WO1998030620A1 - Particules cellulosiques, objets spheriques comportant des particules de polymere reticule et agent adsorbant de purification de fluides corporels - Google Patents
Particules cellulosiques, objets spheriques comportant des particules de polymere reticule et agent adsorbant de purification de fluides corporels Download PDFInfo
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- WO1998030620A1 WO1998030620A1 PCT/JP1998/000015 JP9800015W WO9830620A1 WO 1998030620 A1 WO1998030620 A1 WO 1998030620A1 JP 9800015 W JP9800015 W JP 9800015W WO 9830620 A1 WO9830620 A1 WO 9830620A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/22—After-treatment of expandable particles; Forming foamed products
- C08J9/228—Forming foamed products
- C08J9/236—Forming foamed products using binding agents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/245—Differential crosslinking of one polymer with one crosslinking type, e.g. surface crosslinking
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
- C08J7/02—Chemical treatment or coating of shaped articles made of macromolecular substances with solvents, e.g. swelling agents
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
- C08J9/36—After-treatment
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2207/00—Foams characterised by their intended use
- C08J2207/12—Sanitary use, e.g. diapers, napkins or bandages
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2301/00—Characterised by the use of cellulose, modified cellulose or cellulose derivatives
- C08J2301/02—Cellulose; Modified cellulose
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- Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
- Y10S530/81—Carrier - bound or immobilized peptides or proteins and the preparation thereof, e.g. biological cell or cell fragment as carrier
- Y10S530/812—Peptides or proteins is immobilized on, or in, an organic carrier
- Y10S530/813—Carrier is a saccharide
- Y10S530/814—Cellulose or derivatives thereof
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Definitions
- the present invention relates to a cellulosic particle body and a method for producing the same, a spherical body composed of crosslinked polymer particles interconnected with an organic binder composed of a non-crosslinked polymer, and a method for producing the same.
- the present invention relates to a body fluid purifying adsorbent that removes a target substance at a high speed when a body fluid purifying method is performed in the treatment of diseases and immune-related diseases.
- Cellulose-based particles and spheres composed of cross-linked polymer particles include bacteria, immobilized carriers for enzymes, carriers for adsorption of perfumes and chemicals, carriers for body fluid purification, cosmetic additives, fillers for chromatography, etc. In addition, it is widely used in various fields as various ion exchangers by introducing various functional groups.
- JP-A-63-95001 discloses that a fine particle dispersion is prepared by mixing an anionic water-soluble compound with a mixture of viscose and a water-soluble polymer compound, and heating or coagulating the mixture. coagulated by the use of agents, after regeneration with an acid, coagulation, regeneration, to remove the water-soluble polymer by passing through a higher E washing, average particle size 3 X 1 0- 4 m below , hole diameter 2 X 1 0- to a ⁇ 8 X 1 0- 7 m section has a maximum value of the pore volume, the total pore volume of the pores in the interval 2 5 X 1 0 -. 5 m 3 Z kg A method for obtaining the above porous microcellulose-based particles is disclosed. Particles obtained by this method have fine pores in the microcellulose-based particles themselves.
- Japanese Patent Application Laid-Open No. 63-92,602 discloses that a fine particle dispersion of viscose containing calcium carbonate is prepared by mixing viscose, calcium carbonate and a water-soluble anionic polymer compound. There is disclosed a method of solidifying and neutralizing this, and then acid-decomposing calcium carbonate to obtain porous spherical cellulose-based particles.
- the obtained cellulosic particles are relatively granular. Due to the small diameter, when such cellulosic particles are used in applications such as fillers and adsorbents, it is difficult to process large quantities at high flow rates. Then, the cellulose-based particles could be broken. In addition, when such cellulosic particles are used for body fluid treatment, blood cells may be clogged.
- an adsorber filled with an adsorbent in which a substance having an affinity for a target substance in body fluid is immobilized on a carrier is used as a method of removing and treating substances present in body fluid.
- a body fluid purification method of passing a body fluid to adsorb and remove a target substance has been used. Initially, a method was used in which whole blood was passed through activated carbon, particularly coated activated carbon particles, to adsorb and remove the target substance.
- various adsorbers for adsorbing and removing the target substance from the separated plasma have been developed.
- the dynamic adsorption performance is the magnitude of the adsorption speed.
- As a method for increasing the dynamic adsorption performance it is conceivable to increase the dynamic adsorption performance by optimizing the particle diameter of the adsorbent divided by the intraparticle diffusion coefficient of the target substance.
- the first method is to increase the dynamic adsorption performance by reducing the particle size of the adsorbent to reduce the diffusion distance.But when the particle size of the adsorbent is reduced, the body fluid flows Since the path diameter becomes smaller and the pressure loss increases, it may cause clogging. Therefore, considering safe treatment, it is impossible to make the particle diameter extremely small. Indeed, the particle size of conventional adsorbents, if for plasma perfusion 5 0 X 1 0- 6 m or 1 0 0 0 X 1 0- 6 below m, if 1 0 0 x 1 0, particularly for direct hemoperfusion 8 m or more 4 0 0 0 were less than x 1 0- 6 ⁇ .
- the second method that is, a method for increasing the diffusion coefficient of the target substance in the adsorbent and rapidly increasing the dynamic adsorption performance in order to quickly move the target substance in the adsorbent, the force: For this reason, this method also has its limitations.
- the dispersion coefficient has a constant value depending on the structure of the adsorbent, it is necessary to devise a structure of the adsorbent.
- the diffusion coefficient of the target substance in the adsorbent does not exceed the diffusion coefficient in body fluids without steric hindrance, and this method has limitations.
- the dynamic adsorption performance of the adsorbent As a measure of the dynamic adsorption performance of the adsorbent, a breakthrough curve that represents the change over time in the concentration of the target substance at the outlet of the adsorber when a solution containing the target substance at a constant concentration is passed at a constant speed is used.
- the linear velocity in the adsorber refers to the moving velocity (mZs) of the mobile phase passing through the adsorber.
- the number of theoretical plates is generally used as an index indicating the performance of a column packed with a carrier on which no substance is adsorbed (carrier packed column).
- the number of theoretical plates means the minimum column height required for the target substance to reach the adsorption-desorption equilibrium when the solution containing the target substance is passed through the column packed with the carrier. This is the number of stacks, assuming that the stacks are stacked.
- C is the concentration of the target substance at the outlet of the adsorber [kgZm 3 ], which changes with time.
- C. Is the concentration [kg gm 3 ] of the target substance flowing into the adsorber and is constant.
- V is the volume of the adsorber or the volume [m 3 ] of the column packed with the carrier, and is constant.
- q. The C. C. It is called equilibrium adsorption amount [kg / m 3 ]. A solution with a concentration of 1 is passed through the adsorber, and the amount adsorbed until the amount of adsorption no longer increases is constant.
- F is the flow rate of the solution [m 3 / sec], which is set to be the same as the linear velocity in the adsorber during use, and is constant.
- N is the theoretical plate number, but is a value obtained for the target substance when the solution is passed through the column filled with the carrier at the same flow rate F as when the solution is passed through the adsorber, and is constant.
- You. t— is the average residence time of the target substance in the column [sec].
- ⁇ is the ratio of t to t.
- ⁇ is a parameter that indicates the efficiency of the adsorption amount of the adsorbent.
- Fig. 1 was calculated by adding appropriate numerical values to the above equations.
- the theoretical plate number of a column packed with a carrier is determined by the minimum column height (the height equivalent to the theoretical plate) required for the target substance to reach the adsorption-desorption equilibrium and the height of the column packed with the carrier. expressed.
- L [m] is the height of the column packed with the carrier
- H ETP [m] is the height equivalent to the theoretical plate. Since the column length is constant, increasing the number of theoretical plates in a column packed with a carrier means reducing the height equivalent to the theoretical plate, which is the characteristic of a packed carrier. Effective adsorption performance can be improved. The number of theoretical plates depends on factors such as the shape of the container, whereas the height equivalent to theoretical plates is a characteristic that depends only on the properties of the carrier.In other words, when discussing the height equivalent to theoretical plates, A carrier-filled column having a shape different from that of the adsorber used for the curve measurement may be used. However, the linear velocities in the carrier packed column must be the same.
- particles having through-pores penetrating through the particles and sub-pores which are interconnected with the through-pores and have a smaller pore diameter than the through-pores are used as a carrier for chromatography, affinities.
- a carrier for tea chromatography and a carrier for enzyme immobilization When packed into a container as a carrier for tea chromatography and a carrier for enzyme immobilization and passed through at an appropriate linear velocity, the movement of solutes in the carrier is better than that of a carrier without conventional through-pores. (Perfection effect), and it is known that the respective tasks can be accomplished at high speed (Japanese Unexamined Patent Application Publication No. 450/0726, Japanese Unexamined Patent Application Publication No. 6-5 / 1985). No. 7 313, JP; A. B.
- the carrier has a structure in which a flow penetrates into the particles when there is a flow in the fluid, and when a flow of a liquid such as a body fluid occurs around the carrier particles, a part of the flow is caused by a pressure gradient.
- a carrier having a structure that flows through carrier particles is called a perfusion type carrier.
- the carrier having the through pores and the subpores described above is a perfusion type carrier.
- This perfusion-type support is known as a support having a height equivalent to a theoretical plate.
- the perfusion-type carrier has a height equivalent to the theoretical plate measured for the carrier due to the flow that flows through the inside of the carrier particles, compared with the conventional carrier in which the mass transfer of the target substance is only diffusion. Smaller. Therefore, an adsorber filled with an adsorbent in which a substance having an affinity for the target substance is immobilized on a perfusion-type carrier has improved dynamic adsorption performance.
- Such perfusion type carrier bar one Seputibu - Poros commercially available as a carrier of bio-system, Inc. of click port Matogurafi for one (POROS, (trade name), particle Kai 1 0 X 1 0 - 6 m , 2 0 X 1 0 - s m , 5 0 x 1 0 - 6 m) ( Kohyo flat 4 one 5 0 0 7 2 6) are known. Since this carrier is a carrier for chromatography, it needs to be in a range that does not hinder the operation of the filling solution, and its particle size is small.
- this carrier when this carrier is filled in a container and a solution as obtained from a culture tank, a slurry solution, blood, or the like is passed, clogging is likely to occur due to a small particle size. Further, the carrier, in order to path one Fuyujo down effect occurs, it is necessary to passed through the column at 2. 8 1 0- a m / s or more high linear velocity.
