WO2021066152A1 - 血液処理材料 - Google Patents
血液処理材料 Download PDFInfo
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- WO2021066152A1 WO2021066152A1 PCT/JP2020/037573 JP2020037573W WO2021066152A1 WO 2021066152 A1 WO2021066152 A1 WO 2021066152A1 JP 2020037573 W JP2020037573 W JP 2020037573W WO 2021066152 A1 WO2021066152 A1 WO 2021066152A1
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- Prior art keywords
- blood treatment
- treatment material
- water
- blood
- fiber
- Prior art date
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Definitions
- the present invention relates to a blood treatment material.
- a method of imparting a ligand having a strong interaction with a target substance such as an inflammatory cytokine to the surface of the material and a method of improving the specific surface area of the material in the blood contact portion are generally used.
- a target substance such as an inflammatory cytokine
- Patent Document 1 describes a bead-shaped, hollow-thread-shaped, and solid-thread-shaped adsorbent formed of a hydrophobic polymer resin such as a polyarylate resin and having a surface centerline average roughness of 5 to 100 nm. , It is disclosed that the adsorptivity of leukocytes and platelets can be further improved.
- Patent Document 2 a porous film having a surface roughness (Sa) of 0.5 ⁇ m or less is laminated on at least one surface of a non-woven fabric base material, and the porous film laminate having a predetermined air permeability and tensile strength is laminated. It is disclosed that the body can be applied to medical filters.
- Sa surface roughness
- Patent Document 3 describes a water-insoluble carrier to which a compound containing a functional group having a charge on the surface is bound, and by defining the average roughness of the center line of the surface in a specific range, activated leukocytes-activated platelets. It has been reported to be suitable for removing complexes.
- Patent Document 4 contains a water-insoluble carrier in which a nitrogen-containing compound is bound to the surface, and by defining the arithmetic mean roughness of the surface within a predetermined range, immunosuppressive leukocytes, particularly LAP-positive lymphocytes or LAP-positive, are defined. It is disclosed that it is suitable for adsorption of monocytes.
- Patent Documents 1, 3 or 4 disclose techniques focusing on the center line average roughness and the arithmetic mean roughness.
- the center line average roughness is an index for quantifying the surface roughness specified in JIS B 0601: 1994.
- Arithmetic mean roughness is a term used after JIS B 0601: 2001, and is synonymous with centerline average roughness.
- Patent Documents 1, 3 and 4 disclose the relationship between surface roughness and adsorption performance.
- Patent Document 1 specifically discloses the centerline average roughness of the surface of a substantially perfect circular bead in Examples 1 to 3, and by controlling the centerline average roughness to 5 to 100 nm. It is stated that leukocytes and platelets can be adsorbed at the same time, but if excessive platelets adhere to the adsorbent, the material surface will be covered with platelets, and there is a concern that the adsorption of leukocytes and cytokines to be adsorbed may be hindered. .. In addition, there is no description regarding the relationship between the direction of the center line average roughness and the adsorption performance.
- Patent Document 3 describes the relationship between the developed length ratio or the center line average roughness of the material surface and the activated leukocyte-activated platelet complex, it relates to the relationship between the direction of the center line average roughness and the adsorption performance. There is no description.
- Patent Document 4 it is described that the value in the longitudinal direction is measured as the arithmetic mean roughness in the case of orientation such as fibers, but the description and the adsorption performance regarding the arithmetic mean roughness in other directions are described. There is no description about the relationship.
- Patent Document 2 discloses the relationship between surface roughness and the ease with which air bubbles adhere during filtration and filtration efficiency, but does not describe the relationship between roughness and adsorption performance. Further, only the surface roughness (Sa) per unit area including a plurality of single yarns of the non-woven fabric is described, and the roughness per single yarn is not described.
- an object of the present invention is to provide a blood treatment material that highly efficiently adsorbs and removes blood components such as activated leukocytes and inflammatory cytokines.
- the present inventors have made blood components such as activated leukocytes and inflammatory cytokines highly efficient by giving anisotropy to the arithmetic mean roughness of the material surface. It was found that it can be adsorbed.
- the present invention includes the following [1] to [8].
- a ligand containing an amino group is bound to the surface of the water-insoluble material, and the content of the amino group is 0.20 to 3.00 mmol per 1 g of the dry weight of the water-insoluble material, [1] to [1] to [ 3]
- the blood treatment material according to any one of. [5]
- the shape of the water-insoluble material is a fiber, and the measurement direction of a laser microscope that minimizes the arithmetic mean roughness (Ra) of the surface of the water-insoluble material is the fiber long axis direction [1].
- the blood treatment material according to any one of [4].
- the shape of the water-insoluble material is a sea-island composite fiber, and the sea component of the sea-island composite fiber is selected from the group consisting of polystyrene, polystyrene derivatives, polysulfone and polysulfone derivatives, and mixtures thereof.
- the blood treatment material according to any one of [1] to [6] which is used for adsorbing and removing activated leukocytes and / or inflammatory cytokines.
- a blood purification column comprising the blood treatment material according to any one of [1] to [7].
- the blood treatment material of the present invention can adsorb activated leukocytes and inflammatory cytokines with high efficiency, and can be used as an adsorption carrier for extracorporeal circulation.
- the blood treatment material of the present invention contains a water-insoluble material in the form of fibers or particles, and the maximum value (RaA) and the minimum value (RaA) of the arithmetic mean roughness (Ra) of the surface of the water-insoluble material calculated using a laser microscope.
- the difference between the values (RaB) is 0.30 to 1.50 ⁇ m.
- Blood treatment means treating a patient with a disease derived from blood by adsorbing and removing blood components using an appropriate material.
