JP2007014854A - Filtration filter, manufacturing method of filtration filter, and hemofiltration method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a filtration filter which has a characteristic that a practical filtration velocity is presented by a little pressure difference in filtering a sampling target component from an adhesive material-containing liquid and viscous fluid by an all filtration system, and wherein a sampling yield of a filtrate component with respect to a sample amount is high, and a sufficient sample amount can be obtained up to clogging, and a manufacturing method of the filtration filter. <P>SOLUTION: The filtration filter is formed by a step that a porous filtration film made by curing a composition for forming film containing an active energy ray curing compound and porogen, and a fibrous filtration film are adhered by the curing of the composition for forming film. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a filtration filter for filtering a specific component from an adhesive substance-containing liquid or a viscous fluid by a total filtration method and a method for producing the same.

  Various adhesive materials such as separation and purification of biological components such as proteins, sugar chains, and polynucleotides in biochemistry and medical fields, removal of emulsions such as heavy oil and oligomers, and purification of resist materials in the fields of liquid crystals and semiconductors. Filtration membranes that separate specific components from liquids and viscous fluids that contain water are required in various industrial fields such as pharmaceuticals, diagnostics, and medical materials. In particular, in the medical field, solid components such as red blood cells, white blood cells, platelets, and fibrin are filtered from blood and used for diagnosis of various body functions and pathogens or toxins derived from pathogens. However, since white blood cells, platelets, and fibrin are sticky and adherent, separation of solid components from plasma and serum components has not been easy.

  Centrifugation is usually used to separate such sticky substances, for example, plasma or serum from blood. However, the centrifugation method has many operation steps, it is difficult to fully automate analysis and diagnosis including pretreatment, it takes time for separation, and it is necessary to add an anticoagulant such as heparin, In addition to the current problem of sample misunderstandings, it is expected that handling with micro blood samples will become increasingly difficult as the level of invasiveness advances.

  Against this background, attempts have been made to collect plasma or serum samples by a total blood filtration method. However, when a general-purpose filtration membrane is used to completely filter blood, the filtration membrane is immediately clogged. Almost no plasma or serum sample could be obtained as filtrate. In addition, hemolysis occurred when attempting to filter with a high pressure difference despite clogging. In order to solve this problem, for example, a glass fiber filtration membrane is laminated before a filtration membrane made of polysulfone (Patent Document 1), or a separation column filled with glass fibers is formed (Patent Document 2). Attempts have been made to filter by constructing so-called depth filters.

  However, in the glass fiber laminated filter, as described in Patent Document 1 and as confirmed by the study of the present inventors, a sufficient amount of sample is required before clogging. In order to obtain, it was necessary to laminate as many as six glass fiber filters. For this reason, not only the dead volume of the glass fiber filter part is increased and the adsorption of blood components to the glass fiber surface is not negligible, but the collection yield of plasma or serum sample relative to the sample blood volume is lowered. It was apt. The above problem was the same for column type filters filled with glass fibers.

  It is described that plasma can be filtered by a blood filtration material in which glass fiber filter paper and a microporous membrane are laminated (see Patent Document 3). However, simply laminating clogged with only a small amount of plasma permeating, requiring a filter with a large membrane area and increasing the amount of sample blood does not increase the amount of plasma that can be obtained. there were. Further, the publication discloses that both are integrated with an adhesive. However, as described in Patent Document 4, which is cited as an example of a film bonding method in Patent Document 3, since the film adhered with an adhesive is completely bonded, the microporous film is blocked. In this case, the same problem as in the case of the above-described lamination has occurred.

JP 2000-221189 A JP-A-4-208856 JP-A-9-196911 Japanese Patent Laid-Open No. 62-138756

  The problem to be solved by the present invention has a characteristic of showing a practical filtration rate by a small pressure difference when filtering a component to be collected from an adhesive substance-containing liquid or a viscous fluid by a total filtration method, and Another object of the present invention is to provide a filtration filter that has a high collection yield of the filtrate component with respect to the sample amount and that can provide a sufficient sample amount until clogging, and a method for producing the filter.

  In the present invention, the porous filtration membrane formed by curing the film-forming composition containing the active energy ray-curable compound and the fibrous filtration membrane are fixed, so that the pores in the porous filtration membrane The pores with the fibrous filtration membrane are continuous communication pores, and filtration is possible without the deposition of filtrate between the membranes due to the difference in separation ability between the two membranes. Therefore, the filtration filter of the present invention in which the porous filtration membrane and the fibrous filtration membrane are fixed is not easily clogged even when the separation target component is filtered from the adhesive substance-containing liquid or viscous fluid. In particular, when blood is used as a sample, membrane clogging due to thrombus generation hardly occurs, and serum or plasma components can be suitably filtered from the sample blood.

  That is, the present invention provides a filtration filter in which a porous filtration membrane obtained by curing a film-forming composition containing an active energy ray-curable compound and a pore-forming agent, and a fibrous filtration membrane are fixed. .

  The filtration filter of the present invention is capable of obtaining a sufficient amount of sample before clogging, maintaining a characteristic of showing a practical filtration rate by a small pressure difference, and having a small dead volume and a large amount per fixed membrane area. Therefore, the membrane area for obtaining a certain amount of plasma can be reduced, and the number of sites for adsorbing sample components can be reduced. Therefore, the collection yield of the filtrate component with respect to the sample amount is high, and a sufficient filtrate component can be obtained even with a small sample amount. Moreover, the manufacturing method of this invention can manufacture the filtration filter of this invention easily.

  The filtration filter of the present invention is obtained by fixing a porous filtration membrane obtained by curing a film-forming composition containing an active energy ray-curable compound and a pore-forming agent, and a fibrous filtration membrane. The filtration filter of the present invention can obtain various filtrate components according to the shape and surface characteristics of the porous filtration membrane and the fibrous filtration membrane constituting the filtration filter, the use conditions, and the like. Of course, the solid component separated by filtration can also be collected.