- a perfusion-type carrier that has a large particle size and produces a perfusion effect when passed at a low linear velocity has not been known so far.
- a cellulose-based perfusion type carrier has not been known.
- the above-mentioned poros (trade name) is a carrier in which small particles of a styrene-divinylbenzene copolymer are aggregated.
- porous particles made of a crosslinked polymer have a large specific surface area, and have been widely used as fillers for chromatographies, adsorbents, etc. for the purpose of utilizing this property.
- a linked body of the crosslinked polymer particles a minute space can appear between the linked crosslinked polymer particles.
- various functions that cannot be obtained by using the crosslinked polymer particles alone can be exhibited.
- a method for producing a spherical body or an aggregate in which voids are present between the crosslinked polymer particles by connecting the bridge polymer particles to each other to form a substantially spherical body or an aggregate includes the following: There are technologies like:
- Japanese Patent Application Laid-Open No. 9-250303 discloses a method in which a monomer is polymerized on the surface of crosslinked polymer particles and the particles are connected to each other by a polymerization reaction. That is, the crosslinked polymer particles are dispersed in a dispersion containing a monomer, polyvinyl alcohol, and the like, and the monomer is penetrated into the crosslinked polymer particles. In this method, polymer particles are connected to each other.
- the above method requires a complicated operation of polymerization in order to link the crosslinked polymer particles in the polymerization process, and limits the particle size of the kebashi polymer particles that can be linked (at most 100 X 10 ⁇ m), and the polymerized monomer covers the entire surface of the crosslinked polymer particles, impairing the original function of the particles. There was a problem that the crosslinked polymer particles could not be reused from the body.
- An object of the present invention is to provide a carrier and an adsorbent that can solve the above-mentioned problems.
- an object of the present invention is to provide a cellulosic particle which can be processed at a high flow rate, has excellent mechanical strength, and has a large surface area, and a method for producing the same.
- an object of the present invention is to provide a cellulosic particle which can increase the particle size and which can produce a perfusion effect even when passed at a relatively low linear velocity, and a method for producing the same. There are also things to offer.
- the object of the present invention is to provide a linked body of crosslinked polymer particles in which a minute space exists between the crosslinked polymer particles. (1) It is produced by a simpler operation than before. (2) there is less restriction on the particle size of the linked crosslinked polymer particles than before, and (3) the surface of the crosslinked polymer particles has a portion that is not covered with the polymerized monomer, (4) Another object of the present invention is to provide a conjugate that allows the crosslinked polymer particles to be reused from the conjugate after use.
- Another object of the present invention is to shorten the treatment time while maintaining the amount of adsorption. Another object of the present invention is to provide a body fluid purifying adsorbent capable of removing a target substance at a high speed.
- the present invention provides a cellulosic particle composed of cellulosic small particles, wherein the cellulose small particles are connected to each other, and wherein there are voids between the cellulosic small particles, and
- the method for producing cellulosic particles comprising dispersing cellulosic small particles in an alkaline solution to form a suspension, and bringing the suspension into contact with a coagulating liquid.
- the first invention c is a perfusion-type cellulosic particle body, wherein porous small cellulose particles are dispersed in an alkaline solution.
- a perfusion type cellulose formed by connecting the above-mentioned small cellulosic particles to each other so as to form a suspension and bringing the above-mentioned suspension into contact with a coagulating liquid to form voids between the above-mentioned small cellulosic particles.
- a perfusion-type cellulose-based particle comprising dispersing porous cellulose-based particles in an alkaline solution to form a suspension, and bringing the suspension into contact with a coagulating liquid.
- this is referred to as a second present invention.
- the present invention further particle size 0 1 X 1 0 -. 6 ⁇ 1 0 X 1 0 standard deviation of particle size distribution _ 3 m is less than or equal to 1 0 0% of the average particle diameter of crosslinked polymer particle from configured, a spheroid particle diameter of 1 X 1 0- & ⁇ 1 0 0 X 1 0- 3 m, satisfies the following (a) ⁇ (C), comprising a crosslinked polymer particle It is also a sphere.
- the surface of the crosslinked polymer particles has a portion that is exposed without being covered with the organic binder.
- the present invention further also having a particle size 0 ⁇ X 1 0 -. 6 ⁇ 1 0 X 1 0- 3 standard deviation of the particle size distribution in m is not more than 1 0 0% of the average particle size of the crosslinked polymer
- the organic binder is added to an organic solvent that does not dissolve the above-mentioned crosslinked polymer particles and dissolves an organic binder composed of a non-crosslinked polymer. 1 o Immerse in the solution in which the mixture is dissolved, then volatilize the organic solvent with stirring, and connect the crosslinked polymer particles to each other via the organic binder precipitated on the surface of the crosslinked polymer particles.
- a method for producing the spherical body is a method for producing the spherical body.
- the above-mentioned spherical body may be a substantially spherical body, and in addition to a substantially spherical shape, an ellipsoidal shape having a minor axis Z ratio of up to about 0.7, such as a rotating body, is also included. Include. This is referred to as a third present invention in the present specification.
- the present invention further provides a body fluid purifying adsorbent obtained by immobilizing a substance having an affinity for a target substance on a perfusion-type carrier, a body fluid purifying adsorber filled with the adsorbent, and a body fluid purifying adsorbent. It is also a body fluid purifying method for purifying body fluid using a purifying adsorber. In this specification, this is referred to as a fourth present invention.
- Figure 1 shows the effect of the number of theoretical plates on the breakthrough curve.
- Figure 2 is a graph showing the time course of the adsorption amount with respect to q D.
- FIG. 3 is a photograph in which the particle surface of the cellulose-based particles of Example 1 is magnified 100 times.
- FIG. 4 is a photograph of the particle cross section of the cellulosic particles of Example 1 magnified 100 times.
- FIG. 5 is a photograph in which the particle cross section of the cellulosic particle of Example 1 is enlarged to 1000 times.
- FIG. 6 is a photograph in which the particle cross section of the cellulosic particle of Example 1 is magnified 50,000 times.
- FIG. 7 is a photograph in which the particle surface and cross section of the cellulose-based particles of Example 3 are magnified 100 times.
- FIG. 8 is a photograph in which the particle surface and cross section of the cellulose-based particles of Example 3 are magnified 200 times.
- FIG. 9 is a photograph obtained by enlarging the particle surface of the cellulose-based particles of Example 3 by 1000 times.
- FIG. 10 shows the particle cross section of the cellulosic particles of Example 3 magnified 500 times. It is a photograph.
- FIG. 11 is a photograph of the particle surface of the cellulose-based particles of Example 6 magnified 40 times.
- FIG. 12 shows a photograph J ′ in which the particle cross section of the cellulose-based particles of Example 6 is magnified 40 times.
- FIG. 13 is a photograph in which the particle cross section of the cellulose-based particles of Example 6 is magnified 500 times.
- FIG. 14 is a photograph obtained by enlarging the particle cross section of the cellulose-based particles of Example 6 by a factor of 5,000.
- FIG. 15 is a photograph in which the particle surface of the cellulose-based particles of Example 7 is magnified 200 times.
- FIG. 16 is a photograph in which the particle surface of the cellulose-based particle of Example 7 is magnified 1000 times.
- FIG. 17 is a photograph in which the particle surface of the cellulose-based particle of Example 7 is magnified 50,000 times.
- FIG. 18 shows an elution curve of low-density lipoprotein based on Comparative Example 5.
- FIG. 19 shows an elution curve of the low-density lipoprotein based on Example 8.
- FIG. 20 is a photograph in which the particle surface of the spherical body of Example 9 is magnified 12 times.
- FIG. 21 is a photograph in which the particle surface of the spherical body of Example 9 is magnified 200 times.
- FIG. 22 is a photograph in which the surface of the carrier of Example 10 is magnified 200 times.
- FIG. 23 is a photograph in which the surface of the carrier of Example 10 is magnified 50,000 times.
- FIG. 24 is a photograph in which the cross section of the carrier of Example 10 is magnified 200 times.
- FIG. 25 is a photograph obtained by enlarging the cross section of the carrier of Example 10 to 500 times.
- FIG. 26 shows the elution curve of the low-density lipoprotein based on Reference Example 2.
- FIG. 27 shows the elution curve of the low-density lipoprotein based on Comparative Reference Example 3. 1 z
- the small cellulosic particles are composed of cellulosic materials such as cellulose, cellulose derivatives, and regenerated cellulose.
- the cellulose is not particularly limited, and examples thereof include defatted cotton fibers, hemp, pulp obtained from wood, and purified cellulose obtained by purifying pulp.
- the cell mouth derivative is not particularly limited, and examples thereof include those in which some of the hydroxyl groups of cellulose are esterified (ester derivatives); those in which the hydroxyl groups of cellulose are etherified (ether derivatives). Can be.
- the cellulose ester derivative is not particularly limited, and examples thereof include cellulose acetate, cellulose propionate, nitrocellulose, cellulose phosphate, cellulose acetate butyrate, cellulose nitrate, cellulose dithiocarboxylate (viscose rayon) and the like. Can be mentioned.
- the ether derivative of the above cellulose is not particularly limited. Examples thereof include methylcellulose, ethylcellulose, benzylcellulose, tritylcellulose, cyanoethylcellulose, carboxymethylcellulose, carboxylethylcellulose, aminoethylcellulose, and oxice. Chill cellulose and the like.
- the above-mentioned regenerated cellulose is obtained by converting the above-mentioned cellulose once into a cellulose derivative which is easy to mold, and then, after molding, is converted into cellulose again.
- cellulose esters such as cellulose acetate and cellulose propionate are used. Examples thereof include those prepared by hydrolyzing derivatives and the like.
- the small cellulosic particles may be porous or non-porous, but are preferably porous. When the cellulosic small particles are porous, the surface area with respect to the volume of the cellulosic particles can be further increased.
- cellulosic small particles examples include gel filtration agents, raw materials for cellulosic ion exchangers, affinity chromatography carriers, polymer carriers, and body fluid purification. Conventionally used carriers such as chemical carriers and cosmetic additives can be used.
- the production of the above-mentioned cellulose-based small particles can be carried out by a known method.