- Blood component means a component constituting blood, and examples thereof include cells in blood and humoral factors in blood.
- Cells in blood means cells contained in blood, for example, leukocyte components such as granulocytes, monospheres, neutrophils, and eosinophils, erythrocytes, platelets, activated platelets, and activation. Examples thereof include leukocyte-activated granulocyte complex, but when the blood treatment material according to the present embodiment is used for the treatment of inflammatory diseases, activated leukocyte is preferable as the substance to be adsorbed.
- leukocyte components such as granulocytes, monospheres, neutrophils, and eosinophils, erythrocytes, platelets, activated platelets, and activation. Examples thereof include leukocyte-activated granulocyte complex, but when the blood treatment material according to the present embodiment is used for the treatment of inflammatory diseases, activated leukocyte is preferable as the substance to be adsorbed.
- Liquid factor in blood refers to organic substances dissolved in blood. Specific examples thereof include proteins such as urea, ⁇ 2-microglobulin, cytokines, IgE and IgG, and polysaccharides such as lipopolysaccharide (LPS). Among them, proteins such as urea and cytokines and polysaccharides such as LPS are preferable as substances to be adsorbed, and when the blood treatment material according to the present embodiment is used for the purpose of treating inflammatory diseases, the substances to be adsorbed are inflammatory. Cytokines are more preferred.
- Intra cytokine means a group of proteins produced from various cells including immunocompetent cells and released extracellularly to act by stimulation such as infection or trauma.
- the "blood treatment material” means a material containing a water-insoluble material in at least a part of the material, and includes a water-insoluble material alone or a material in which a water-insoluble material is immobilized or mixed with an appropriate reinforcing material.
- the immobilization or mixing operation may be performed before processing into a shape or after processing.
- Water-insoluble material is a material that is insoluble in water.
- insoluble in water means that the change in dry weight before and after putting the water-insoluble material in water is 1% or less. This change in dry weight is caused by immersing the water-insoluble material in water at 37 ° C., which is 9 times the dry weight, for 1 hour, pulling it up with a tweezers, etc., and vacuum-drying the remaining water at 50 ° C. or lower to dry the remaining solid content.
- the ratio of the weight to the dry weight of the material before immersion If it is not insolubilized, there is a risk that the amount of eluate will increase when it is actually used, which is not preferable for safety.
- Dry weight means the weight of a solid in a dry state.
- the dry solid represents a solid in which the amount of the liquid component contained in the solid is 1% by weight or less, and after measuring the weight of the solid, it is heated and dried at 80 ° C. and atmospheric pressure for 24 hours. When the weight loss of the remaining solid is 1% by weight or less of the weight before drying, the solid is considered to be in a dry state.
- Adsorption means a state in which a substance adheres to a material and does not easily peel off, or a state of adsorption equilibrium.
- the principle of adsorption is not particularly limited, but for example, the state of attachment by intermolecular force such as electrostatic interaction, hydrophobic interaction, hydrogen bond, van der Waals force, cell adhesion, leukocyte phagocytosis, etc. It means the state of being attached to the target.
- components constituting the water-insoluble material include polyethylene terephthalate, polybutylene terephthalate, polyaromatic vinyl compound, polyester, polysulfone, polyethersulfone, polystyrene and derivatives thereof (for example, polycarbonate, polyether ketone, polyether ether).
- Ketone polyphenylene sulfide, polyphenol, polyphenylene ether, polyphenylene ethynylene, polyamideimide, polystyrene sulfonic acid, poly (4-methylstyrene), poly (4-ethylstyrene), poly (4-isopropylstyrene), poly (2-chloro Polysulfone), poly (4-chlorostyrene), poly (3-hydroxystyrene), poly (4-methoxystyrene), poly (4-carboxystyrene), poly (4-nitrostyrene), poly (4-chloromethylstyrene).
- Polymers of choice include, when the ligand is attached to the surface, polystyrene, polystyrene derivatives, polysulfones, polysulfone derivatives, because of the large number of aromatic rings per unit weight and the ease with which amino groups can be immobilized. It is preferably a polymer selected from the group consisting of polyethersulfone and derivatives of polyethersulfone and mixtures thereof, and polymers selected from the group consisting of polystyrene, derivatives of polystyrene, polysulfone and derivatives of polysulfone and mixtures thereof. Is more preferred, and polystyrene is even more preferred.
- polystyrene derivatives include polystyrene sulfonic acid, poly (4-methylstyrene), poly (4-ethylstyrene), poly (4-isopropylstyrene), poly (2-chlorostyrene), and poly (4-chlorostyrene).
- polysulfone derivative examples include sulfonated polysulfone
- polyethersulfone derivative examples include sulfonated polyethersulfone
- a fiber shape or a particle shape is preferable because it has a large specific surface area and is excellent in handleability.
- the shape of the water-insoluble material is preferably a yarn bundle, yarn, net, knitted fabric, woven fabric, felt, net or the like obtained by processing the above fibers, has a large specific surface area, and has a flow resistance.
- yarn bundles, knitted fabrics, woven fabrics, felts and nets are more preferable.
- knitted fabrics, felts and nets can be produced by a known method using fibers as raw materials.
- the felt manufacturing method include a wet method, a carding method, an air array method, a spunbond method, and a melt blow method.
- the method for manufacturing the knitted fabric and the net include a plain weave method and a tubular knitting method.
- a knitted fabric produced by a tubular knitting method is preferable from the viewpoint of filling a blood purifier with a large filling weight per unit volume.
- the shape of the water-insoluble material is preferably a sea-island composite fiber from the viewpoint of maintaining the strength per single yarn.