[Porous filtration membrane]
The porous filtration membrane constituting the filtration filter of the present invention is formed of a cured product of an active energy ray curable compound. By forming the porous filtration membrane with the cured product, the filtrate components can be filtered at a practical filtration rate and with a sufficient yield. Although the details of the reason are unknown, it can be fixed to the nonwoven fabric without clogging the pores of the porous filtration membrane, it is easy to form an aggregated particulate porous filtration membrane suitable for the present invention, It is presumed that the hardness of the porous filtration membrane is easily increased, the dimensional stability of the pores is excellent, and the surface modification for suppressing the adsorption of the contained components is easy. Moreover, it is more preferable that the cured product is a crosslinked polymer because a porous filtration membrane having high hardness can be easily obtained.

  The active energy ray-curable compound is arbitrary as long as it is cured by polymerization and / or crosslinking with an active energy ray in the presence or absence of a polymerization initiator, for example, an addition polymerizable compound, a condensation polymerizable property, and the like. The compound may be a compound, a ring-opening polymerizable compound, etc., but an addition polymerizable compound is preferable, a compound having a polymerizable carbon-carbon double bond is more preferable, and among them, a highly reactive acryloyl group and / or methacryloyl. Group [Hereafter, these are described together as “(meth) acryloyl group”. In the molecule, it is most preferable to be a maleimide compound that cures even in the absence of a photopolymerization initiator, such as a compound (referred to as “(meth) acrylic compound”), vinyl ethers, or a photopolymerization initiator. .

  The active energy ray-curable compound is preferably a polymerizable compound that is polymerized to form a crosslinked polymer. That is, in the case of an addition polymerizable compound or a ring-opening polymerizable compound, it is preferably a compound having two or more polymerizable functional groups in one molecule, and in the case of a condensation polymerizable compound such as an epoxy compound. Preferably has 3 or more polymerizable functional groups in one molecule. (Hereinafter, a compound having such a number of polymerizable functional groups is referred to as a “polyfunctional” polymerizable compound.

  Such an active energy ray-curable compound may be a monomer having the above functional group or a polymerizable oligomer (also referred to as a prepolymer).

  Examples of the (meth) acrylic monomer include diethylene glycol di (meth) acrylate, neopentyl glycol di (meth) acrylate, 1,6-hexanediol di (meth) acrylate, and 2,2′-bis (4- (meth) ) Acryloyloxypolyethyleneoxyphenyl) propane, 2,2′-bis (4- (meth) acryloyloxypolypropyleneoxyphenyl) propane, hydroxydipivalic acid neopentyl glycol di (meth) acrylate, dicyclopentanyl diacrylate, bis Bifunctional monomers such as (acryloxyethyl) hydroxyethyl isocyanurate and N-methylenebisacrylamide; trimethylolpropane tri (meth) acrylate, trimethylolethane tri (meth) acrylate, tris Acryloxy) isocyanurate, caprolactone-modified tris (acryloxyethyl) isocyanurate and other trifunctional monomers; pentaerythritol tetra (meth) acrylate and other tetrafunctional monomers; dipentaerythritol hexa (meth) acrylate and other functional monomers Can be mentioned.

  Examples of maleimide monomers include 4,4′-methylenebis (N-phenylmaleimide), 2,3-bis (2,4,5-trimethyl-3-thienyl) maleimide, 1,2-bismaleimide ethane, 1 , 6-bismaleimide hexane, triethylene glycol bismaleimide, N, N′-m-phenylene dimaleimide, m-tolylene dimaleimide, N, N′-1,4-phenylene dimaleimide, N, N′-diphenylmethane di Maleimide, N, N′-diphenyl ether dimaleimide, N, N′-diphenylsulfone dimaleimide, 1,4-bis (maleimidoethyl) -1,4-diazoniabicyclo- [2,2,2] octane dichloride, 4 , 4′-isopropylidenediphenyl dicyanate, N, N ′-(methylenedi-p-phenyle ) Bifunctional maleimides such as dimaleimide; N-(9-acridinyl) maleimide having a polymerizable functional group other than the maleimide group and a maleimide group such as maleimide. These maleimide monomers can be copolymerized with a compound having a polymerizable carbon / carbon double bond, such as vinyl monomers, vinyl ethers, and acrylic monomers.

  Examples of the polymerizable oligomer having a (meth) acryloyl group or a maleimide group in the molecular chain include those having a mass average molecular weight of 500 to 50,000. For example, (meth) acrylic acid ester of epoxy resin, ( Examples thereof include (meth) acrylic acid esters, (meth) acrylic acid esters of polybutadiene resins, and polyurethane resins having a (meth) acryloyl group at the molecular terminals.

  These active energy ray-curable compounds can be used alone or in admixture of two or more. Monofunctional (meth) acrylic monomers, monofunctional maleimide monomers, etc. for the purpose of adjusting viscosity, adhesiveness and adhesiveness in semi-cured state, or adding functions such as reactivity and hydrophilicity These may be used in combination with a monofunctional monomer. For example, you may add the below-mentioned amphiphilic compound.

  Examples of the monofunctional (meth) acrylic monomer include methyl methacrylate, alkyl (meth) acrylate, isobornyl (meth) acrylate, alkoxy polyethylene glycol (meth) acrylate, phenoxydialkyl (meth) acrylate, and phenoxy polyethylene glycol (meth) acrylate. , Alkylphenoxypolyethylene glycol (meth) acrylate, nonylphenoxypolypropylene glycol (meth) acrylate, hydroxyalkyl (meth) acrylate, glycerol acrylate methacrylate, butanediol mono (meth) acrylate, 2-hydroxy-3-phenoxypropyl acrylate, 2- Acryloyloxyethyl-2-hydroxypropyl acrylate, ethylene oxide Phthalic acid acrylate, w-carboxyaprolactone monoacrylate, 2-acryloyloxypropyl hydrogen phthalate, 2-acryloyloxyethyl succinic acid, acrylic acid dimer, 2-acryloyloxypropylpyrihydrohydrogen phthalate, fluorine-substituted alkyl ( (Meth) acrylate, chlorine-substituted alkyl (meth) acrylate, sulfonic acid sodaethoxy (meth) acrylate, sulfonic acid-2-methylpropane-2-acrylamide, phosphoric ester group-containing (meth) acrylate, glycidyl (meth) acrylate, 2- Isocyanatoethyl (meth) acrylate, (meth) acryloyl chloride, (meth) acrylaldehyde, sulfonate group-containing (meth) acrylate, silano group-containing ( ) Acrylate, ((di) alkyl) amino group-containing (meth) acrylate, quaternary ((di) alkyl) ammonium group-containing (meth) acrylate, (N-alkyl) acrylamide, (N, N-dialkyl) acrylamide, Examples include achloroyl morpholine.