- the above-mentioned porous cellulose-based small particles are disclosed in JP-A-63-9501, JP-A-63-9501. It can be manufactured by a method disclosed in, for example, Japanese Patent Application Laid-Open No. 9-260202. Specifically, for example, it can be produced by the following method or the like.
- An aqueous polymer solution containing a cellulose zirconate and a water-soluble polymer compound is mixed with a water-soluble anionic polymer compound to prepare a fine particle dispersion of the water-soluble polymer solution.
- the dispersion is heated, or mixed with a coagulant of cellulose xanthate to coagulate the cellulose xanthate in the dispersion as fine particles.
- the fine particles of cellulose xanthate contain a water-soluble polymer compound, they are removed.
- the cellulose fine particles of cellulose xanthate are neutralized with an acid to regenerate the cellulose, thereby obtaining desired small cellulosic particles.
- coagulating the fine particles of cellulose xanthate in addition to the above, it can be performed by adding an acid to the dispersion. In this case, after removing the water-soluble high molecular compound, the added acid is neutralized to regenerate the cellulose, thereby obtaining the desired small cellulosic particles.
- Viscose, calcium carbonate and a water-soluble anionic polymer compound are mixed to form a fine particle dispersion of viscose containing calcium carbonate, and the above dispersion is heated or a coagulant is mixed. By doing so, the viscose in the dispersion is coagulated, and then neutralized with an acid to produce cellulose fine particles. Thereafter, the cellulose fine particles are separated from the dispersion, and calcium carbonate is removed by acid decomposition, followed by drying to obtain the desired small cellulose particles.
- the average particle size of the cellulose-based fine particles, 1 X 1 0- 6 ⁇ 5 0 0 X 1 0- 6 m is preferred arbitrariness. If it is less than 1 X 1 0- 6 m, it is difficult to provide a sufficient gap between the particles of the cellulosic small particles constituting the cellulosic particle body, Exceeding 5 0 0 X 1 0- 6 m However, since the self-weight of the cellulosic small particles is large, the cellulosic small particles constituting the cellulosic particle body of the present invention may not be able to be maintained while being connected to each other. Preferably, a 5 X 1 0 one 6 ⁇ 1 0 0 X 1 0- 6 m.
- Cellulosic particle body of the first aspect of the present invention is to provide an air gap between the particles of the cellulose-based fine particles, c the void is made in mutually by connecting the cellulose-based fine particles, the first This is a void formed inside the cellulosic particles of the present invention, whereby the cellulosic particles can have many fine pores on the surface and inside.
- the cellulosic particles of the first aspect of the present invention are preferably formed by interconnecting cellulosic small particles in the presence of a binder.
- the present inventors have found that the strength of the cellulose-based particles of the present invention is significantly increased by interposing a binder between the above-mentioned small cellulose-based particles, as compared with the case where no binder is used. It is an advantage of using a binder that the strength can be adjusted by adjusting the amount of the binder.
- the binder is not particularly limited, and examples thereof include an organic compound, an inorganic compound, an organic synthetic low molecule, an inorganic synthetic low molecule, an organic natural low molecule, an inorganic natural low molecule, an organic synthetic polymer, an inorganic synthetic polymer, and an organic synthetic polymer.
- examples include natural polymers and inorganic natural polymers.
- the inorganic compound is not particularly limited, and for example, a compound that generates a three-dimensional network structure by contact with a coagulating liquid can be used.
- a material includes, for example, water glass.
- the water glass generally refers to a concentrated aqueous solution of sodium or potassium oxide and silicon dioxide. This solution reacts with various metal salts, and precipitates grow in the solution.
- Cellulose-based small particles and water glass (used as a binder) are dispersed in an alkaline solution, and the above suspension is converted to an aqueous solution of a metal salt.
- the inorganic synthetic polymer is not particularly limited, and examples thereof include inorganic polymer flocculants such as polyaluminum chloride, polyaluminum sulfate, ferric chloride, and ferric polysulfate.
- the organic synthetic polymer is not particularly limited, and examples thereof include organic polymer flocculants such as polyacrylonitrile, polyacrylamide, sodium polyacrylate, and acrylic acid-acrylamide copolymer.
- the organic natural polymer is not particularly limited, and examples thereof include a cellulosic substance, Starch-based substances, alginic acid-soluble salts and the like.
- a substance having a functional group capable of hydrogen bonding to a hydroxyl group in a cellulose molecule or a cellulose derivative molecule is preferable, and a substance having a chemical structure similar to that of cellulose is more preferable.
- Specific examples include cellulose-based substances, starch-based substances, and alginic acid-soluble salts. These have a chemical structure similar to that of cellulose, and have a glucose structure similar to that of cellulose and a hydroxyl group attached thereto, so that they can form hydrogen bonds with the hydroxyl groups of cellulose molecules or cellulose derivative molecules.
- these will be described in detail.
- the cellulosic substance may be the same as or different from the cellulosic molecules such as cellulose, cellulose derivative, regenerated cellulose, etc. constituting the cellulosic small particles.
- the cellulose is not particularly limited, and those described above can be used.
- the cellulose derivative is not particularly limited, and those described above can be used.
- the regenerated cellulose is not particularly limited, and those described above can be used.
- the above-mentioned starch-based substance is not particularly limited.
- starch esters such as starch acetate, succinate ester, nitrate ester, phosphate ester, xanthate ester; starch aryl ether, methyl ether, carboxymethyl ether And starch ethers such as carboxyethyl ether, hydroxyquinethyl ether and hydroxypropyl ether; degradation products of natural starch such as roasted dextrin and oxidized starch.
- the baked dextrin is not particularly limited, and examples thereof include white dextrin, yellow dextrin, and pretty gum.
- the oxidized starch is not particularly limited, and includes, for example, oxidized starch hypochlorite, starch starch and the like.
- the alginic acid-soluble salt is not particularly limited, and includes, for example, sodium alginate.
- the aqueous solution of the alginate-soluble salt forms an insoluble salt upon contact with an aqueous solution of a divalent or higher valent metal salt excluding magnesium ions and mercury ions. Since this insolubilization occurs instantaneously, the droplets of the aqueous salt solution of alginic acid
- An insoluble salt can be easily formed by dropping into an aqueous solution of a divalent metal salt such as lucium.
- a cellulosic small particle and the above-mentioned alginic acid-soluble salt (used as a binder) are dispersed in an alkaline solution to form a suspension, and the suspension is a divalent or higher-valent metal salt excluding magnesium ions and mercury ions.
- binders may be used alone or in combination of two or more, including the above-mentioned cellulose-based substances and starch-based substances.
- a binder that is a covalent conjugate of two or more molecules constituting the binder can be used.
- the copolymer of the organic synthetic polymer and the organic natural polymer includes, for example, acrylamide carboquine methylcellulose graft polymer and the like.
- the mode in which the above-mentioned cellulosic small particles are connected to each other does not necessarily have to be formed by a covalent bond, and it is possible to substantially stably maintain a connected state between the particles. Any condition is acceptable as long as it can be performed. That is, examples of the mode of connecting the cellulosic small particles to each other include, in addition to the above-mentioned covalent bond, for example, a connection by entanglement of a cellulose molecule or a cellulose derivative molecule, a connection by a chemical bond such as a hydrogen bond, and the like.
- the above-mentioned cellulose has a structure in which D-glucoviranose is linked by 31 ⁇ 4 glucosidic bonds, and has three hydroxyl groups per glucose unit in the main chain. It is presumed that hydrogen bonds are formed between and within the molecule, and also between acetal oxygens. In the case of the above-mentioned cellulose derivatives, it is considered that unsubstituted hydroxyl groups have the same effect.
- cellulosic particles are formed by mutually connecting cellulosic small particles in the presence of a binder
- connection between the cellulosic small particles and the binder by entanglement of molecules, cellulose It also includes the connection between the small system particles and the binder by a chemical bond such as a hydrogen bond.
- the state of the above (3) may be included.
- structures having other shapes are binders.
- the space formed between the small particles in any one of the three connected states described above is a space between the small cellulose particles in the cellulose particle body of the present invention.
- the average particle size of the cellulose-based particles of the present invention is preferably from 10 ⁇ 10 to 500 ⁇ 10 6 m, and is appropriately set according to the use.
- the average particle size of the cellulose-based fine particles if it is 1 X 1 0- 6 m or more, cellulosic particles body formed by coupling the cellulose-based fine particles, stable in 1 0 X 1 0 m or more It can be a particle. If it is less than 1 0 X 1 ⁇ — ⁇ ⁇ , the number of connection points is small and the particles are easily broken, so that the particles may not exist stably.
- the specific surface area of the above-mentioned cellulosic particles at the time of drying is preferably 2 ⁇ 10 4 m 2 / kg or more. If it is less than 2 ⁇ 10 4 m 2 g, the working area for the purpose will be small. More preferably, it is 5 X 1 (m 2 kg or more.)
- the shape of the cell opening-based particles is a cellulosic particle composed of cell opening-based small particles,
- the cellulosic small particles are not particularly limited as long as they are connected to each other so as to provide voids in the space.
- the particles may be shaped like a spheroid, and may be substantially spherical. There may be.
- the cellulose-based particles of the first aspect of the present invention are produced by dispersing the cellulose-based small particles in an aqueous solution to form a suspension, and bringing the suspension into contact with a coagulating liquid. be able to.
- the alkaline solution is not particularly limited, and examples thereof include an aqueous solution of sodium hydroxide, an aqueous solution of lithium hydroxide, an aqueous solution of potassium hydroxide, an aqueous solution of cesium hydroxide, and water.
- An example is an aqueous rubidium oxide solution.
- a thickener such as glycerin may be added to the alkaline solution for adjusting the viscosity.
- the hydrogen ion concentration of the above-mentioned aqueous solution is not particularly limited as long as it is within the range of the aqueous solution, but the pH is preferably 9 or more. More preferably, the pH is 10 or more, even more preferably 12 or more. When the pH is less than 10, when the suspension in which the cell-orifice-based small particles are dispersed is brought into contact with a coagulation liquid, the above-mentioned cellulosic small particles are in a dispersed state and cannot be connected. There are cases.
- the suspension concentration of the small cellulosic particles is preferably 50 to 75% by volume.
- the suspension concentration is a ratio of the total volume of the cellulosic small particles present in the suspension to the volume of the suspension.
- the sediment obtained by filtering the suspension has a suspension concentration of 100% by volume.