- the sea-island composite fiber may contain an immobilized or mixed suitable reinforcing material, and for example, the island component described later can be regarded as a reinforcing material.
- the island component is also a part of the water-insoluble material.
- a material that is insoluble in water and has a structure capable of binding a ligand to the surface is preferable.
- polyethylene terephthalates, polybutylene terephthalates, polyaromatic vinyl compounds, polyesters, polysulfones, polyethersulfones, polystyrenes and derivatives thereof eg, polycarbonates, polyetherketones, polyetheretherketones, polyphenylene sulfides, polyphenols, polyphenylene ethers, etc.
- a polymer selected from the group consisting of derivatives and mixtures thereof is more preferred, and polystyrene is even more preferred.
- derivative refers to a compound having one or two substituents on the aromatic ring, which is a polystyrene.
- Examples of the derivative include polystyrene sulfonic acid, poly (4-methylstyrene), poly (4-ethylstyrene), poly (4-isopropylstyrene), poly (2-chlorostyrene), poly (4-chlorostyrene), and the like.
- examples thereof include sulfonated polysulfone
- examples of derivatives of polyether sulfone include sulfonated polyether sulfone.
- a ligand when a ligand is introduced into the surface (sea component) of the fiber, it can follow changes in mechanical properties such as swelling and contraction of the sea component, and changes in chemical and mechanical properties due to chemicals.
- a polymer selected from the group consisting of polypropylene, polyethylene and polypropylene / polyethylene copolymers and mixtures thereof can be mentioned, and a good cross section is formed in composite spinning.
- a polymer selected from the group consisting of polypropylene and polypropylene / polyethylene copolymers and mixtures thereof is more preferable, and polypropylene is even more preferable.
- the sea component consists of a group consisting of polystyrene, a polystyrene derivative, a polypropylene, a polypropylene derivative, a polyether sulfone, a polyether sulfone derivative, and a mixture thereof.
- the polymer of choice is preferably a polymer in which the island component is a group consisting of polypropylene, polyethylene and polypropylene / polyethylene copolymers and mixtures thereof, and the sea component is polystyrene, polystyrene derivatives, polysulfones and It is more preferable that the polymer is selected from the group consisting of a derivative of polysulfone and a mixture thereof, and the island component is a polymer consisting of polypropylene, polyethylene and a polypropylene / polystyrene copolymer and a mixture thereof.
- the sea component is a polymer selected from the group consisting of polystyrene, polystyrene derivatives, polysulfone and polysulfone derivatives and mixtures thereof
- the island component is a group consisting of polypropylene and polypropylene / polypropylene / polyethylene copolymers and mixtures thereof. It is more preferable that the polymer is selected from the above, the sea component is polystyrene, and the island component is polypropylene.
- the single yarn diameter (hereinafter, also referred to as fiber diameter) of the fiber (eg, Kaishima composite fiber) constituting the water-insoluble material may be any thickness, but the contact area with the substance to be adsorbed is improved. From the viewpoint of maintaining the strength of the material, 3 to 200 ⁇ m is preferable, 5 to 50 ⁇ m is more preferable, and 10 to 40 ⁇ m is further preferable. Any preferred lower limit can be combined with any preferred upper limit.
- Single thread diameter means that 10 small fiber pieces are randomly sampled, 1000 to 3000 times larger photographs are taken using a scanning electron microscope, and 10 locations (100 locations in total) are taken around each photograph. It means the average value of the measured values of the diameter of the fiber.
- the single yarn diameter of the Kaijima composite fiber that constitutes the water-insoluble material can be reduced by reducing the amount of polymer discharged during spinning and increasing the winding speed.
- the single yarn diameter of the Kaijima composite fiber can be increased by swelling by impregnating with a solvent at the time of introducing the ligand. Can be controlled within the range of.
- the diameter of the particles is preferably 1 to 500 ⁇ m from the viewpoint of ensuring a sufficient specific surface area for adsorbing the target substance.
- the "arithmetic mean roughness (Ra)" is an index for quantifying the smoothness of the surface specified in JIS B 0601: 2001, and in the present specification, the uneven state of the blood contact surface of the water-insoluble material.
- Ra is a laser confocal optical system, capable of two-dimensional scanning, and equipped with a line roughness analysis function (eg, shape analysis application VK-H1A1 / VK-H2A1, manufactured by KEYENCE) (eg, KEYENCE).
- FIG. 1 shows the extracted reference length l (el ( ⁇ m)), the contour curve, and the average line, and the absolute values ( ⁇ m) of the deviations from the average line to the contour curve of the extracted portion are summed and averaged.
- the value is the arithmetic mean roughness, and the calculation method is as shown in Equation 1 below.
- Ra is an arithmetic mean roughness
- f (x) is a function representing a surface uneven shape at an arbitrary position x in a laser microscope image.
- the material to be measured needs to be dried in advance in consideration of the change in shape due to surface hydration and the change in wet state due to evaporation of water.
- the "average line” refers to a line in which the contour curve is replaced with a straight line by the least squares method as defined by JIS B 0601: 2001.
- the "contour curve” is a curve that traces the contour of the material surface when an image of the material surface to be measured is captured using a laser microscope, and is also referred to as a measurement cross-sectional curve. To tell.
- the “maximum value of the arithmetic mean roughness (Ra)” is the value at which the arithmetic average roughness (Ra) is the maximum among the arithmetic average roughness (Ra) of the surface of the water-insoluble material obtained by the above method. means. Specifically, according to the above-mentioned calculation method of "arithmetic mean roughness (Ra)", 10 line segments are randomly extracted from the obtained image so that they do not have a parallel positional relationship. This operation is performed on images of three different fields of view, and the arithmetic mean roughness (Ra), which is the maximum value among the arithmetic average roughness (Ra) calculated from a total of 30 line segments extracted from the images of the three fields of view.
