this was used as a blood pool to allow blood to pass through the column at a rate of 1.0 mL / min for 25 minutes in one pass. During that time, there was no clogging of the column or a decrease in flow rate. A small amount of blood was sampled from the column inlet side and the outlet side, and the number of blood cells was measured using a blood cell counter. As a result, the red blood cell and white blood cell passage was good, but the platelet passage was poor.

  On the other hand, in a batch experiment, the particles were 0.5 mL in sedimentation volume, and IL-6, which is one of inflammatory cytokines, was added to human serum to obtain an initial concentration of 859 pg / mL. When the adsorption rate was determined by contact for a time, it was 79.2%. In order to examine non-specific adsorption, the adsorption rate of albumin from human plasma having an initial concentration of 3.0 g / dL under the conditions of IL-6 batch experiment was 0.0%.

(Comparative Example 3)
A 2 L separable flask having a stirring blade was charged with 378.2 g of water, 1.75 g of a 3 wt% aqueous solution of sodium alpha olefin sulfonate, and 120.0 g of a 10 wt% slurry of particulate calcium triphosphate, and gently stirred. I was allowed to.

Production of droplets for forming core particles was carried out in the same manner as in Example 1. From the monomer mixture tank for core particle formation, 100 parts by weight of vinyl acetate, 70 parts by weight of TAIC, 182 parts by weight of ethyl acetate, 35 parts by weight of heptane, 3.6 parts by weight of polyvinyl acetate (average polymerization degree 400), V -400.0 g of a monomer mixture consisting of 5.7 parts by weight of -65 was supplied to the nozzle at a rate of 27.6 mL / min, and charged into a separable flask via a droplet generator. At the same time, 500.0 g of a dispersion medium consisting of 133 g of 3 wt% PVA aqueous solution, 7.39 g of 6 wt% NaNO ₂ aqueous solution and 3859 g of water is supplied to the column from the dispersion medium tank, and is separable via a droplet generator. The flask was charged.

  At this time, the monomer mixture was subjected to mechanical vibration with a constant frequency (500 Hz) and an intensity of 0.14 G by a vibrator. The liquid column of the monomer mixture ejected from the nozzle hole is divided by the mechanical vibration to form droplets of uniform diameter in the dispersion medium in the column, and into the separable flask together with the dispersion medium supplied at the same time. Sent. The contents of the separable flask were held at 65 ° C. for 5 hours under a nitrogen atmosphere to polymerize the droplets. Next, the stirring speed was increased and the mixture was vigorously stirred, and 100 parts by weight of vinyl acetate as a monomer mixture for shell formation, 11 parts by weight of TAIC, 111 parts by weight of ethyl acetate, 30 parts by weight of heptane, polyvinyl acetate (average polymerization) Degree 400) 100.0 g of a monomer mixture consisting of 2.7 parts by weight and 4.2 parts by weight of V-65 was charged from the upper nozzle of the separable flask. Polymerization was further carried out by maintaining at 65 ° C. under a nitrogen atmosphere for 5 hours after the addition.

  The contents of the separable flask were then cooled to room temperature.

  Thereafter, the same operation as in Example 1 was performed to obtain crosslinked polymer particles having a uniform particle size of about 450 μm, in which 80% by volume or more of the particles were in the range of 0.9 to 1.1 times the volume average particle size. .

  Hereinafter, evaluation of the obtained crosslinked polymer particles was performed in the same manner as in Example 1.

  Elemental analysis was performed in the same manner as in Example 1, and the N content in the dry weight of the crosslinked polymer particles was determined to be 11.0% by weight. The ratio of TAIC units to the total polymer units constituting the crosslinked polymer particles was calculated to be 64.9% by weight.

  XPS analysis was performed in the same manner as in Example 1, and the surface N concentration was determined to be 9.7 at%. The ratio of TAIC units on the surface of the crosslinked polymer particles was determined to be 56.8% by weight.

  A column with a mesh diameter of 150 μm at the inlet and outlet is filled with 6.5 mL of the particles whose water content has been replaced with physiological saline in a sedimentation volume, and 55 mL of heparin-added physiological saline is circulated to perform the priming operation. went. 200 mL of fresh blood of a healthy person to which heparin was added was placed in a 37 ° C. water bath, and this was used as a blood pool to allow blood to pass through the column for 25 minutes at a rate of 1.3 mL / min. During that time, there was no clogging of the column or a decrease in flow rate. A small amount of blood was sampled from the column inlet side and the outlet side, and the number of blood cells was measured using a blood cell counter. As a result, the red blood cell and white blood cell passage was good, but the platelet passage was poor.