- the apparent specific gravity is not much different from the specific gravity of the solution, so that the volume% is substantially equal to the weight%.
- the suspension concentration of the above-mentioned cellulose-based small particles is less than 50% by volume, when the droplets of the suspension are brought into contact with the coagulating liquid, fragmentary cellulose-based particles are obtained, and the strength is weak.
- the content exceeds 75% by volume, liquid droplets having a smooth surface cannot be obtained, and the shape of the cellulose-based particles may be massive. More preferably, it is 60 to 70% by volume.
- the suspension may be one in which small cellulosic particles and a binder are dispersed in an aqueous solution.
- the method for suspending the binder is not particularly limited. For example, a method in which the binder is previously dissolved in the alkaline solution, and then the solution or suspension is mixed with the cellulose-based small particles. And the like.
- the amount of the binder to be added cannot be unconditionally determined depending on the molecular weight of the binder, etc., but was prepared by dispersing the cellulose-based small particles and the binder in the alkaline solution. Usually, 0.01 to 50% by weight in the suspension is preferred. If the content is less than 0.01% by weight, the effect as a binder is insufficient, and it contributes to an increase in the mechanical strength of the cellulosic particles compared to the cellulosic particles using no binder. not, more than 5 0% by weight, more preferably c that may gaps exist excessively between the cellulosic small particles is eliminated, a 0.1 to 3 0 wt%, more preferably, 0.2 -20% by weight.
- the average particle size of the cellulose-based fine particle is 1 X 1 0 6 ⁇ 5 0 0 X 1 0- 6 m is the preferred, as described above, if it is within this range, ⁇ particle size 1 X 1 0 - if 6 is less than m, when applying a binding agent, enters binders in the gap cellulose-based fine particles that constitute the cellulosic particle body can be the avoidance disadvantage that fills the gap .
- the viscosity at room temperature of the suspension in which the cellulosic small particles and the binder are dispersed in the above alkaline solution is preferably 5 ⁇ 10 4 to 1 ⁇ 10 4 Pa's.
- 5 x 1 0 is less than 1 P a • s, not to easily spherical deformed when the droplets of the suspension is in contact with the coagulating liquid, 1 X 1 0 4 P a - exceeds s, When the suspension is formed into droplets, it may be difficult to deform and may not be spherical.
- the method and apparatus for measuring the viscosity is not particularly limited as long as 5 X 1 0- 4 ⁇ 1 X 1 0 1 P a ⁇ s known viscometry and viscosity measuring device the solution viscosity can be measured in the range of .
- the viscosity referred to here is the viscosity specified in JISZ880-2—19559, and when there is a shear rate (shear rate) in the liquid, the viscosity increases in the direction of the shear rate (shear rate).
- shear rate shear rate
- the internal resistance of a fluid is indicated by the magnitude of the stress generated per unit area in the direction of velocity, and its dimension is (mass) (length x time).
- the viscosity measuring device is not particularly limited, and examples thereof include a capillary viscometer, a short tube viscometer, a falling ball viscometer, a falling ball viscometer, a column falling viscometer, a coaxial cylindrical rotational viscometer, and a bubble viscometer.
- a capillary viscometer a capillary viscometer
- a short tube viscometer a falling ball viscometer
- a falling ball viscometer a falling ball viscometer
- a column falling viscometer a coaxial cylindrical rotational viscometer
- a bubble viscometer preferably used.
- cellulose or a cellulose derivative By suspending the cellulosic small particles in an alkaline solution, cellulose or a cellulose derivative is swelled as alkaline cellulose at the surface of the cellulosic small particles, and further hydrogen is added. The bond is broken, and the mobility of the cellulose molecule or cellulose derivative molecule is significantly improved. When a binder is co-present, the binder is easily taken up.
- the time for suspending the cellulosic small particles in the above-mentioned alkaline solution is preferably 1 minute or more.
- the time is less than 1 minute, it becomes difficult to swell cellulose or a cellulose derivative as alkali cellulose at the surface portion of the above-mentioned cellulose-based particles, and it is difficult to sufficiently connect the above-mentioned cellulose-based particles.
- the suspension is brought into contact with a coagulation liquid, and the cellulosic small particles are interconnected.
- the mobility of the cellulose molecules or cell derivative molecules is significantly reduced, and the entanglement or hydrogen bonding between the cellulose molecules or cellulose derivative molecules of the cellulose-based small particles is reduced. It can happen.
- the mobility of the binder is significantly reduced, and entanglement of molecules between the cellulosic small particles and the binder, hydrogen bonding, and the like may occur.
- the coagulation liquid is not particularly limited, as long as it can lose the fluidity of the above-mentioned Alli-Licellulose or the above-mentioned Alli-Licellulose and the above-mentioned binder.
- an organic solvent such as ethanol or acetone is used;
- Salt solutions such as calcium salts: inorganic acid solutions such as hydrochloric acid, sulfuric acid, phosphoric acid, etc .; organic acids such as acetic acid; solutions which are acidic solutions and have a pH value lower than the pH value of the above suspension, pure water, etc. No. These may be used alone or in combination of two or more.
- the method of bringing the suspension into contact with the coagulation liquid is not particularly limited.
- a method of dispersing the suspension in the coagulation liquid Method: A method in which the coagulation liquid is made finer, for example, in the form of a mist, and brought into contact with the suspension.
- the suspension is formed into droplets, and the droplets are brought into contact with a coagulating liquid because the average particle size of the obtained cellulose-based particles can be easily controlled. Is preferred.
- the suspension droplets when contacting the droplet to the coagulating liquid, the droplets of the suspension, it is preferred diameter is less than 5 X 1 0- 3 m. If the diameter exceeds 5 ⁇ 10 " 3 m, the effect of surface tension is reduced, and it is difficult to form droplets.
- the method for forming the above-mentioned suspension into droplets is not particularly limited. Examples of the method include a method of discharging the suspension into a gaseous phase from a capillary, a method of using a sprayer, etc. Among them, a sprayer is preferably used because a fine droplet can be obtained. Can be
- the sprayer is not particularly limited as long as it can subdivide the particle diameter of the droplets to 5 XI 0 to 3 m or less.
- a rotary disk type sprayer, a pressure nozzle type sprayer, A fluid nozzle type sprayer and the like can be mentioned.
- the rotating disk type sprayer is for flowing a solution onto a high-speed disk, shakes the solution by centrifugal force, and collides with a gas such as air to atomize the solution.
- the average particle size of the atomized droplets can be easily controlled by appropriately adjusting the solution supply speed and the rotation speed of the high-speed disk.
- the pressure nozzle type sprayer discharges a high-pressure solution from a small hole and collides the solution with a gas such as ambient air to spray the solution.
- the average particle size of the atomized droplets can be easily controlled by appropriately adjusting the solution supply rate, applied pressure, and pore diameter.
- the two-fluid nozzle sprayer atomizes the solution by blowing it off with a high-speed gas using compressed gas even if the solution itself is at a low pressure.
- the average particle size of the atomized droplets can be easily controlled by appropriately adjusting the ejection speed of the solution and the ejection speed of the compressed gas.
- the particle size of the droplets of the suspension can be relatively freely designed by appropriately selecting the above-described method for forming the droplets.
- the time for bringing the suspension into contact with the coagulating liquid is preferably 1 second or more. If the time is less than 1 second, the cellulosic small particles may not be sufficiently linked. More preferably, it is 1 minute or more.
- the cellulosic particles of the first invention have voids between the particles of the cellulosic small particles. Since it is provided, it has a large surface area with respect to the volume of the cellulosic particles, and can be suitably used as a carrier for immobilizing bacteria and enzymes, a carrier for adsorbing fragrances and chemicals, a cosmetic additive and the like. In addition, since the above-mentioned cellulose-based particles have high strength, high flow rate treatment is possible. These applications can be appropriately selected depending on the size, internal structure, and the like of the cellulosic particles of the present invention.
- cellulosic particles may be used as they are, or may be modified by filling the gaps between the cellulosic small particles with a string or organic matter, or by reacting various substances. May be used.
- the cellulosic small particles can be easily connected to each other, and voids can be provided between the particles of the cellulosic small particles.
- the average particle size of the obtained cellulose-based particles can be relatively freely adjusted depending on the application. It will be described in detail.
- the alkaline solution used in the second present invention is not particularly limited, and for example, the above-described examples and the like can be used.
- Glycerin a water-soluble polymer or the like may be added to the alkaline solution for adjusting the viscosity.
- the alkaline solution preferably has a value of ⁇ ⁇ 13 or more (solution concentration of 0.1N or more). More preferably, ⁇ 1 is 14.3 or more (solution concentration is 2N or more). If ⁇ 1 is less than 13, when the suspension containing the cellulosic small particles is brought into contact with the coagulating liquid, the above-mentioned cellulosic small particles may be in a state of being mutually dispersed and may not be linked. .
- cellulosic small particles used in the second invention for example, the cellulosic small particles described in detail above as the cellulosic small particles used in the first invention can be used.
- the cellulosic small particles according to the second aspect of the present invention are porous having a pore size according to the application.
- the porous cellulose-based small particles can be produced by the method for producing cellulose-based particles described in detail in the first aspect of the present invention.
- a perfusion-type cellulosic particle is obtained by dispersing the above-mentioned small cellulosic particles in the above-mentioned alkaline solution to form a suspension, and bringing the suspension into contact with a coagulated liquid. It can be manufactured by the following.
- the time for dispersing the above-mentioned small cellulose particles in the above-mentioned aqueous solution is preferably 1 minute or more. If the time is less than 1 minute, it may be difficult to sufficiently connect the small cellulosic particles. More preferably, it is one hour or more.
- the suspension concentration of the small cellulosic particles is preferably 50 to 75% by volume.
- the suspension concentration is the ratio of the total volume of cellulosic small particles in the suspension to the volume of the suspension.
- the suspension concentration of the above-mentioned cellulose-based small particles is less than 50% by volume, when a droplet of the suspension is brought into contact with a coagulating liquid, a fragmented cellulose-based molded product is obtained, and the strength is low.
- the content exceeds 75% by volume, liquid droplets having a smooth surface cannot be obtained, and the shape of the cellulose-based molded product may be agglomerated. More preferably, it is 60 to 70% by volume.
- the average particle size is preferably 3 XI (T 3 m or less.