- RaA The "minimum value of arithmetic mean roughness (Ra)" can also be obtained by the same method as described above. That is, among the arithmetic average roughness (Ra) calculated from the above-mentioned extracted total of 30 line segments, the arithmetic average roughness (Ra) which is the minimum value is defined as RaB.
- RaB the arithmetic average roughness
- the maximum value (RaA) of the arithmetic mean roughness (Ra) on the surface of the water-insoluble material is such that cells in blood can easily recognize the material by forming sufficient irregularities on the surface and have a sufficient specific surface area. As a result, humoral factors in blood can be adsorbed and removed with high efficiency, so the thickness is preferably 0.50 ⁇ m or more, more preferably 0.60 ⁇ m or more, and even more preferably 0.63 ⁇ m or more. Further, the maximum value (RaA) of the arithmetic mean roughness (Ra) is preferably 3.0 ⁇ m or less because of the concern about the generation of fine particles.
- the maximum arithmetic mean roughness (Ra) (RaA) of the surface of the water-insoluble material is 0.50 ⁇ m or more and 3.0 ⁇ m or less, 0.50 ⁇ m or more and 2.0 ⁇ m or less, 0.50 ⁇ m or more and 1.6 ⁇ m or less. , 0.60 ⁇ m or more and 1.6 ⁇ m or less, 0.63 ⁇ m or more and 1.6 ⁇ m or less.
- the minimum value (RaB) of the arithmetic mean roughness (Ra) on the surface of the water-insoluble material depends on the value of the maximum value (RaA), but is, for example, 0.10 ⁇ m or more and less than 0.50 ⁇ m.
- the “difference between the maximum value (RaA) and the minimum value (RaB)" is the maximum value (RaA) to the minimum value (RaB) using the maximum value (RaA) and the minimum value (RaB) calculated by the above method. Is calculated by subtracting.
- the difference between the maximum value (RaA) and the minimum value (RaB) in the range of 0.30 to 1.50 ⁇ m, the adsorption rate of blood components such as activated leukocytes and inflammatory cytokines can be improved. It is considered that this is because the unevenness of the material surface has a directionality.
- the difference between the maximum value (RaA) and the minimum value (RaB) needs to be 0.30 to 1.50 ⁇ m, preferably 0.33 to 1.30 ⁇ m, and more preferably 0.33 to 1. It is 0.000 ⁇ m, more preferably 0.35 to 1.00 ⁇ m, and even more preferably 0.40 to 1.00 ⁇ m. Any preferred lower limit can be combined with any preferred upper limit.
- the measurement direction of the laser microscope that minimizes the arithmetic mean roughness (Ra) of the surface of the water-insoluble material includes, for example, the fiber long axis direction.
- the arithmetic mean roughness (Ra) value is smaller in the fiber major axis direction than in the fiber minor axis direction, so that the leukocyte component having phagocytic ability makes the fiber more while suppressing the generation of fine particles. It can be recognized and the adsorption performance can be improved.
- the measurement direction refers to the direction of the line segment extracted on the image when the arithmetic average roughness of the captured image is calculated by the line roughness analysis function.
- the “fiber major axis direction” refers to the traveling direction (discharge method) when the fiber is discharged by spinning. Further, as shown in FIG. 2, the “fiber minor axis direction” refers to a direction orthogonal to the traveling direction at the time of discharge.
- the measurement direction of the laser microscope that minimizes the arithmetic mean roughness (Ra) on the surface of the water-insoluble material is, for example, orthogonal to the measurement direction that is the maximum value (RaA). The direction to do is mentioned.
- the shape of the material surface can be appropriately adjusted by, for example, the manufacturing process of a water-insoluble material, the substrate concentration when introducing a ligand containing an amide group or an amino group, the reaction time, and the reaction temperature. It becomes.
- the ligand to be introduced is not particularly limited, and examples thereof include a chloroacetamide methyl group. When introducing a chloroacetamide methyl group onto the surface of a water-insoluble material, the maximum arithmetic mean roughness (Ra) (RaA) tends to increase as the reaction progresses.
- a ligand containing a functional group having an anionic charge or a functional group having a cationic charge may be bound to the surface of the water-insoluble material.
- a ligand containing an amino group may be attached to the surface of the water-insoluble material.
- ligand is meant a compound that binds to the surface of a water-insoluble material, the chemical structure of which is particularly limited as long as it has an anionic or cationically charged functional group.
- a compound containing a sulfonic acid group or a carboxyl group which is an anionic functional group, or a compound containing an amino group which is a cationic functional group can be mentioned.
- the ligand is preferably a compound containing a cationic functional group, particularly a compound containing an amino group.
- the functional group may be a combination of a plurality of the same or different functional groups.
- the ligand may further have a neutral functional group as long as it has the above-mentioned anionic functional group or cationic functional group, and the neutral functional group includes, for example, a methyl group or an ethyl group.
- a neutral functional group includes, for example, a methyl group or an ethyl group.
- an alkyl group or a phenyl group a phenyl group substituted with an alkyl group (for example, para (p) -methylphenyl group, meta (m) -methylphenyl group, ortho (o) -methylphenyl group, para (p)).
- -Ethylphenyl group meta (m) -ethylphenyl group or ortho (o) -ethylphenyl group, etc.
- a phenyl group substituted with a halogen atom for example, para (p) -fluorophenyl group, meta (m)- Allyl groups such as fluorophenyl group, ortho (o) -fluorophenyl group, para (p) -chlorophenyl group, meta (m) -chlorophenyl group or ortho (o) -chlorophenyl group) are anionic functional groups.