Examples of monofunctional maleimide monomers include N-alkylmaleimides such as N-methylmaleimide, N-ethylmaleimide, N-butylmaleimide and N-dodecylmaleimide; N-alicyclic maleimides such as N-cyclohexylmaleimide; N -Benzylmaleimide; N-phenylmaleimide, N- (alkylphenyl) maleimide, N-dialkoxyphenylmaleimide, N- (2-chlorophenyl) maleimide, 2,3-dichloro-N- (2,6-diethylphenyl) maleimide N- (substituted or unsubstituted phenyl) maleimide such as 2,3-dichloro-N- (2-ethyl-6-methylphenyl) maleimide; N-benzyl-2,3-dichloromaleimide, N- (4′- Halogens such as fluorophenyl) -2,3-dichloromaleimide Maleimide having a hydroxyl group such as hydroxyphenylmaleimide; maleimide having a carboxy group such as N- (4-carboxy-3-hydroxyphenyl) maleimide; maleimide having an alkoxy group such as N-methoxyphenylmaleimide; N- [ Maleimides having amino groups such as 3- (diethylamino) propyl] maleimide; polycyclic aromatic maleimides such as N- (1-pyrenyl) maleimide; N- (dimethylamino-4-methyl-3-coumarinyl) maleimide, N- And maleimide having a heterocyclic ring such as (4-anilino-1-naphthyl) maleimide.
As these monofunctional monomers, it is also preferable to use a monomer having a functional group that can serve as an anchor for immobilizing a blood coagulation inhibitor or the like or an ionic functional group in the molecule.

  The porous filtration membrane constituting the filtration filter of the present invention comprises the active energy ray-curable compound and a pore-forming agent (called porogen) for forming a porous body when the active energy ray-curable compound is cured. A film-forming composition (hereinafter sometimes referred to simply as “composition”), and after curing by irradiation with active energy rays, the pore-forming agent is removed. That is, it can be obtained by a reaction-induced phase separation method using active energy rays.

  The pore-forming agent is uniformly compatible with the active energy ray-curable compound, but any pore forming agent can be used as long as the active energy ray-curable compound is cured and phase-separated to form pores. What can be used as a pore-forming agent is, for example, (a) a homogeneously compatible with the active energy ray-curable compound, but compatible with a polymer produced from the active energy ray-curable compound (dissolved mutually) Liquid (hereinafter referred to as “poor solvent”), (b) uniformly compatible with the active energy ray-curable compound, but not compatible with the polymer produced from the active energy ray-curable compound. A solid that does not dissolve, (c) a solvent that is compatible with the active energy ray-curable compound and that is compatible with the polymer or that gels the polymer (hereinafter, such a solvent is referred to as a “good solvent”). It can be illustrated. However, in the case of the above (c), it is necessary to use a compound that gives a crosslinked polymer having a high crosslinking density (that is, a low swelling degree) as the active energy ray-curable compound. In this case, the compound swells as the crosslinking polymerization proceeds. The degree decreases and the good solvent is pushed out of the gel and phase-separated (exudation). The pore-forming agent may be a single compound or a mixture. In the case of a mixture, the component alone does not have the properties (a), (b), or (c). It may be.

  Examples of the poor solvent (a) include alkyl esters of long chain fatty acids such as methyl decanoate, methyl octoate and diisobutyl adipate; ketones such as diisobutyl ketone; alcohols such as decanol and glycerin; Examples include aqueous solutions of water-soluble solvents such as propanol, ethanol, and acetone.

  Examples of the solid (b) include amide group-containing vinyl polymers such as polyvinyl pyrrolidone, styrene polymers such as polystyrene and poly α-methyl thiolene, polysulfone polymers such as polysulfone and polyethersulfone, and polycarbonate. Non-crosslinked organic polymers such as (meth) acrylyl polymers such as polymethyl methacrylate, polyacrylic acid, poly N, N-dimethylacrylamide, polyarylate polymers, polyethylene glycol polymers, etc. .

  The good solvent of (c) is a solvent that dissolves a chain polymer or gels a low crosslink density polymer with a long distance between crosslinks. As such a good solvent, For example, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, sulfoxide solvents such as dimethyl sulfoxide, chlorinated solvents such as chloroform and dichloroethane, 1,4-dioxane And ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, ketone solvents such as acetone and 2-butanone, and hydrocarbon solvents such as toluene.

  In the reaction-induced phase separation method using active energy rays, the pore diameter of the porous filtration membrane can be adjusted by the composition ratio of the active energy ray-curable compound and the pore-forming agent in the membrane-forming composition. For example, as the composition ratio of the pore forming agent is higher, the pore diameter of the obtained porous filtration membrane tends to be larger. The content of the pore-forming agent in the film-forming composition is preferably 30 to 80% by mass, more preferably 45 to 70% by mass. By setting it as this range, it becomes easy to adjust to the preferable hole diameter and water permeation | transmission flow rate for this invention. When the pore size preparation is the poor solvent (a), the pore size of the porous filtration membrane can be adjusted depending on the degree of solubility. For example, when a (meth) acryloyl group-containing compound is used as the active energy ray-curable compound and a mixed solution of isopropanol and water is used as a poor solvent, the pore size decreases as the content of isopropanol in the poor solvent increases.

  Various additives such as an energy beam polymerization initiator, a water-soluble polymer for hydrophilicity, and a surfactant may be added to the film-forming composition as necessary.