- the average particle size exceeds 3 XI 0 to 3 m, the effect of surface tension is reduced, Drops are less likely to form.
- the method for forming the suspension into droplets is not particularly limited.
- the method for forming the suspension into droplets described in the first aspect of the present invention can be used.
- the coagulating liquid is not particularly limited, and for example, the coagulating liquid used in the first present invention can be the coagulating liquid described in detail above. Among these, it is preferable to use an acidic solution.
- a solution having a pH of 1 or less (solution concentration of 0.1 N or more) is preferable. More preferably, the pH is -0.3 (solution concentration is 2N or more).
- the pH exceeds 1, when the suspension containing the cellulosic small particles is brought into contact with an acidic solution as a suspension, the cellulosic small particles are in a state of being mutually dispersed, and it may be difficult to connect them.
- the acidic solution is not particularly limited, and examples thereof include an aqueous solution of hydrochloric acid, an aqueous solution of sulfuric acid, and nitric acid. Acid aqueous solution, phosphoric acid aqueous solution and the like can be mentioned.
- Glycerin a water-soluble polymer or the like may be added to the acidic solution for adjusting the viscosity.
- the method for bringing the droplets of the suspension into contact with the coagulation liquid is not particularly limited, and includes, for example, a method of immersing the droplets in the coagulation liquid; Examples of the method include contacting the droplet with the droplet.
- the time for bringing the droplets of the suspension into contact with the coagulation liquid is preferably 1 minute or more. If the time is less than 1 minute, the small cellulosic particles may not be sufficiently linked. More preferably, it is one hour or more.
- the mode in which the above-mentioned cellulosic small particles are connected to each other is not necessarily required to be formed by a covalent bond. Any state can be used as long as the state of connection can be stably maintained.
- the connection of cellulosic small particles includes a connection by entanglement of cellulose molecules between particles, a connection by a chemical bond such as a hydrogen bond, and the like.
- the average particle size of the perfusion-type cellulose-based particles is preferably such that the value of the ratio to the average particle size of the small cellulose-based particles is less than 50.
- the value of the above ratio is 50 or more, the voids between the small particles that become through pores become small, and the perfusion effect becomes small.
- the average particle size is appropriately set according to the application. Usually, it is preferable that 2 0 X 1 0- B ⁇ 3 X 1 0 3 m.
- the cellulosic particle body of the Pafuyu one John types with Takashi ⁇ the container in the case of liquid permeation of the solvent have easy jam, an average particle diameter of the particle body is not less than 1 0 0 X 1 0- 6 m
- the flow rate is preferably 3 ⁇ 10 4 mZs or more as long as clogging does not occur.
- the average particle size, 1 0 0 X 1 0 - is less than e m, clogging ease occurs no longer, and, when liquid permeation rate is less than 3 X 1 0- 4 mZs, Pafuyu one John effect And the efficiency of the target work per hour becomes poor.
- the perfusion type cellulosic particles preferably have a specific surface area when dried of at least 2 ⁇ 10 4 m 2 / kg by the BET method. 2 X 10 1 m 2 no If it is less than kg, the working area according to the application becomes small. More preferably, it is at least 5 ⁇ 10 ⁇ m 2 / kg.
- the perfusion type cellulosic particle body uses the cellulosic particle body itself described in detail above.
- the perfusion-type cellulosic particles are composed of a plurality of cellulosic small particles in which the cellulosic small particles are interconnected so as to provide voids between the particles of the cellulosic small particles.
- the voids become through pores, and the pores of the plurality of connected cellulosic small particles facing the through pores become subpores.
- the shape of the particles thereof is generally cellulosic particles of c the Pafuyu one John type a spheroidal or spherical sets according cellulosic small particles and the above-mentioned particle size ratio with a pore size on the application By doing so, it can be used for multiple purposes. For example, it can be used as a carrier for gel filtration, a raw material for cellulosic ion exchangers, a carrier for affinity chromatography, a carrier for adsorption of fragrances and chemicals, a carrier for immobilizing bacterial cells and enzymes, a carrier for purifying body fluids, etc. No.
- a porous cellulosic small particle is dispersed in an alkaline solution to form a suspension, and the suspension is converted into a coagulation liquid.
- the cellulosic small particles are connected to each other so as to provide a space between the small cellulosic particles by contact.
- the cellulosic small particles can be easily connected, and a void can be formed between the cellulosic small particles.
- a void can be formed between the cellulosic small particles.
- washing is easy, and it is very preferable in preventing environmental pollution.
- Lylic acid or methacrylic acid [hereinafter referred to as (meth) acrylic acid] and its alkyl ester derivative; vinyl acetate, vinyl pyridine and its quaternary compound; 2-acryloylamino-12-methyl-propanesulfonic acid, 2-acrylyl amide 2-vinyl sulfonic acid such as propane sulfonic acid and methacryloyl propyl sulfonic acid; vinyl cyanide compounds such as acrylonitrile and methacrylonitrile; vinyl halides such as vinyl chloride and vinyl bromide; Etc., but are not limited to these. No.
- These monomers may be used alone or in combination of two or more.However, since a polymer can be produced by any polymerization reaction such as radical polymerization, anion polymerization, and cationic polymerization, styrene is used as a monomer. It is preferable to use one component. These monomers are polymerized by a known polymerization method in the presence of a cross-linking agent to obtain a cross-linked polymer.
- the monomer has a salt functional group, for example, for a cationic group, hydrochloric acid, sulfuric acid, phosphoric acid, organic acid, etc., and for an anionic group, an alkali metal, ammonia, lower amine, alkanol Amines and the like are used as counterions, and these are used alone or in combination of two or more, but are not limited thereto.
- a salt functional group for example, for a cationic group, hydrochloric acid, sulfuric acid, phosphoric acid, organic acid, etc.
- an anionic group an alkali metal, ammonia, lower amine, alkanol Amines and the like are used as counterions, and these are used alone or in combination of two or more, but are not limited thereto.
- crosslinking agent for producing the crosslinked polymer particles examples include vinyl group, hydroxyl group, carboxyl group, amino group, pyridinium group, epoxy group, isocyanate group, mercapto group, aldehyde group, acid chloride group, and acid amine.
- polyfunctional compounds having a carboxylic acid group and the like These can be used alone or in combination of two or more. Specific examples thereof include, but are not limited to, aromatic compounds having two or more vinyl groups such as divinylbenzene, divinyltoluene, divinylxylene, and divinylnaphthalene. Incidentally, divinylbenzene is preferred from the viewpoint of high reactivity with a monomer having a vinyl group.
- the crosslinked polymer particles used in the third invention are preferably porous.
- suspension polymerization is carried out with a mixture of a monomer, a crosslinking agent, and a solvent that is a solvent of the monomer and is a non-solvent of the polymer.
- a non-solvent is removed from the precipitate to make the ghost a pore.
- Porous crosslinking The polymer particles are suitable for use as a filler for chromatography and various adsorbents in the medical field.
- the crosslinked polymer particles the particle size is 0. 1 X 1 0- 6 ⁇ 1 0 X 1 0- 3 m range, it is favored properly 1 X 1 0- & ⁇ 5 X 1 0- 3 m, more preferably is a cross-linked polymer particles is 1 0 X 1 0- 6 ⁇ 1 X 1 0- a m. 0.1 In X 1 0- s m below the crosslinked polymer particles having a particle size, since the organic binder will fill from entering gap clearance between the crosslinked polymer particles constituting the shaped body, object of the present invention Is not obtained.
- the standard deviation of the particle size distribution of the crosslinked polymer particles is 100% or less of the average particle size, preferably 50% or less. If the standard deviation exceeds 100%, the small crosslinked polymer particles themselves enter the minute space between the linked crosslinked polymer particles, and the distribution of the minute space becomes non-uniform.
- the crosslinked polymer particles cannot exhibit excellent functions that cannot be obtained by themselves and are unique to the linked body.
- the organic binder composed of a non-crosslinked polymer is a conventionally known polymer.
- the polymer composed of the monomer exemplified for the crosslinked polymer particles for example, an ethylene monoacetate copolymer and Genidized product or its chlorinated product, polyethylene and its chlorinated product, polybutadiene, polyisoprene, styrene-butadiene copolymer, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, polyurethane, polyethylene, polyethylene oxide , Polysulfone, polyamide, polyamide imide, polyimide, cellulose, cellulose acetate cell, nitrocellulose, chitosan and derivatives thereof, melamine resin, epoxy resin and derivatives thereof.
- the bonding mode of these copolymers may be any of random, block or graft copolymer.
- Examples of the organic solvent that does not dissolve the crosslinked polymer particles and dissolves the organic binder composed of the noncrosslinked polymer include ketone derivatives such as acetone, methylethylketone, and cyclohexanone; methyl acetate, and acetic acid.
- the amount used is not limited at all, but if the amount of organic solvent is too large, it will take a long time to volatilize the organic solvent after immersion, so 1-3 times the sedimentation volume of the crosslinked polymer particles A moderate volume is preferred.
- the spherical body is produced, for example, by a series of steps of 1-1 1 I below.
- Particle size 0. 1 X 1 0- 6 ⁇ 1 0 X 1 0- 3 m standard deviation of the particle size distribution of 1 0 0% or less is crosslinked polymer particles of the average particle size, the crosslinked polymer A step of immersing the organic binder in a solution in which the organic binder is dissolved without dissolving the particles and in which the organic binder comprising the non-crosslinked polymer is dissolved.
- the organic solvent is volatilized and reduced, and the crosslinked polymer particles are connected to each other via the organic binder precipitated on the surface of the crosslinked polymer particles.
- a crosslinked polymer particle, an organic binder composed of a non-crosslinked polymer, and a crosslinked polymer particle By appropriately selecting the type and amount of the organic solvent that does not dissolve the polymer and dissolves the organic binder composed of the non-crosslinked polymer, a spherical body having a desired connection strength or a crosslinked polymer particle to a desired degree can be obtained. A spherical body having a portion which is exposed without being covered with an organic binder on the surface thereof can be obtained.
- the spherical body of the present invention in which the crosslinked polymer particles are linked is obtained.
- the spherical body satisfies the following characteristics.