- a compound bonded to a compound containing a cationic functional group (eg, tetraethylenepentamine to which a para (p) -chlorophenyl group is bonded) is included in the ligand.
- the neutral functional group and the ligand may be directly bound or may be bound via a spacer (the spacer involved in the binding is also referred to as spacer 1).
- the spacer 1 include a urea bond, an amide bond, and a urethane bond.
- amino group is, for example, an amino group derived from a primary amine such as methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine or dodecylamine, methylhexylamine, diphenylmethylamine.
- Amino groups derived from secondary amines such as dimethylamine
- amino groups derived from amines having unsaturated alkyl chains such as allylamine
- aminos derived from tertiary amines such as trimethylamine, triethylamine, dimethylethylamine, phenyldimethylamine and dimethylhexylamine.
- Amino groups derived from amines having an aromatic ring such as groups, 1- (3-aminopropyl) imidazole, pyridine-2-amine, 3-sulfoaniline, or tris (2-aminoethyl) amines, ethylenediamines, diethylenetriamines, triethylenes.
- polyamine The derived amino group can be mentioned.
- the amino group in the polyamine structure is more preferably an amino group derived from a primary amine or a secondary amine.
- the polyamine may be linear, branched or cyclic.
- the polyamine may contain the following structures as substituents on the basic nitrogen atom. Examples of the structure include an alkyl group having 1 to 10 carbon atoms, an unsaturated alkyl chain such as a vinyl group or an allyl group, an aromatic substituent such as a phenyl group, a naphthyl group or an anthracyl group, or an imidazolyl group, a pyridyl group or a piperidyl. Examples thereof include heterocyclic substituents such as groups.
- the water-insoluble material and the ligand containing an amino group may be directly bonded, or a reactive functional group between the water-insoluble material and the ligand.
- a spacer of origin may be used (the spacer involved in the binding is also referred to as spacer 2).
- the spacer 2 may have an electrically neutral chemical bond such as a urea bond, an amide bond, an ether bond, an ester bond, or a urethane bond, and has an amide bond or a urea bond. Is preferable.
- Examples of the reactive functional group that mediates the bond between the water-insoluble material and the ligand include a haloalkyl group (for example, a halomethyl group and a haloethyl group), a haloacyl group (for example, a haloacetyl group and a halopropionyl group), and a haloacetamide alkyl.
- Examples thereof include an active halogen group such as a group (for example, a haloacetamide methyl group or a haloacetamide ethyl group), an epoxiside group, a carboxyl group, an isocyanic acid group, a thioisosocyanic acid group or an acid anhydride group.
- an active halogen group is preferable, and a haloacetamide alkyl group, particularly a haloacetamide methyl group, is more preferable.
- a haloacetamide alkyl group particularly a haloacetamide methyl group
- the water-insoluble material into which a reactive functional group has been introduced include polystyrene having a chloroacetamide methyl group introduced on the surface and polysulfone having a chloroacetamide methyl group introduced on the surface.
- the reactive functional group can be bonded to the water-insoluble material by reacting the water-insoluble material with an appropriate reagent in advance.
- the sea component of the sea-island composite fiber constituting the water-insoluble material is polystyrene and the reactive functional group is chloroacetamide methyl group
- chloroacetamide methyl is formed by reacting polystyrene with N-hydroxymethyl-2-chloroacetamide.
- a polystyrene with bonded groups can be obtained.
- polystyrene having a chloroacetamide methyl group bonded with tetraethylenepentamine having an amino group polystyrene in which tetraethylenepentamine is bonded via an acetamide methyl group can be obtained.
- the acetamide methyl group corresponds to the spacer 2 and the tetraethylenepentamine corresponds to the ligand.
- the materials of the sea component and the island component of the water-insoluble material, the spacers (spacer 1 and spacer 2), and the ligand can be arbitrarily combined.
- constituents of water-insoluble materials to which a ligand is bound include polystyrene, ethylenediamine, diethylenetriamine, and triethylene in which a ligand containing a polyamine such as ethylenediamine, diethylenetriamine, triethylenetetramine, or tetraethylenepentamine is bound via an acetamide methyl group.
- a ligand containing a polyamine such as ethylenediamine, diethylenetriamine, triethylenetetramine, or tetraethylenepentamine is bound via an acetamide methyl group.
- examples thereof include polysulfones in which a ligand containing a polyamine such as tetramine or tetraethylenepentamine is bound via an acetamidomethyl group.
- the content of amino groups is not particularly limited, but from the viewpoint of adsorption performance to charged organic substances such as blood components, 0.20 mmol or more per 1 g of dry weight of the water-insoluble material is preferable, and the pH of blood is increased. In consideration of the influence of the above, 3.00 mmol or less is preferable per 1 g of the dry weight of the water-insoluble material. That is, the content of the amino group is preferably 0.20 to 3.00 mmol, more preferably 0.50 to 2.00 mmol, and 0.70 to 1.50 mmol per 1 g of the dry weight of the water-insoluble material. Is more preferable. Any preferred lower limit can be combined with any preferred upper limit.
- the content of amino groups can be measured by an acid-base titration method using hydrochloric acid or an aqueous solution of sodium hydroxide.
- the blood treatment material according to the present embodiment can be produced by, for example, the following method, but is not limited to this method.
- DMSO dimethyl sulfoxide
- a compound containing an amino group for example, tetraethylenepentamine
- the sea-island composite fiber in which a ligand containing an amino group is bonded to the surface is obtained by washing the fiber with water after adding and reacting with and taking out the fiber.