  By adding an energy ray polymerization initiator, it is possible to use a combination of an active energy ray-curable compound and an active energy ray that does not polymerize in the absence of the polymerization initiator. For example, a combination of an acrylic monomer and an ultraviolet ray having a wavelength of 300 nm or more can be used.

  The energy ray polymerization initiator is not particularly limited as long as it is active with respect to the active energy ray to be used and can polymerize the active energy ray-curable compound, and includes a radical polymerization initiator and anion polymerization. Initiators, cationic polymerization initiators and the like can be used. Examples of radical polymerization initiators include p-tert-butyltrichloroacetophenone, 2,2′-diethoxyacetophenone, 2-hydroxy-2-methyl-1-phenyl. Acetophenones such as propan-1-one; ketones such as benzophenone, 4,4′-bisdimethylaminobenzophenone, 2-chlorothioxanthone, 2-methylthioxanthone, 2-ethylthioxanthone, 2-isopropylthioxanthone; benzoin, benzoin methyl Ether, benzoin isop Pills ether, benzoin ethers such as benzoin isobutyl ether; and the azide such as N- azide sulfonyl phenyl maleimide; benzyl dimethyl ketal, benzil ketals, such as hydroxycyclohexyl phenyl ketone. A polymerizable photopolymerization initiator such as a maleimide compound can also be used.

  Examples of the water-soluble polymer that can be added include polyethylene glycol, polyvinyl pyrrolidone, poly N, N-dimethylacrylamide, and polyacrylic acid. These water-soluble polymers preferably have a weight average molecular weight of 300,000 or more, more preferably 400,000 or more, and most preferably 500,000 or more. The upper limit of the weight average molecular weight is arbitrary as long as it dissolves uniformly in the film-forming composition, but is preferably 2 million or less, and more preferably 1.5 million or less.

  Further, the surfactant may be a known and conventional one, and examples thereof include ionic surfactants such as sodium alkylbenzene sulfonate and nonionic surfactants such as nonylphenoxypolyethylene glycol.

  As a support for shaping the film-forming composition into a film shape, a temporary support may be used, which may be removed after the porous filtration membrane is cured, or a porous support may be used. It may be used as a porous filtration membrane as it is integrated with curing. The temporary support body should just be what can form a porous filtration membrane and a filtration filter on it. That is, it does not dissolve in the film-forming composition, does not permeate the film-forming composition, does not substantially decompose due to the active energy rays used, and can hold the film-forming composition on the surface. Any porous filter membrane can be used as long as it can be removed.

  Examples of such a support include polymers, crystals such as glass and quartz, ceramics, semiconductors such as silicon, and metals. Among these, polymers and metals are difficult to break and can be deformed. Is particularly preferable because it is easy to form a support. The polymer may be a homopolymer, a copolymer, a thermoplastic polymer, or a thermosetting polymer. The support may be composed of a polymer blend or a polymer alloy, or may be a laminate or other complex. Further, the support may contain additives such as a modifier, a colorant, a filler, and a reinforcing material. The metal is optional and, for example, stainless steel can be preferably used. The shape of the support is also arbitrary, and may be a flexible film shape, a flat plate shape, a roll shape, or a belt shape. Moreover, in order to form the porous filter membrane of the target dimension shape, it is also preferable to have a recessed part for arrange | positioning the said film forming composition.

The method for forming the film-forming composition into a film on the support is optional, and when the support has a recess for holding the film-forming composition, the recess by an applicator or the like. Examples thereof include methods such as dispensing into a portion, casting into a portion including the concave portion, and scraping. In addition, when the support has a flat or curved shape without a recess for arranging the film-forming composition, a known coating method such as spraying, dipping, bar coater coating, spin coating, etc. Examples thereof include a coating method and partial application using an applicator.
The irradiation method of the active energy ray is also arbitrary, and may be irradiation of the entire coated surface, or only the portion forming the porous filtration membrane may be selectively irradiated. The selective irradiation may be irradiation through an optical pattern such as a photomask or a liquid crystal device, or irradiation by scanning with a laser or the like.

  The pore diameter of the pores of the porous filtration membrane is arbitrary, but the average pore diameter is preferably 0.1 μm or more, more preferably 0.2 μm or more. Moreover, it is preferably 3 μm or less, more preferably 2 μm or less. By setting the amount within this range, it is easy to obtain a filtration filter in which the obtained filtration filter has a sufficient plasma or serum permeation flux and filtration amount and does not leak blood cell components. The average pore diameter of the pores can be determined by electron microscope measurement or the like, but more precisely, it can be measured by filtering particles (eg, polystyrene beads) having a known diameter. At this time, the pore diameter of the particles having a rejection rate of 50% is defined as the average pore diameter.

  The pore shape is arbitrary, and may be, for example, an aggregated particle shape (particle sintered body shape), a sponge shape (three-dimensional network shape), a network shape composed of continuous particles, and the like. It is preferable because it is easy to obtain a filtration filter that is not easily clogged and that can be filtered with a sufficient permeation flux.

  The thickness of the porous filtration membrane is arbitrary, but the lower limit is preferably 0.05 mm or more, more preferably 0.1 mm or more, and most preferably 0.2 mm or more. The upper limit of the thickness is preferably 1 mm or less, more preferably 0.85 mm or less, and most preferably 0.7 mm or less. By setting the thickness above this lower limit, the amount of plasma or serum that can be collected before clogging increases, and by setting the thickness below this upper limit, an increase in dead volume can be suppressed and a small amount of material can be easily filtered.

  When the pore surface of the porous filtration membrane is hydrophilic, it is preferable to make it hydrophilic when filtering blood in order to prevent hemolysis and to prevent loss due to adsorption of plasma components and serum components. The degree of hydrophilicity is preferably hydrophilic to such an extent that water droplets are immediately absorbed when placed on the porous filtration membrane. Any hydrophilic method may be used, for example, a method of chemically modifying a hydrophilic group on a porous filtration membrane, a method of graft copolymerizing a hydrophilic polymer on a porous filtration membrane, or a method of coating a hydrophilic polymer on a porous filtration membrane , Use of a copolymer of a polymerizable compound having a hydrophilic group or an amphiphilic group as a porous membrane-forming polymer, formation of a semi-IPN structure between the porous membrane-forming polymer and a hydrophilic group-containing polymer, corona treatment, Examples thereof include plasma treatment and surfactant coating.