- the limitation on the particle size of the linked crosslinked polymer particles is smaller than in the conventional method. That is, the spheroids, the particle size 0. 1 X 1 0 _ 6 ⁇ 1 0 X 1 0 3 m standard deviation of the particle size distribution is not more than 1 0 0% of the average particle diameter of crosslinked polymer particles Although it can be produced by linking, heretofore, no example has been reported in which a spherical body was produced on the same principle for such a crosslinked polymer particle having such a wide particle size range.
- the surface of the crosslinked polymer particle has a portion not covered with the organic binder. That is, by appropriately selecting the amount of the organic binder, the organic binder can be distributed only in the spaces between the crosslinked polymer particles, and the surface of the crosslinked polymer particles can be coated or exposed to a desired degree. It is possible. This makes it possible to provide a novel spherical body capable of effectively exerting its function without impairing the function inherent in the crosslinked polymer particle.
- the crosslinked polymer particles are porous, the surface has a portion that is exposed without being covered with the porous structure, so that the substance adsorption function and the like of the porous structure is maintained and exhibited as it is.
- the crosslinked polymer particles can be reused from the conjugate.
- Conventional spherical bodies had to be discarded in their original form after use.
- the organic binder used in the spheroid of the present invention is soluble in the organic solvent used in the process of preparing the spheroid, after the spheroid is used, the original crosslinked polymer particles are regenerated from the spheroid. Can be reused.
- the spherical body of the present invention has excellent characteristics as described above and can be used in a wide variety of fields.
- it can be used as a packing material for liquid chromatography and a packing material for gel permeation chromatography in the field of analytical chemistry.
- the spherical particles of the present invention in which the crosslinked polymer particles are connected to each other have a gap between the crosslinked polymer particles, and thus have It can be used as a so-called perfusion type, which generates a flow that penetrates through.
- the solute can be prepared in a shorter time. Separation and purification are possible.
- the bulbous body of the present invention can be used as an adsorbent for a body fluid purification system in the field of medical treatment using the body fluid purification method.
- the substance having an affinity for the target substance in the body fluid which is a pathogenic substance, may be present in the crosslinked polymer particles which are a component of the spherical body of the present invention, or the spherical body may be formed by bonding the crosslinked polymer particles. After that, a substance having an affinity for the target substance may be fixed. Further, after the spherical body of the present invention is coated with a substance having a functional group, a substance having an affinity for the target substance may be fixed.
- pathogen examples include, but are not limited to, low density lipoprotein, endotoxin, ⁇ 2-microglobulin, tumor necrosis factor- ⁇ , and the like.
- Substances having an affinity for the target substance in body fluids that are pathogenic substances include, for example, substances having negative groups such as sulfonic acid groups, positive groups such as amino groups, and hydrophobic groups such as alkyl groups.
- substances having negative groups such as sulfonic acid groups, positive groups such as amino groups, and hydrophobic groups such as alkyl groups.
- the substance is not limited thereto.
- the spherical body of the present invention has a perfusion-type characteristic, it can be expected to reduce the execution time of the body fluid purification method.
- the particle size is 1 X 1 0- 6 ⁇ 1 0 0 X 1 0- 3 m, at most be larger to conventional 5 0 X 1 0- 6 m of about perfusion type
- a very wide particle size range can be realized compared with particles, and it can be used for detailed research on the flow in individual particles of a chromatography-particle packed bed.
- the fourth invention will be specifically described.
- the body fluid purifying adsorbent of the present invention is obtained by immobilizing a substance having an affinity for a target substance on a perfusion type carrier.
- the perfusion type carrier needs a through hole having a sufficient diameter.
- a flow penetrating the carrier particles is generated,
- the ratio of the average particle diameter of the carrier to the average direct diameter of the through hole of the carrier is preferably 70 or less, More preferably, it is 50 or less.
- the perfusion-type support in the present invention is packed in a column, and a solution containing only the target substance is applied at a linear velocity of 1 ⁇ 10 ⁇ mZs or more and i0X10 ⁇ mZs or less.
- the height equivalent to the theoretical value, which is the carrier characteristic is preferably 0.5 m or less, more preferably 0.1 m or less.
- a typical method for measuring the height equivalent to a theoretical plate is as follows. Inject the target substance into a column packed with a carrier in a pulsed manner and detect the elution curve. When the number of theoretical plates is large as in chromatography, the elution curve has a Gaussian distribution, and the theoretical plate equivalent height (H ETP) is calculated using the following equation.
- L Cm is the height of the packed column
- Tr [sec] is the retention time
- W t [sec] is the half width.
- the retention time is the time when the peak apex of the elution curve is detected
- the half width is the time width at half the position of the peak term (F. Gais, "Optimization of Liquid Chromatography", Kodansha, 18 pages, (1980).
- the adsorbent for body fluid purification has a large particle size, the length of the container is limited, and the purpose obtained under the conditions of a container filled with the adsorbent for body fluid purification
- the elution curve of a substance is rarely Gaussian in its shape.
- the shape of the elution curve can be used as an index that qualitatively indicates the performance of the carrier.This corresponds to the case where the height of the theoretical plate is large and the number of the theoretical plates is small.
- Solution filled in container without much contact with carrier Elutes with the flow of. Therefore, the position of the peak top exists immediately after the solution corresponding to the void volume between the particles of the carrier has been completely dissolved, and thereafter, the target substance gradually elutes as the elution time increases.
- the shape of the through-holes of the carrier particles is not limited as long as a part of the flow in the container only flows through the carrier particles, and the shape, the number, and the like are not limited.
- the cross-sectional shape may be circular, polygonal or irregular, and the through-path in the carrier particle may be straight or winding.
- the carrier only needs to have a structure in which a bodily fluid flow passing through the carrier is generated when a bodily fluid flows around the carrier.
- the shape of the carrier may be any of a particle shape, a slab shape, and an irregular shape, but a particle shape is preferable in terms of liquid permeability, ease of handling, and the like.
- the above-mentioned carrier is not particularly limited, and examples thereof include a porous body having a through-hole, a fine particle aggregated into a particle, a fiber aggregated into a particle, and a particle processed into a through-hole. And others.
- the microparticles or fibers used for the above-mentioned microparticles aggregated into particles or the above-mentioned fibers aggregated into particles are those having small holes capable of adsorbing the target substance, that is, It is preferable that the contact surface capable of adsorbing is large.
- the particles before processing have many small holes capable of adsorbing the target substance.
- the carrier has such a pressure that the particles are deformed when the bodily fluid passes and hinder the passage of bodily fluid. It is preferable to have a strength that does not cause densification.
- Examples of the method for producing the carrier include a method of assembling particles to form through holes, a method of assembling fibers, and a method of forming processed holes.
- Examples of methods for assembling particles and fibers include: methods of assembling during the polymerization reaction to form particles or fibers-organic solvents, heating, bonding only to adjacent surfaces without destroying the structure of the particles or fibers There is a method in which they are bonded to each other by treating them with an agent, an acid, or an alkaline solution. The space of the aggregated particles or fibers is a through hole. Examples of the method of forming a drilled hole include a laser drilling technique and solvent leaching.
- Examples of the material of the carrier include: natural polymer compounds such as cellulose, chitin, chitosan, and agarose; modified natural compounds such as acyl cellulose and anruchitin; polystyrene, polymethacrylic acid and derivatives thereof, and copolymers thereof. Further, synthetic polymer compounds such as polyvinyl alcohol and styrene divinylbenzene copolymer; and inorganic materials such as glass, alumina, and ceramics are used.
- natural polymer compounds such as cellulose, chitin, chitosan, and agarose
- modified natural compounds such as acyl cellulose and anruchitin
- polystyrene polymethacrylic acid and derivatives thereof, and copolymers thereof.
- synthetic polymer compounds such as polyvinyl alcohol and styrene divinylbenzene copolymer
- inorganic materials such as glass, alumina, and ceramics are used.
- a spherical body composed of a perfusion-type cellulose-based particle of the second invention and a crosslinked polymer particle of the third invention can be suitably used.
- target substance examples include, in addition to the pathogenic substances exemplified in the third aspect of the present invention, lipoproteins: immunoglobulin (A, D, E, G, M) which are the causative substances of arteriosclerosis such as ultra-low density lipoprotein. ), Autoantibodies such as anti-DNA antibodies, anti-acetylcholine receptor antibodies, anti-blood group antibodies, anti-platelet antibodies, and antigen-antibody complexes; and target substances such as rheumatoid factors, macrophages, and cancer tissue infiltrating T cells.
- lipoproteins immunoglobulin (A, D, E, G, M) which are the causative substances of arteriosclerosis such as ultra-low density lipoprotein.
- Autoantibodies such as anti-DNA antibodies, anti-acetylcholine receptor antibodies, anti-blood group antibodies, anti-platelet antibodies, and antigen-antibody complexes
- target substances such as rheumatoid factors, macrophages, and
- the substance having an affinity for the target substance is not particularly limited as long as it adsorbs the target substance. Although described in the third aspect of the present invention, a more detailed description will be given.
- the affinity between a substance having an affinity for the target substance and the target substance is classified into two categories: biological affinity and physicochemical affinity.
- the substances having an affinity for the target substance utilizing the above-described biological interaction include substances on which an antigen is immobilized, substances on which an antibody is immobilized, and biological interactions such as complement binding and Fc binding. Substances and the like.
- Substances having an affinity for the target substance utilizing physical interaction include substances utilizing electrostatic interaction and hydrophobic interaction.
- a substance having an affinity for a target substance utilizing physical interaction when a low-density lipoprotein is to be adsorbed, a substance having a negative group can be used.
- the substance having the above negative group include dextran sulfate, heparin, chondroitin sulfate, chondroitin polysulfate, heparitin sulfate, quinrane sulfate, caronine sulfate, cellulose sulfate, chitin sulfate, chitosan sulfate, pectin sulfate, Sulfonated polysaccharides such as inulin sulfate, alginate sulfate, glycogen sulfate, polylactose sulfate, potassium lagenin sulfate, starch sulfate, polyglucose sulfate, laminaran sulfate, galact
- sulfated polysaccharide is particularly effective.
- a preferred example in terms of clinical utility is heparin-dextran sulfate.
- Substances with the above negative groups are examples of substances that have an affinity for the target substance utilizing physical interaction and are used when trying to adsorb low-density lipoprotein.
- a substance having a positive group and a hydrophobic group and exhibiting physical interaction is used.
- a plurality of substances having an affinity for the target substance may be fixed.