- the ligand containing an amino group corresponds to a compound containing an amino group (for example, tetraethylenepentamine).
- Examples of the solvent used when producing the amidomethyl group-bonded sea-island composite fiber include nitrobenzene, nitropropane, chlorobenzene, toluene and xylene when the sea component is polystyrene, and nitrobenzene or nitropropane is preferable.
- Examples of the cross-linking agent used when producing the amidomethyl group-bonded sea-island composite fiber include aldehyde compounds such as paraformaldehyde, acetaldehyde and benzaldehyde.
- Examples of the catalyst for the cross-linking reaction used in producing the amidomethyl group-bonded sea-island composite fiber include sulfuric acid, hydrochloric acid, nitrate, aluminum halide (III) (for example, aluminum chloride (III)) or iron halide (III).
- aluminum halide (III) for example, aluminum chloride (III)
- iron halide (III) for example, Lewis acid such as iron (III) chloride
- Lewis acid such as iron (III) chloride
- sulfuric acid or iron (III) chloride is preferably mixed.
- the concentration of the catalyst in the mixed solution when producing the amidomethyl group-bonded sea-island composite fiber is preferably 5 to 80 wt%, more preferably 30 to 70 wt%.
- the impregnation temperature at the time of producing the amidomethyl group-bonded sea-island composite fiber is preferably 0 to 90 ° C, more preferably 5 to 40 ° C.
- the impregnation time for producing the amidomethyl group-bonded sea-island composite fiber is preferably 1 minute to 120 hours, more preferably 5 minutes to 24 hours.
- Examples of the solvent used for producing the sea-island composite fiber in which a ligand containing an amino group is bonded to the surface include N, N-dimethylformamide, diethyl ether, dioxane, tetrahydrofuran or dimethyl sulfoxide, and dimethyl sulfoxide is preferable. ..
- Examples of the catalyst used for producing the sea-island composite fiber in which a ligand containing an amino group is bonded to the surface include triethylamine, an organic base such as 1,4-diazabicyclo [2.2.2] octane, or sodium hydroxide. Examples thereof include inorganic bases, but organic bases such as triethylamine are preferable.
- the concentration of the catalyst in the mixed solution when producing a sea-island composite fiber in which a ligand containing an amino group is bonded to the surface is preferably 50 to 1000 mM, more preferably 300 to 700 mM.
- the impregnation temperature at the time of producing a sea-island composite fiber in which a ligand containing an amino group is bonded to the surface is preferably 15 to 80 ° C, more preferably 40 to 60 ° C.
- the impregnation time for producing a sea-island composite fiber in which a ligand containing an amino group is bonded to the surface is preferably 30 minutes to 24 hours, preferably 1 hour to 8 hours.
- the blood treatment material according to the present embodiment is preferably used as a carrier to be filled in a blood purification column, and particularly when extracorporeal circulation is performed for the purpose of treating an inflammatory disease, adsorption of activated leukocytes and / or inflammatory cytokines. It is preferably used as a carrier for removal.
- a blood purification column using a blood treatment material is used as an extracorporeal circulation column for blood purification therapy, the blood drawn out of the body may be passed directly through the column, or it may be used in combination with a plasma separation membrane or the like. Good.
- Inflammatory disease refers to the entire disease in which an inflammatory reaction is induced in the body, for example, systemic erythematosus, rheumatoid arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, drug-induced hepatitis, alcoholic disease.
- Hepatitis hepatitis A, hepatitis B, hepatitis C, hepatitis D or hepatitis E, sepsis (eg, gram-negative strain-derived sepsis, gram-positive strain-derived sepsis, culture-negative sepsis, fungal septicemia), influenza , Acute respiratory distress syndrome (ARDS, also referred to as acute respiratory distress syndrome, acute respiratory distress syndrome), acute lung injury (ALI), pancreatitis, idiopathic interstitial pneumonia (Idiopathic) Pulmonary Fibrosis (IPF), inflammatory enteritis (eg, ulcerative colitis, Crohn's disease), blood preparation blood transfusion, organ transplantation, reperfusion disorder after organ transplantation, respiratory distress, cholangitis or neonatal blood type incompatibility, etc.
- sepsis eg, gram-negative strain-derived sepsis, gram-positive strain-derived sepsis, culture-negative sepsis, fun
- Hepatitis eg, gram-negative bacterium-derived sepsis, gram-positive bacterium-derived sepsis, culture-negative sepsis, fungal sepsis
- influenza eg, acute respiratory distress syndrome, acute lung injury, pancreatitis, idiopathic interstitial pneumonia, Can be mentioned.
- the above-mentioned therapeutic use for inflammatory diseases is preferable, and among them, diseases that are difficult to treat with drugs alone and involve both activated leukocytes and inflammatory cytokines.
- Treatment of possible sepsis eg, gram-negative bacterium-derived sepsis, gram-positive bacterium-derived sepsis, culture-negative sepsis, fungal sepsis
- influenza eg, gram-negative bacterium-derived sepsis, gram-positive bacterium-derived sepsis, culture-negative sepsis, fungal sepsis
- influenza eg, gram-negative bacterium-derived sepsis, gram-positive bacterium-derived sepsis, culture-negative sepsis, fungal sepsis
- influenza eg, acute respiratory distress syndrome, acute lung injury, idiopathic interstitial pneumonia
- acute respiratory distress syndrome e.g, acute respiratory distress syndrome, acute lung injury, idiopathic interstitial pneumonia
- IL-8 is a kind of inflammatory cytokine contained in blood components, and is known to be remarkably high in blood components of diseases caused by bronchiolitis or viral infection in patients with inflammatory diseases. Therefore, it is suitable as a blood component for evaluating blood purification performance. It can be judged that the higher the adsorption rate of IL-8, the higher the blood purification performance of the blood treatment material.