  In any of the above cases, the hydrophilic group for hydrophilization is arbitrary, for example, polyethylene glycol group, polyoxymethylene group, hydroxyl group, sugar-containing group, N, N-dimethylamide group, N-methylpyrrolidone group. Nonionic hydrophilic group such as carboxyl group, sulfone group, phosphoric acid group, phosphorous acid group, etc., cationic hydrophilic group such as amino group, amide group, ammonium group, amino acid-containing group, phosphoric acid group and ammonium group And amphoteric hydrophilic groups such as both. Among these, a nonionic hydrophilic group, an amphoteric hydrophilic group, and / or an anionic hydrophilic group are preferable from the viewpoint of suppressing a temporal decrease in flux and biocompatibility. As the nonionic hydrophilic group, a polyethylene glycol group and / or N, N-dimethylamide group having a repeating number of 6 or more are particularly preferable, and as the anionic hydrophilic group, a sulfone group is particularly preferable. Of course, it is also possible to use a mixture of these.

[Fiber filtration membrane]
The fiber filtration membrane used in the filtration filter of the present invention is arbitrary, and may be, for example, a fiber filtration membrane formed of glass fiber, carbon fiber, ceramic fiber, etc., but it depends on organic fiber, that is, organic polymer fiber. A fibrous filtration membrane is preferred. Examples of the fiber polymer include polyester polymers such as polyethylene terephthalate, polyamide polymers such as aromatic polyamide and nylon 6,6, polyolefin polymers such as polyethylene and polypropylene, cellulose acetate, nitrocellulose, It may be a cellulose polymer such as regenerated cellulose, a polysulfone polymer such as polysulfone or polyethersulfone, and the like. The effects of the present invention can be more effectively exhibited by using organic fibers, particularly polyester polymers and polysulfone polymers.

  The fibrous structure of the fibrous filtration membrane is arbitrary, and may be, for example, a nonwoven fabric, filter paper, a knitted fabric, a short fiber fixed filter, etc., but the nonwoven fabric is easy to exert the effects of the present invention and has high productivity. Therefore, it is preferable.

Although the fiber diameter of a fibrous filtration membrane is arbitrary, 5-200 micrometers is preferable and 10-100 micrometers is still more preferable. By setting it within this range, it is possible to obtain a good capturing property of the solid component, and even when a sticky substance or viscous fluid in the sample solution contacts the fiber filtration membrane and solidifies, there is a sufficient non-occluding portion. And the effects of the present invention are obtained. Density of fiber filtration membrane is preferably 40~160g / ^{m 2,} further preferably 50 to 100 g / ^{m 2.} Within this range, it is easy to obtain a sufficient permeation flux and filtration amount of the filtration component, the dead volume does not increase, and the filtration yield of the filtration component can be increased even when the sample solution is small. I can do it.

Air permeability of fibrous filtration membrane [Fragile method. The measurement pressure difference 125 Pa] is preferably 3 to 20 [cm / s], and more preferably 4 to 12 [cm / s]. Alternatively, the water permeation flux of the fibrous filtration membrane is preferably 3 to 20 [m · s · MPa ⁻¹ ], more preferably 4 to 12 [m · s · MPa ⁻¹ ]. By setting the amount within this range, sufficient permeation flux of the filtration component and good trapping property of the solid component can be obtained, and the adhesive substance or viscous fluid in the sample solution is solidified by contacting the fibrous filtration membrane. Even in this case, a sufficient non-occluding portion can be obtained, and the effects of the present invention can be obtained.

  In addition, when collecting plasma or serum components from blood, it is preferable that the fiber surface of the fibrous filtration membrane be hydrophilic in order to prevent hemolysis and loss due to adsorption of blood components. The degree of hydrophilicity is preferably hydrophilic to such an extent that water droplets are immediately absorbed when placed on a fibrous filtration membrane. The method for hydrophilizing is arbitrary, and the method shown as the method for hydrophilizing the porous filtration membrane can be used.

[Filtration filter]
In the filtration filter of the present invention, the porous filtration membrane and the fibrous filtration membrane are fixed to each other without a gap therebetween. These films are not simply laminated, but the effects of the present invention can be obtained by being substantially integrated. The term “integration” as used herein means that the pores in the porous filtration membrane and the pores of the fibrous filtration membrane are continuous communication pores, and the porous filtration membrane and the fibrous filtration membrane are Although it is only partially bonded, the positional relationship between the two films does not change, but there is no gap between the two films as in the case where they are simply laminated.

  The theoretical reason why the effect of the present invention can be obtained by using such a structure is not clear yet, but is estimated as follows. That is, the difference in pore diameter (position distribution of the pore diameter) at each position in the membrane surface direction of a fibrous filtration membrane such as a nonwoven fabric is extremely large. , And coagulation components) tend to pass through without being completely removed. In this way, if there is a gap between the porous filtration membrane and the fibrous filtration membrane, the solid component that has permeated the fibrous filtration membrane will spread into the gap and cover the entire surface of the porous filtration membrane. . For this reason, it is considered that the filter is easily clogged.

On the other hand, in the blood phase filtration filter of the present invention, the porous filtration membrane and the fibrous filtration membrane are fixed to each other without a gap therebetween, and the pores in the porous filtration membrane and the fibrous filtration membrane These pores are continuous communication pores. For this reason, even if a solid component is permeated without being removed from a portion having a particularly large pore diameter of the fibrous filtration membrane, only a part of the surface of the porous filtration membrane is blocked, and other portions can be filtered. Therefore, it seems that the effect of the present invention can be obtained. Therefore, it is considered that an excellent filtration effect is exhibited even when an adhesive substance-containing liquid or a viscous fluid is used as a sample.
However, a porous membrane formed by a wet method using a nonwoven fabric as a support, as known in the art, is adhered to the nonwoven fabric support and the porous membrane without leaving a gap between them. The effect of the invention cannot be obtained. The reason for this is not clear, but these membranes do not provide sufficient permeation flux of the filtrate components because the porous material penetrates deeply into the nonwoven fabric support, or in the vicinity of the adhering portion. It is presumed that a large cavity called a macro void is formed and the effect of the present invention cannot be obtained.