- a substance having affinity for the low-density lipoprotein includes aniline.
- a method for immobilizing a substance having an affinity for the target substance on a carrier there are known methods such as covalent bond, ionic bond, physical adsorption, embedding, and insolubilization to precipitate on the surface.
- An appropriate method can be selected depending on the substance and the material of the carrier. Considering the elution of a substance having an affinity for the target substance during sterilization, a method using covalent bonding is preferred. If necessary, a spacer may be introduced between the carrier and a substance having an affinity for the target substance.
- examples of a method for bringing the reactivity to the substance having an affinity for the target substance to the carrier include a halogenated cyanide method and an epichlorohydrid method.
- Method, bisepoxide method, The romide method is known.
- Specific functional groups used in the above reaction include amino group, carboxyl group, hydroxyl group, thiol group, acid anhydride group, succinylimid group, chlorine group, aldehyde group, epoxy group, tresyl group.
- an epoxy group derived by the epichlorohydrin method is particularly preferred from the viewpoint of stability during heat sterilization.
- the mean particle size is 100 ⁇ 10 ⁇ sm or more. when it passed through the column at 3 X 1 0 one 4 mZ s or more is caused perfusion effect.
- the particle size of the adsorbent should be at least 100 x 10 6 m and 400 x X, taking into account clogging of blood cells and dynamic adsorption performance. 1 0 - preferably 6 less than m, and more preferably 1 0 0 X 1 0- 6 m or more, and 6 0 0 X 1 0 less than a 6 m.
- the carrier since the carrier produces a perfusion effect, the carrier is compared with the conventional carrier in which the mass transfer of the target substance is only diffusion. Good mass transfer. Therefore, the particle size is 1 0 0 X 1 0- 6 ⁇ above, 4 0 0 0 X 1 0 less than a 6 m, more preferably 1 0 0 X 1 0- 6 m or more, 6 0 0 x 1 0 one 11
- the adsorbent for body fluid purification of the present invention having a molecular weight of less than m particularly improves dynamic adsorption performance when it comes into direct contact with whole blood.
- the present invention also includes a body fluid purification adsorber in which a container is filled with a body fluid purification adsorbent in which a substance having an affinity for a target substance is immobilized on the perfusion-type carrier.
- the method of using the adsorber is the same as that of the body fluid purifying adsorber used in the conventional plasma perfusion method and the direct blood perfusion method.
- An anticoagulant can be used in accordance with normal body fluid purification methods, such as continuously injecting an anticoagulant into the body fluid circuit to prevent coagulation or providing a pressure gauge for detecting the occurrence of clogging.
- Example 1
- Carboxymethyl cellulose (manufactured by Wako Pure Chemical Industries, Ltd.) and a 6N aqueous sodium hydroxide solution (pH 2 14.8) were mixed to prepare a 5.6% by weight solution of carboxymethyl cellulose.
- droplets of the suspension 9 9. brought into contact with a 5% ethanol solution by the microphone port pipette Bok hole diameter 0.
- the liquid in the obtained cellulosic particles was replaced with pure water, then replaced with ethanol, and then replaced with 2-methyl-2-propanol, and then freeze-dried (Eiko Eng. C o., Ltd.), and after gold deposition, observation with a scanning electron microscope (Topcon) revealed that the cellulose was obtained as shown in Fig. 3.
- the shape of the system particles was substantially spherical. As shown in FIGS. 4 and 5, there were voids between the interconnected cellulose small particles. Moreover, as shown in FIG. 6, even after the connection, pores originally present in the porous cellulose-based small particles could be observed.
- Cellulose-based particles obtained by the present production method without using a binder can be obtained after washing, washing with pure water, and shaking the cellulosic particles in pure water.
- the compressed nitrogen gas was ejected from the outer nozzle of a two-fluid nozzle (having an inner nozzle and an outer nozzle concentrically), and at the same time, the suspension was ejected from the inner nozzle in a mist state.
- Nitrogen gas ejection speed 3. 3 X 1 0- 4 m 3 / s, a suspension discharge speed is 1. a 1 X 1 0 one 7 m 3 Z s. Diameter 2. 6 X 1 0- a m of the inner nozzle, the outer nozzle diameter using two-fluid nozzle 4. 4 X 1 0- 3 m. The discharge height was 4 m.
- a 99.5% ethanol solution was used as a coagulation liquid, and this solution was brought into contact with the droplets of the above suspension to obtain the cellulose-based particles of the present invention in the solution.
- the average particle size was about 2 X 1 (T 4 rn.)
- the shape of the cellulosic particles in pure water was shaken. Did not crumble.
- the liquid in the obtained cellulosic particles was replaced with pure water, then replaced with ethanol, and then replaced with 2-methyl-2-propanol, and then freeze-dried (Eiko Eng. Co., Ltd.). , Ltd., Ltd.), and gold was deposited, and observed with a scanning electron microscope (Topcon).
- the shape of the obtained cellulosic particles was substantially spherical, and there were voids between the interconnected cellulosic small particles. Even after the connection, pores originally present in the porous cellulose-based small particles could be observed.
- a mixture of sodium alginate (manufactured by Wako Pure Chemical Industries, Ltd.) and 6N aqueous sodium hydroxide solution (pH 14.8) was used to form a 3.6% by weight solution of sodium alginate. Prepared.
- the average particle diameter of 2 5 X 1 0- s m of the porous cellulose small particles (manufactured by Chisso Corporation), mixed aqueous solution of sodium hydroxide of the alginate Na preparative potassium (suspension concentration is 6 5 vol%, bond (1.3% by weight) was contacted for 6 hours with stirring. Later, where droplets of the suspension is brought into contact with calcium chloride solution of 6N microphone port pipette Bok hole diameter 0.
- substantially spherical cellulose A system particle was obtained.
- the particle size was about 0. 7 X 1 0- 3 m.
- the shape of the cellulosic particles in pure water was not disturbed even when shaken.
- the liquid in the obtained cellulosic particles was replaced with pure water, then replaced with ethanol, and then replaced with 2-methyl-1-propanol, and then freeze-dried (Eiko Eng. Co., Ltd.). , Ltd. (Ltd.), and gold was deposited, and observed with a scanning electron microscope (Topcon).
- the shape of the obtained particles was substantially spherical as shown in FIG. 7 in which a part of the obtained cellulosic granules were cut.c
- FIGS. 8 and 9 the particles were interconnected. Voids were formed between the small cellulose particles. Further, as shown in FIG. 10, even after the connection, pores originally present in the porous cellulose-based small particles could be observed.
- substantially spherical cellulosic particle The body is obtained.
- the particle size was about 0. 5 X 1 0- 3 m.
- the shape of the cellulosic particles in pure water was not disturbed by shaking. Also, holding this cellulosic particle body between the belly between the thumb and index finger, the finger each other by Awa sliding parallel to the longitudinal direction of the finger, rolled between about 5 XI 0- 3 m 5 reciprocating or However, the shape did not collapse.
- the liquid in the obtained cellulosic particles was replaced with ethanol, then replaced with 2-methyl-2-propanol, and then freeze-dried (Eiko En. COL td.). After freeze-drying and depositing gold, observation with a scanning electron microscope (manufactured by Topcon Corporation) revealed that the shape of the obtained cellulose-based particles was spherical, as shown in FIG. As shown in FIG. 13, there were voids between the connected cellulose small particles. Further, as shown in FIG. 14, pores of the porous cellulose small particles after the connection were also observed. Comparative Example 1
- Porous small cellulose particles manufactured by Chisso having an average particle diameter of 20 ⁇ 10 6 m were mixed with a 6N aqueous sodium hydroxide solution (pH 24.8) so that the suspension concentration was 70% by volume. ). After thoroughly stirring at a stirrer and foremost, it was a droplet of the suspension is brought into contact with pure water Kiyapi Lari one diameter 0. 7 X 1 0- 3 m, disc-shaped cellulosic molded body was obtained . Upon shaking, the shape of the molded product collapsed, and the cellulose small particles were each in a dispersed state. Comparative Example 3
- the compressed nitrogen gas was ejected from the outer nozzle of a two-fluid nozzle (having an inner nozzle and an outer nozzle on a concentric circle), and at the same time, the suspension was discharged from the inner nozzle. Nitrogen injection pressure at 5 X 1 0 3 kg / m 2, the discharge rate of the suspension 5. 1 9 X 1 0 - was 4 m 3 Zs.
- the cellulose-based particles of the present invention were obtained in an acidic solution.
- the average particle size of about 2 0 0 X 1 0 - was e m.
- the liquid in the obtained cellulosic particles was replaced with ethanol, then replaced with 2-methyl 2-propanol, and lyophilized using a freeze dryer (Eiko Eng. CO Ltd.). After gold deposition, observation with a scanning electron microscope (manufactured by Topcon Corporation) revealed that the shape of the obtained cellulose-based particles was spherical, as shown in FIG. As shown in FIG. 16, there were voids between the connected cellulose small particles. Further, as shown in FIG. 17, pores of the cellulosic small particles after the connection were also observed. Comparative Example 5
- Porous cellulosic particles having the same structure (pore hole or the like) as the small cellulose particles used in Examples 6 and 7 and Comparative Examples 1 to 4 and having a different average particle size (average particle size: 1 79 ⁇ 10 16 m) ) (Manufactured by Chisso) into a column (0.01 m ID, 0.05 m long)
- the cellulosic particles used had pores through which low-density lipoprotein could enter. Therefore, the result of the elution curve is not due to the lack of pores that allow low-density lipoprotein to enter the cellulosic particles, but due to the large particle size, the mass transfer distance is long and the low-density lipoprotein is low. This is considered to be because the protein elutes from the column outlet together with the flow between the cellulosic particles packed in the column without being able to sufficiently move into the cellulosic particles.
- Example 8
- divinylbenzene crosslinked polystyrene carrier HP21 synthetic adsorbent Diaion (registered trademark) HP21
- HP21 synthetic adsorbent Diaion (registered trademark) HP21
- the particle size is from 350 to 10 x 6 to 4 25 x 10 to 6 m, and the standard deviation of the particle size distribution is the average particle size. 29% of the particles were used.
- Methyl ethyl ketone was used as an organic solvent that did not dissolve the crosslinked polymer particles and dissolve the organic binder.
- FIG. 21 shows a photograph.
- ABT-32 T OP CON
- Fig. 21 shows a photograph.