- an evaluation method of the blood purification performance of the blood treatment material there is a method of evaluating the removal rate of activated leukocytes.
- a method of calculating the removal rate of activated leukocytes for example, a container having an inlet and an outlet is filled with a material for blood purification, a liquid containing activated leukocytes is passed through the container, and their concentrations at the inlet and outlet are used. There is a method of calculating the removal rate of each of them from the change of.
- the removal rate of the activated leukocytes is preferably 80% or less. ..
- the fiber surface may be peeled off as fine particles due to brittle fracture due to friction with the liquid, and may be mixed in the passed solution.
- the generated fine particles may be mixed into the body, so that it is necessary to install a separate filter to ensure safety, which complicates management. Therefore, it is desirable that the blood treatment material does not break as brittle as possible during circulation. Whether or not brittle fracture has occurred can be evaluated by measuring the number of fine particles generated from the blood treatment material.
- First method: light shielding particle counting method; pp.1-2 can be used as a reference. Specific examples thereof include a method in which a blood treatment material is cut out in a fixed area and filled in a cell, water in the cell is stirred to extract fine particles, and the number of fine particles obtained by the extraction is measured.
- the blood purification column of the present invention is characterized by including the above-mentioned blood treatment material.
- the "blood purification column” means a column having at least a liquid inlet portion, a case portion, and a liquid outlet portion, and the case portion is filled with a blood treatment material.
- Examples of the column include a radial flow type column.
- the blood purification column according to the present embodiment can adsorb blood components and the like from the liquid by passing the liquid, it is used to purify or remove the target blood component from the liquid containing the blood components and the like. It can be used, for example, for the separation of specific blood components.
- the blood purification column according to the present embodiment is suitably used for adsorbing and removing humoral factors in blood and cells in blood among blood components, and among them, adsorbing and removing inflammatory cytokines and activated leukocytes. It is particularly preferably used as a blood purification column for.
- the shape of the container of the blood purification column may be a container having an inlet, an outlet, and a case of a liquid containing a blood component or the like (hereinafter, liquid), and the case may be filled with a blood treatment material.
- a container in which a blood treatment material is wound around a pipe and formed into a cylinder (hereinafter, a cylinder) can be filled inside, and the liquid enters from the outer circumference of the cylinder and flows into the inside of the cylinder. Examples thereof include a container in which the liquid goes out of the container or a container in which the liquid enters from the inside of the cylinder and flows out of the cylinder, and then the liquid goes out of the container.
- a structure in which the blood treatment material is wound around a pipe having holes on the side surface is preferable, and specifically, in order to allow the supplied liquid to flow out.
- Examples thereof include a radial flow type container including a plate which is sealed and arranged so as to fix the water-insoluble material in the space around the central pipe, and the shape of the container is cylindrical or triangular.
- Examples thereof include a prismatic container such as a square columnar, a hexagonal columnar column, or an octagonal columnar column, but the structure is not limited to this.
- a container having a cylindrical space inside which can be filled with a circularly cut blood treatment material, and having a liquid inlet and a liquid discharge port can be considered.
- a plate having a liquid inlet provided for discharging the supplied liquid a plate having a liquid discharge port provided for discharging the supplied liquid, and a circular blood treatment material.
- Examples thereof include a container having a cylindrical case portion filled with a cut-out material, and having a liquid inlet and a liquid discharge port.
- the shape of the blood treatment material is not limited to a circular shape, and can be appropriately changed to an elliptical shape, a polygonal shape such as a triangle or a quadrangle, or a trapezoidal shape according to the container shape of the blood purification column.
- Examples of the container for the blood purification column include those made of glass, plastic / resin, stainless steel, etc., and the size of the container is appropriately selected according to the purpose of use.
- the size of the blood purification column container There is no particular limitation on the size of the blood purification column container, but considering the operability and ease of disposal at clinical sites and measurement locations, the material is preferably plastic or resin, and the size is hand-held.
- An easy size is preferable, the height of the entire blood purification column is 1 cm or more and 30 cm or less, the outer diameter is 1 cm or more and 10 cm or less, and the internal volume is 200 cm 3 or less.
- a blood purification column having an internal volume of 0.94 cm 3 (inner diameter 1.0 cm x height 1.2 cm) and an outer diameter of 2.0 cm is used because of the ease of measurement. This is not the case.
- the blood treatment material is preferably laminated and filled in the blood purification column.
- laminating means stacking two or more blood treatment materials in close contact with each other, and as a method of laminating and filling, for example, a plurality of blood treatment materials processed into a sheet form such as an axial flow column are used. Examples include a method of stacking sheets and a method of winding a blood treatment material processed into a sheet form around a pipe having holes such as a radial flow column.
- the blood purification column may be filled with the blood treatment material alone, or may be filled with other water-insoluble materials and various spacers in combination.
- the spacer include fibers in the form of sheets such as knitted fabrics, woven fabrics, and non-woven fabrics, membranes, beads, hydrogels, and the like.
- the island ratio was controlled to 50 wt% to obtain a sea-island composite fiber A (hereinafter referred to as fiber A) having a single fineness of 3.0 dtex, a fiber diameter of 20 ⁇ m, 700 islands, and 36 filaments.
- fiber A sea-island composite fiber A having a single fineness of 3.0 dtex, a fiber diameter of 20 ⁇ m, 700 islands, and 36 filaments.
- the island ratio was controlled to 50 wt% to obtain a sea-island composite fiber B (hereinafter referred to as fiber B) having a single fineness of 3.0 dtex, a fiber diameter of 20 ⁇ m, 700 islands, and 36 filaments.