  The fixing method and method are arbitrary. For example, the film-forming composition is prepared by irradiating the film-forming composition containing the active energy ray-curable compound and the pore-forming agent applied on the support with active energy rays. Is cured, and the obtained semi-cured membrane is laminated with a fibrous filtration membrane, and further irradiated with active energy rays to cure the semi-cured membrane, and the cured film of the film-forming composition and the fibrous filtration are cured. After fixing the membrane, it can be formed by removing the pore-forming agent to make the cured membrane a porous filtration membrane and removing the support. In this method, the semi-cured porous filtration membrane is in the form of a gel or a viscous liquid and has adhesiveness but almost no fluidity, so that the fibrous filtration membrane is not clogged. This is a particularly suitable method since the above effect is sufficiently exhibited. In particular, when a crosslinkable compound is used as the active energy ray curable compound, the semi-cured product becomes a gel, and there is no fluidity unless the gel is broken. Even if the fibrous filtration membrane is closely attached, the pores are preferably not blocked.

  In the filtration filter of the present invention, it is preferable that the porous filtration membrane and the fibrous filtration membrane are fixed to each other without substantially entering each other, as produced by the production method of the present invention. Such a fixed state has a structure different from that of a filtration membrane having a known fibrous filtration membrane as a support, for example, a microfiltration membrane, an ultrafiltration membrane, or a reverse osmosis membrane. In the existing filtration membrane using a fibrous filtration membrane as a support, the composition is used to form a porous filtration membrane by applying a liquid membrane-forming composition to the fibrous filtration membrane and then coagulating it. A non-negligible proportion of the material has entered the fiber filtration membrane. The permeation flux and filtration amount of the filtrate components can be increased by adopting a structure in which the filtration filter of the present invention does not substantially enter each other.

  The filtration filter of the present invention is suitably selected from a sample such as an adhesive substance-containing liquid or viscous fluid by appropriately adjusting the shape and surface characteristics of the porous filtration membrane and the fibrous filtration membrane constituting the filtration filter. Can be collected as a filtrate. Examples of liquids and viscous fluids that can be separated include, for example, filtration of plasma and serum from blood, separation of proteins, sugar chains, polynucleotides, etc. from cell components, and low molecular hormones from biological samples. Separation, filtration of a dispersion of heavy oil, pressure-sensitive adhesive, and oligomer, filtration of impurities mixed in a resist material, and the like.

    Among them, the porous filtration membrane and the fibrous filtration membrane constituting the filtration filter can be suitably used as a plasma filtration filter for filtering plasma or serum from blood, and the shape of each membrane or the like. By appropriately adjusting the pore size and the like, plasma, serum, or an intermediate thereof can be obtained as a filtrate. For example, serum components can be easily obtained when high-density porous filtration membranes or fibrous filtration membranes are used, or when the hydrophilicity of these surfaces is not so high. In addition, when a blood coagulation inhibitor such as heparin is fixed to a porous filtration membrane or a fibrous filtration membrane, a plasma component is easily obtained. In addition, when using the filtration filter of the present invention, whether plasma, serum, or an intermediate thereof is obtained as a filtrate can vary depending on the method of use. For example, when blood coagulation inhibitors such as heparin are added to blood or filtered slowly with a small pressure difference, plasma is easily obtained.

The water permeation flux of the present filtration filter is arbitrary and may be adjusted so as to obtain the permeation flux (filtration rate) of the target filtrate component and the amount of filtration. However, at a measurement pressure difference of 50 kPa, the lower limit is preferred. 0.5 × 10 ⁻³ [m · s ⁻¹ · MPa ⁻¹ ] or more, more preferably 1 × 10 ⁻³ [m · s ⁻¹ · MPa ⁻¹ ] or more, most preferably 2 × 10 ⁻³ [ m · s ⁻¹ · MPa ⁻¹ ] or more. Further, the upper limit is preferably 30 × 10 ⁻³ [m · s ⁻¹ · MPa ⁻¹ ] or less, more preferably 20 × 10 ⁻³ [m · s ⁻¹ · MPa ⁻¹ ] at the same measurement pressure difference. Hereinafter, it is most preferably 15 × 10 ⁻³ [m · s ⁻¹ · MPa ⁻¹ ] or less. By setting it within this range, a sufficient plasma or serum permeation flux and filtration amount can be obtained.

  The water permeation flow rate may be affected by the density of the fibrous filtration membrane and the adhesion method, but the characteristics of the porous filtration membrane, that is, the pore diameter and distribution, the porosity, the pore shape, the porous filtration membrane It can be adjusted by the thickness.

  The filtration filter of the present invention can be used by being incorporated in an arbitrary housing. The primary side (stock solution side) of the housing is provided with an inlet for introducing the sample, and a primary channel for guiding the sample introduced from the inlet to the primary side of the filtration filter. On the secondary side (filtrate side), there are a perforated plate for holding the filtration filter, a secondary side channel for guiding the filtrate component that has passed through the filtration filter to the outlet, and an outlet for allowing the component to flow out. Is provided. However, when the diameter of the filtration filter is extremely small, for example, when the diameter is 3 mm or less, the perforated plate is unnecessary. In addition, when the present filtration filter is incorporated into a microfluidic device, the inflow port or the outflow port may be a connection part with another mechanism in the microfluidic device.

  The form of the housing is arbitrary, and may be a form integrated with the filtration filter or a form in which the filtration filter can be replaced. In addition, it may be a type of filtration from the bottom to the top, a form of filtration from the top to the bottom, a method of filtering horizontally, or a type of filtration by pressurization. It is also possible to use a form that is filtered.