- two states were observed on the surface of the sphere, that is, the organic binder part and the HP 21 surface. That is, it was confirmed that there was a surface portion of the crosslinked polymer particles that remained exposed without being covered with the organic binder. Further, in the cross section obtained by cutting the spherical body, it was confirmed that there was a gap between the crosslinked polymer particles.
- Carboquin methylcellulose (manufactured by Wako Pure Chemical Industries, Ltd.) and 6N NaOH aqueous solution were mixed to prepare a solution containing 2.9% by weight of carboquin methylcellulose.
- the ratio of the total volume of the particles was 65% by volume, and the ratio of the weight of carboxylmethylcellulose to the weight of the suspension was 1.0% by weight).
- the resulting carrier was washed with pure water, and the wet classification using a sieve of mesh opening 1 8 0 X 1 0- 6 m and 3 5 5 X 1 0- 6 m, an average particle size of 2 5 6 to obtain a carrier of X 1 0 one 6 m.
- the liquid in the obtained carrier was replaced with ethanol, then replaced with 2-methyl-2-propanol, freeze-dried (manufactured by Eiko En. Co. Ltd.), and gold was evaporated.
- voids (through holes) between the connected cellulose particles were found on the carrier surface and cross section, respectively, as shown in Figs. 22 and 24. Yes, and as shown in Figs. 23 and 25, Small holes (pores that can be adsorbed) were also observed on the surface and cross section of the carrier.
- the resulting carrier was a particle having a through hole and a hole capable of adsorbing, and had a structure in which, when there was a flow around the particle, a flow penetrating into the particle occurred.
- Reference example 1
- Example 1 (average particle size 2 5 6 X 1 0 e m ) inner diameter 1 0 x 1 0 one 3 m, a column length 1 1 0 X 1 0- 3 m, Fresh blood from cattle supplemented with citrate anticoagulant was kept warm at 37 ° C and passed. When the flow was at a constant linear velocity and the pressure loss became constant, it was switched to a higher linear velocity and the upper limit linear velocity at which a constant pressure loss could be maintained was measured. As a result, the upper limit line speed 7. was 3 2 X 1 0- 4 ms. Comparative Reference Example 1
- Example 1 Cellulose using small particles (average particle diameter 2 5 X 1 0 - 6 m ) and pores of pore diameters are the same structure, the cellulose carrier having an average particle diameter is larger than the porous (Chi Tsu Seo Co., average particle size 2 2 0 X 1 0 - 6 m) in the same manner as in reference example 1 to obtain a linear velocity below which can maintain a constant pressure drop in Tsuchi of fresh blood solutions of bovine It was measured. As a result, the upper limit linear velocity was 5.78 X 10—AmZs.
- Example 1 0 carrier (average particle diameter 2 5 6 X 1 0- G m ) is from mass transfer carrier of Comparative Reference Example 3 (average particle size 2 2 0 X 1 0 ⁇ 6 m) It was found that the carrier was good and the performance of the carrier was good.
- Cellulose small particles constituting the carrier used in Reference Example 2 (average particle diameter 2 5 X 1 0 - 6 m ) and comparative carrier of Reference Example 3 (average particle size 2 2 0 X 1 0 ⁇ 6 m) is a small
- the pores have the same pore size, etc., so that low-density lipoprotein can enter the pores.
- the entry of the low-density lipoprotein into the pores of this structure was confirmed by adsorbing the low-density lipoprotein in Examples 11 and 12 using the carrier of Example 10.
- Example 10 The carrier obtained in Example 10 was reacted with epichlorohydrin at 45 ° C. for 2 hours, and then reacted with dextran sulfate at 40 ° C. for 24 hours to obtain an adsorbent on which dextran sulfate was immobilized. Obtained.
- the ratio of sedimentation volume to 6 volumes of fresh human serum solution is 1 volume, After adding the above adsorbent and shaking at 37 ° C. for 10 hours, the concentration of the supernatant was measured to determine the adsorption rate.
- Example 10 The carrier obtained in Example 10 was reacted with epichlorohydrin at 45 for 2 hours, and then reacted with aniline at 50 ° C for 6 hours to obtain an adsorbent carrier on which aniline was immobilized.
- the carrier obtained in Example 10 was reacted with epichlorohydrin at 45 for 2 hours, and then reacted with aniline at 50 ° C for 6 hours to obtain an adsorbent carrier on which aniline was immobilized.
- the adsorption rate of the adsorbent was determined under the same conditions as in Example 11.
- the adsorption rates for low-density lipoprotein monocholesterol, high-density lipoprotein monocholesterol, and albumin were 55%, 0%, and 0%, respectively, indicating affinity for low-density lipoprotein.
- Example 10 From Examples 11 and 12, it was found that the carrier obtained in Example 10 in which a substance having an affinity for the target substance was immobilized can be applied as an adsorbent.
- the size of the particles can be relatively freely designed according to the application. Depending on its size and internal structure, it can be used as a carrier for gel filtration, a raw material for cellulosic ion exchanger, a carrier for affinity mouth chromatography, a carrier for adsorption of fragrances and chemicals, bacteria and enzymes. It can be suitably used for applications such as immobilized carriers and body fluid purifying carriers. Further, the method for producing the cellulosic particles of the first invention and the method for producing the perfusion-type cellulosic particles of the second invention are as described above.
- the cellulosic particles of the present invention and the perfusion type cellulosic particles of the second present invention can be easily produced.
- the crosslinked polymer particles are connected to each other via an organic binder, whereby the particle size of the linked crosslinked polymer particles is less restricted, and A novel sphere having the structural feature that the surface has an exposed portion without being covered with the organic binder can be easily obtained.
- the spherical body of the third aspect of the present invention has the above-mentioned structural characteristics, it can effectively exert its function without impairing the function of the crosslinked polymer particles. It is useful as various adsorbents in the medical field such as systems.
- the spherical body of the present invention can also be used by regenerating the crosslinked polymer particles as constituents by eluting the organic binder.
- the body fluid purifying adsorbent of the fourth aspect of the present invention has the above-described configuration, the dynamic adsorbing performance is large, and the treatment time can be shortened to improve the quality of life of the patient. .
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- External Artificial Organs (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/341,181 US6599620B2 (en) | 1997-01-07 | 1998-01-07 | Cellulosic particles, spherical object comprising cross-linked polymer particles, and adsorbent for body fluid purification |
EP19980900162 EP0955332B1 (en) | 1997-01-07 | 1998-01-07 | Adsorbent for body fluid purification |
DE1998635275 DE69835275T2 (de) | 1997-01-07 | 1998-01-07 | Absorbens zum reinigen von körperflüssigkeiten |
US11/938,212 US7763348B2 (en) | 1997-01-07 | 2007-11-09 | Cellulosic particles, spherical object comprising cross-linked polymer particles, and adsorbent for body fluid purification |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP9/600 | 1997-01-07 | ||
JP60097 | 1997-01-07 | ||
JP9/227525 | 1997-08-07 | ||
JP22752597A JP3599536B2 (ja) | 1997-08-07 | 1997-08-07 | 架橋重合体からなる球状体及びその製造方法 |
JP9/237761 | 1997-08-18 | ||
JP23776197A JP3941980B2 (ja) | 1997-08-18 | 1997-08-18 | セルロース系担体及びその製造方法 |
JP34074797A JP4021980B2 (ja) | 1997-11-25 | 1997-11-25 | セルロース系粒子体及びその製造方法 |
JP9/340747 | 1997-11-25 | ||
JP9369666A JPH10248927A (ja) | 1997-01-07 | 1997-12-25 | 体液浄化用吸着材 |
JP9/369666 | 1997-12-25 |
Related Child Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/341,181 A-371-Of-International US6599620B2 (en) | 1997-01-07 | 1998-01-07 | Cellulosic particles, spherical object comprising cross-linked polymer particles, and adsorbent for body fluid purification |
US09341181 A-371-Of-International | 1998-01-07 | ||
US10/421,722 Division US20030186041A1 (en) | 1997-01-07 | 2003-04-24 | Cellulosic particles, spherical object comprising cross-linked polymer particles, and adsorbent for body fluid purification |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998030620A1 true WO1998030620A1 (fr) | 1998-07-16 |
Family
ID=27517979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1998/000015 WO1998030620A1 (fr) | 1997-01-07 | 1998-01-07 | Particules cellulosiques, objets spheriques comportant des particules de polymere reticule et agent adsorbant de purification de fluides corporels |
Country Status (4)
Country | Link |
---|---|
US (3) | US6599620B2 (ja) |
EP (2) | EP1693402A3 (ja) |
DE (1) | DE69835275T2 (ja) |
WO (1) | WO1998030620A1 (ja) |
Cited By (2)
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US7056577B1 (en) * | 1999-04-28 | 2006-06-06 | Tigran Technologies Ab | Body for providing ingrowth and growth of bone tissue and/or connective tissue and method of making such a body |
US20130331563A1 (en) * | 2011-03-08 | 2013-12-12 | Kaneka Corporation | Method for producing porous cellulose beads |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7056577B1 (en) * | 1999-04-28 | 2006-06-06 | Tigran Technologies Ab | Body for providing ingrowth and growth of bone tissue and/or connective tissue and method of making such a body |
US7553539B2 (en) | 1999-04-28 | 2009-06-30 | Tigran Technologies Ab | Grain for providing cell growth |
US20130331563A1 (en) * | 2011-03-08 | 2013-12-12 | Kaneka Corporation | Method for producing porous cellulose beads |
US9487595B2 (en) * | 2011-03-08 | 2016-11-08 | Kaneka Corporation | Method for producing porous cellulose beads |
Also Published As
Publication number | Publication date |
---|---|
US20030012941A1 (en) | 2003-01-16 |
EP0955332A1 (en) | 1999-11-10 |
DE69835275D1 (de) | 2006-08-31 |
EP1693402A2 (en) | 2006-08-23 |
US6599620B2 (en) | 2003-07-29 |
US20030186041A1 (en) | 2003-10-02 |
DE69835275T2 (de) | 2007-07-19 |
US20080070027A1 (en) | 2008-03-20 |
EP0955332B1 (en) | 2006-07-19 |
EP1693402A3 (en) | 2009-05-27 |
EP0955332A4 (en) | 2000-05-24 |
US7763348B2 (en) | 2010-07-27 |
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