  On the other hand, in a batch experiment, the particles were 0.5 mL in sedimentation volume, and 5.5 mL of an initial concentration of 659 pg / mL by adding IL-6, which is one of inflammatory cytokines, to human serum was stirred at 37 ° C. with stirring. When the adsorption rate was determined by contact for a time, it was 67.2%. In order to examine non-specific adsorption, the adsorption rate of albumin from human plasma of albumin having an initial concentration of 2.9 g / dL was 0.0% under the conditions of a batch experiment of IL-6.

  The characteristics and evaluation results of the crosslinked polymer particles are shown in Tables 1-2.

Claims (11)

Cross-linked polymer particles containing vinyl alcohol units and nitrogen-containing polymer units as components , and forming droplets of a monomer mixture containing a vinyl compound having a carboxylic acid vinyl ester and a triazine ring in a dispersion medium, After the droplets are polymerized to obtain core particles, a monomer mixture different from the monomer mixture is charged into the dispersion medium containing the core particles to be polymerized so as to be core / shell particles. Surface nitrogen concentration specified by X-ray photoelectron spectroscopic analysis on the particle surface is 3.0 to 9.5 at%, and in dry weight specified by elemental analysis. Crosslinked polymer particles having a nitrogen content of 10.0 to 18.0% by weight relative to the total weight of the particles. Cross-linked polymer particles comprising a synthetic polymer containing vinyl alcohol units and nitrogen-containing polymer units as constituents , wherein droplets of a monomer mixture containing a vinyl compound having a carboxylic acid vinyl ester and a triazine ring are dispersed in the dispersion medium After forming the core and polymerizing the droplets to obtain the core particles, a monomer mixture different from the monomer mixture is put into the dispersion medium containing the core particles, and the core-shell particles It is polymerized so that the process, obtained by modifying the proportion of polymerized units containing nitrogen in crosslinked polymer particle surface is 20.0 to 55.0 wt%, constituting the crosslinked polymer particles Crosslinked polymer particles in which the ratio of polymerized units containing nitrogen to all polymerized units is 60.0 to 95.0% by weight.   The ratio of the polymerized units containing nitrogen to the total polymerized units constituting the crosslinked polymer particles is lower than the ratio to the total weight of the particles, the ratio on the particle surface is low, and the ratio of the polymerized units containing nitrogen to the total weight of the particles; The crosslinked polymer particle according to claim 1 or 2, wherein the difference from the ratio on the particle surface is 10.0 to 75.0% by weight.   A part or all of the carboxylic acid vinyl ester units of a crosslinked polymer containing a carboxylic acid vinyl ester unit obtained by polymerization of a monomer mixture containing a vinyl compound having a carboxylic acid vinyl ester and a triazine ring. The crosslinked polymer particle according to claim 1, which is formed by hydrolysis and / or transesterification. The crosslinked polymer particle according to claim 4, wherein the polymerization conversion of the carboxylic acid vinyl ester in the polymerization of the monomer mixture containing the carboxylic acid vinyl ester and the vinyl compound having a triazine ring is 10 to 80%. The volume average particle diameter of the crosslinked polymer particles is 50 to 3000 µm, and 80 volume% or more of the particles have a volume average particle diameter of 0.8 to 1.2 times the volume average particle diameter. The crosslinked polymer particle in any one. The cross-linked polymer particles according to any one of claims 1 to 6, wherein the volume average particle diameter is 150 to 3000 µm, and the number of particles having a particle diameter of less than 100 µm is 5% by volume or less. A regular vibration disturbance is applied to the liquid column of the monomer mixture ejected from the nozzle hole into the dispersion medium to form droplets of uniform diameter in the dispersion medium, and then the droplets are joined or added. The crosslinked polymer particle according to any one of claims 1 to 7, wherein the core particle is obtained by polymerizing under a condition that does not cause excessive dispersion. Body fluid treatment material consisting of cross-linked polymer particles according to any one of claims 1-8. After forming droplets of the monomer mixture in the dispersion medium and polymerizing the droplets to obtain core particles, a single amount different from the monomer mixture in the dispersion medium containing the core particles The method for producing crosslinked polymer particles according to any one of claims 1 to 8, wherein a body mixture is introduced and polymerized so as to be core / shell particles. A regular vibration disturbance is applied to the liquid column of the monomer mixture ejected from the nozzle hole into the dispersion medium to form droplets of uniform diameter in the dispersion medium, and then the droplets are joined or added. the process according to claim 1 0, wherein for Do dispersed polymer core particles under conditions that do not cause.