  The filtration filter and housing may be integrated by bonding, fusing (welding), fitting, screws, screwing, or the like, but adhesion or fusing is preferred. It is also possible to use an O-ring or the like to make it liquid-tight. The material of the housing is arbitrary, but an organic polymer is preferable, and a thermoplastic resin is more preferable. For example, styrene polymers such as polystyrene, (meth) acrylic polymers such as polymethyl methacrylate and polyacrylonitrile, polycarbonate polymers, polysulfone polymers such as polysulfone and polyethersulfone, and olefin polymers such as polyethylene, polypropylene and polymethylpentene. Is preferred.

  The present filtration filter is also preferably a syringe filter type, that is, a type that is mounted between a syringe and an injection needle. Moreover, the form which sucks up from a blood collection tube and filters may be sufficient. Further, a form incorporated in a part of the microfluidic device, for example, a shape installed in a sample introduction port or incorporated inside is also preferable.

The area of the present filtration filter is arbitrary, and can be determined by the amount of the target filtrate component, the amount of the sample to be filtered, and the like. For example, the membrane area of the present filtration filter is preferably 1 mm ^{2 to} 100 cm ² , more preferably 3 mm ^{2 to} 30 cm ² , and most preferably 10 mm ² to 10 cm ² in terms of effective membrane area.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, the scope of the present invention is not limited only to these Examples. In addition, the part in an example is a mass part.

(Adjustment of film-forming composition)
As shown in Table 1, the crosslinkable polymerizable compound A, the pore-forming agent B, and the pore-forming agent C were uniformly mixed to form a film-forming composition No. 1-3 were prepared.

However, in Table 1, the crosslinkable polymerizable compounds A-1 to A-3, the hole forming agents B-1 and B2, and the hole forming agent C are as follows.
A-1: Trifunctional urethane acrylate oligomer ("Unidic V-4263" manufactured by Dainippon Ink & Chemicals, Inc.)
A-2: Dicyclopentanyl diacrylate ("DCA-200" manufactured by Dainippon Ink and Chemicals, Inc.)
A-3: Methoxy nonaethylene glycol acrylate (“NK-ester AM-90G” manufactured by Shin-Nakamura Chemical Co., Ltd.)
B-1: Isopropanol B-2: Distilled water C: 1-hydroxycyclohexyl phenyl ketone ("Irgacure 184" manufactured by Ciba Geigy)

(UV irradiation)
Using a UE031-353CHC type UV irradiation device manufactured by Eye Graphics Co., Ltd. using a 3 kW metal halide lamp as a light source, ultraviolet rays having an ultraviolet intensity at 365 nm of 40 mW / cm ² were irradiated at room temperature.

Example 1
[Production of fibrous filtration membrane]
First, the nonwoven fabric was hydrophilized to produce a fibrous filtration membrane. Non-woven fabric [manufactured by Nippon Vilene, MF-80K, mass 80 g / m ² , air permeability 7 cm / s (catalog value)], trifunctional urethane acrylate oligomer (“Unidic V-” manufactured by Dainippon Ink & Chemicals, Inc. 4263 "), 2 parts, 1,6-hexanediol diacrylate (Daiichi Kogyo Seiyaku Co., Ltd." New Frontier HDDA "2 parts, nonylphenoxy polyethylene glycol (n = 17) acrylate (Daiichi Kogyo Seiyaku Co., Ltd. An ultraviolet curable composition comprising 1 part of “N-177E”, 95 parts of ethanol, and 0.1 part of 1-hydroxycyclohexyl phenyl ketone (“Irgacure 184” manufactured by Ciba Geigy Co., Ltd.) was applied and dried in hot air at 50 ° C. After removing ethanol, irradiated with ultraviolet rays in a nitrogen atmosphere for 60 seconds to produce hydrophilic fibrous material To obtain a filtration membrane.

[Production of filtration filter]
A glass plate is used as a temporary support, and a 0.5 mm thick polydimethylsiloxane (PDMS) sheet with a 25 mm diameter circular hole is placed on the glass plate and pressed with a finger on the glass plate. A form was made by closely contacting. In composition of the PDMS sheet, no. 1 was dropped and the composition No. 1 overflowed from the hole with a glass rod. 1 is scraped off and composition No. 1 and filled with ultraviolet rays for 1 second in an air atmosphere. Place the circular fiber filtration membrane with a diameter of 25 mm on the semi-transparent gel-like material that has lost its fluidity in the pores, obtained by UV irradiation, and press it lightly with your finger to adhere to the gel-like material. Then, when the same ultraviolet rays were irradiated for 60 seconds from the top of the fibrous filtration membrane in a nitrogen atmosphere, the gel-like material was cured to become a porous filtration membrane. The porous filtration membrane was peeled from the glass plate in distilled water, the PDMS sheet was also removed, washed with ethanol to remove the poor solvent, and vacuum dried at 40 ° C. to obtain a filtration filter.

[Characteristic evaluation of filtration filter]
As a result of observing the surface and cross section of the obtained filtration filter on the porous filtration membrane side with a scanning electron microscope (SEM), the surface and the cross section show a shape in which particles having a diameter of about 0.3 μm are aggregated. A pore having an average pore diameter of about 1 μm was observed. The fibrous filtration membrane had an average pore size of about 30 μm. The porous filtration membrane did not penetrate the fibrous filtration membrane, and a clear boundary was observed.
When 1 drop of distilled water was dropped on the porous filtration membrane side surface and the fibrous filtration membrane side surface of the obtained filtration filter, the distilled water soaked into the membrane in a few seconds.

[Water permeation test and plasma filtration test]
A filtration filter is attached to a 25 mm diameter metal filter holder (effective membrane diameter 17.5 mm, effective membrane area 2.4 × 10 ⁻⁴ m ² ) manufactured by Whatman, with the nonwoven fabric side as the primary side. Distilled water was introduced at a temperature of 25 ° C. and a pressure of 50 kPa with the side up. The permeation flux of water was an average of 5 minutes after water began to flow out from the outlet of the filtration holder. The results are shown in Table 2.

A plasma filtration test was conducted in the same manner as the distilled water filtration test except that 5 ml of heparinized bovine blood was introduced at 35 ° C. instead of distilled water and the pressure was 200 mmHg (26 kPa). It was. The hematocrit (He) value of the used bovine blood was 35% by mass, and the total protein (TP) was 70 kg / m ³ . The permeation flux. The average for one minute after the plasma began to flow out from the outlet of the filtration holder was taken. The amount of plasma collected was the amount of plasma collected until the outflow of plasma stopped.

The measurement results are shown in Table 2. A high blood permeation flux and a sufficient plasma collection amount of about 1/3 of the blood volume were obtained. Further, visually, almost no hemolysis was observed as compared with the centrifuged plasma.
In addition, when the water permeation | transmission test (measurement pressure difference 10kPa) was done by the fiber filtration membrane used for manufacture of the filtration filter alone, the water permeation flux was 6 (m * s < ^{-1 >} * MPa < ^-1 >).

(Example 2)
As a film-forming composition, composition No. A plasma filtration filter was prepared in the same manner as in Example 1 except that No. 2 was used. The porous filtration membrane observed by SEM showed a shape in which particles having a diameter of about 0.3 μm aggregated, and pores having an average pore diameter of about 1.5 μm were observed as the gap. The results of tests similar to those in Example 1 are shown in Table 2. Similar to Example 1, a high blood permeation flux and a sufficient plasma collection amount of about 1/3 of the blood volume were obtained. In addition, almost no hemolysis was observed visually.

(Example 3)
As a film-forming composition, composition No. A plasma filtration filter was prepared in the same manner as in Example 1 except that No. 3 was used. The porous filtration membrane observed by SEM showed a shape in which particles having a diameter of about 0.3 μm were aggregated, and pores having an average pore diameter of about 2 μm were observed as the gap. The results of tests similar to those in Example 1 are shown in Table 2. Relatively high blood flux and plasma collection were obtained. Further, visually, almost no hemolysis was observed as compared with the centrifuged plasma.

(Comparative Examples 1 and 2)
Composition No. 2, no. 3 was used to produce a porous filtration membrane without fixing the nonwoven fabric. The porous filtration membranes observed by SEM were the same as the porous filtration membranes of Example 1 and Example 2, respectively. Table 3 shows the results of tests similar to those of Example 1 using the obtained filtration filter. Compared to Examples 1 and 2 using the same composition, the water permeation flux was high, but the plasma permeation flux was low, and the amount of plasma collected was small.

(Comparative Example 3)
Instead of semi-curing the film-forming composition, the film was completely cured by irradiating with ultraviolet rays for 60 seconds, washed before adhering to the fibrous filter membrane to remove the pore-forming agent, and at the same time A porous filtration membrane was obtained by peeling from the support, and an epoxy adhesive (Araldite 30-minute curing type) was applied to the porous filtration membrane in the form of a dot having a diameter of about 1 mm to produce a fibrous material. A plasma filtration filter was prepared in the same manner as in Example 1 except that it was laminated with a filtration membrane and cured and adhered at room temperature for 24 hours. The results of tests similar to those in Example 1 are shown in Table 4. The water permeation flow rate was higher than in Example 1, but plasma did not flow out of the holder outlet.

(Comparative Example 4)
Instead of applying 6 points of epoxy adhesive (Araldite 30-minute curing type) to a porous filter membrane in a dot shape with a diameter of about 1 mm, the epoxy adhesive was applied to the fiber filtration membrane using a roller. A plasma filtration filter was prepared in the same manner as in Comparative Example 3 except for the above. The results of tests similar to those in Example 1 are shown in Table 4. The water permeation flow rate was lower than in Example 1, and plasma did not flow out of the outlet of the holder.

(Comparative Example 5)
A filtration filter in which a porous membrane made of nitrocellulose and a glass fiber filtration membrane are laminated as a porous filtration membrane [Syringe filter GD / X manufactured by Whatman, membrane diameter of about 25 mm, pore size of porous membrane (catalog value) 0.45 μm ] Was subjected to the same test as in Example 1. The results are shown in Table 5. Compared with Examples 1 and 2, the water permeation flux was faster, but plasma did not flow out of the outlet of the holder.

Claims (10)

A filtration filter in which a porous filtration membrane obtained by curing a film-forming composition containing an active energy ray-curable compound and a pore-forming agent, and a fibrous filtration membrane are fixed by curing the film-forming composition. . The filtration filter according to claim 1, wherein the porous filtration membrane is hydrophilic. The filtration filter according to claim 1 or 2, wherein the fixation is fixation in which the fibrous filtration membrane is laminated on a membrane obtained by semi-curing the film-forming composition to cure the semi-cured membrane. The average pore diameter of the porous filtration membrane is in the range of 0.2 to 3 µm, and the air permeability at a pressure difference of 125 Pa of the fibrous filtration membrane is in the range of 3 to 20 cm / s. Filtration filter. The ratio of the active energy ray-curable compound to the pore-forming agent in the film-forming composition is 1 / 2.5 to 1/7 in a mass ratio represented by the active energy ray-curable compound / pore-forming agent. The filtration filter according to claim 1, which is in a range. The filtration filter according to any one of claims 1 to 4, wherein the porous filtration membrane has a thickness in the range of 50 to 700 µm, and the fibrous filtration membrane has a thickness in the range of 50 to 700 µm. The filtration filter according to any one of claims 1 to 5, wherein the active energy ray-curable compound is a (meth) acryloyl group-containing compound. The filtration filter according to claim 1, wherein the fibrous filtration membrane is a filter paper or a nonwoven fabric. The film-forming composition containing the active energy ray-curable compound and the pore-forming agent applied on the support is irradiated with active energy rays to semi-cure the film-forming composition, and the resulting semi-cured film is obtained. After laminating a fibrous filtration membrane, further irradiating active energy rays to cure the semi-cured membrane, and fixing the cured membrane of the film-forming composition and the fibrous filtration membrane, a pore-forming agent A method for producing a filtration filter, wherein the cured membrane is removed to form a porous filtration membrane and the support is removed. A blood filtration method, wherein plasma or serum components are filtered from blood using the filtration filter according to claim 1.