- fiber B sea-island composite fiber B having a single fineness of 3.0 dtex, a fiber diameter of 20 ⁇ m, 700 islands, and 36 filaments.
- fiber C sea-island composite fiber C having a single fineness of 3.0 dtex, a fiber diameter of 20 ⁇ m, 700 islands, and 36 filaments.
- the island component consists of a core component and a sheath component.
- the core component polypropylene having an MFR of 12 g / 10 min (manufactured by Prime Polymer Co., Ltd.), and as the sheath component, polystyrene having an MFR of 18 g / 10 min (weight average molecular weight 18).
- Polyethylene terephthalate copolymerized PET1 melt viscosity: 45 Pa ⁇ s obtained by copolymerizing 8.0 mol% of 5-sodium sulfoisophthalic acid and 10 wt% of polyethylene glycol having a number average molecular weight of 1000 as sea components.
- each polymer component is weighed with a measuring plate having a plurality of measuring holes, and a distribution plate having a plurality of distribution holes formed in a confluence groove for merging the copolymers discharged from the measuring holes. It was constructed, and the sheath component in the island component was flowed into a spinning pack incorporating a sea-island composite base processed so as to have a slit shape to form a sea-island composite flow, which was melt-discharged.
- the core / sheath ratio is controlled to 50/50 (v / v)
- the sea / island ratio is controlled to 30/70 (v / v)
- the single fineness is 5.0 dtex
- the fiber diameter is 30 ⁇ m
- the number of filaments is 24. Obtained fiber.
- 1 g of the obtained sea-island composite fiber is immersed in chloroform 50 cm 3 at room temperature and allowed to stand overnight to dissolve the sea component of the sea-island composite fiber, and then washed in the order of methanol and ion-exchanged water.
- a core-sheath composite slit fiber D (hereinafter referred to as fiber D) having 16 slits and a slit gap of 2 ⁇ m was obtained.
- knitted fabric A (Preparation of knitted fabric A) Using fiber A, adjust the basis weight adjustment scale of the tube knitting machine (model name: circular knitting machine MR-1, Maruzen Sangyo Co., Ltd.), and adjust the basis weight to 56 g / m 2 and bulk density to 0.20 g / cm 3 .
- a knitted fabric A (hereinafter referred to as knitted fabric A) was produced.
- knitted fabric B (Preparation of knitted fabric B) Using fiber B, adjust the basis weight adjustment scale of the tube knitting machine (model name: circular knitting machine MR-1, Maruzen Sangyo Co., Ltd.), and adjust the basis weight to 55 g / m 2 and bulk density to 0.20 g / cm 3 .
- a knitted fabric B (hereinafter referred to as knitted fabric B) was produced.
- knitted fabric C (Preparation of knitted fabric C) Using fiber C, adjust the basis weight adjustment scale of the tubular knitting machine (model name: circular knitting machine MR-1, Maruzen Sangyo Co., Ltd.), and the basis weight is 54 g / m 2 and the bulk density is 0.19 g / cm 3 .
- a knitted fabric C (hereinafter referred to as knitted fabric C) was produced.
- knitted fabric D (Preparation of knitted fabric D) Using fiber D, adjust the basis weight adjustment scale of the cylinder knitting machine (model name: circular knitting machine MR-1, Maruzen Sangyo Co., Ltd.), and adjust the basis weight to 70 g / m 2 and bulk density to 0.22 g / cm 3 .
- a knitted fabric D (hereinafter referred to as knitted fabric D) was produced.
- N- hydroxymethyl-2-chloroacetamide (hereinafter, NMCA) after addition of 3.3g nitrobenzene 26cm 3 and 98 wt% sulfuric 17cm 3 mixture was stirred at 10 ° C. until NMCA dissolved, prepare NMCA solution did.
- NMCA N- hydroxymethyl-2-chloroacetamide
- PFA paraformaldehyde
- TEPA Tetraethylenepentamine
- DMSO40cm 3 Tetraethylenepentamine 0.2 cm 3 and triethylamine 2.9 cm 3 in a mixture dissolved in DMSO40cm 3, the knitted fabric A after washing with the above methanol added as it, 3 at 40 ° C. Impregnated for hours.
- a blood treatment material 1 was composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 1 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 1 The average roughness (Ra) was calculated by analyzing the blood treatment material 1.
- the content of the amino group contained in the blood treatment material 1 was determined by back titrating the content of the amino group contained in the blood treatment material 1 by acid-base back titration.
- a blood treatment material 1 was dried by allowing 1.5 g of the blood treatment material 1 in a 200 cm 3 eggplant flask and allowing it to stand at 80 ° C. for 48 hours under normal pressure in a dryer.
- 1.0 g of the blood treatment material 1 and 50 cm 3 of a 6M sodium hydroxide aqueous solution were added to a polypropylene container, and the mixture was stirred for 30 minutes, and the blood treatment material 1 was filtered off using a filter paper.
- the blood treatment material 1 was added to 50 cm 3 of ion-exchanged water, stirred for 30 minutes, and filtered using a filter paper.
- the blood treatment material 1 after desalting is obtained by repeating the operations of adding the blood treatment material 1 to the ion-exchanged water, washing and filtering until the pH of the washing liquid after filtering the added ion-exchanged water reaches 7. It was.
- the desalted blood treatment material 1 was allowed to stand for 8 hours under vacuum conditions in a vacuum dryer set at 30 ° C. Subsequently, 1.0 g of the blood treatment material 1 and 30 cm 3 of 0.1 M hydrochloric acid were added to a polypropylene container, and the mixture was stirred for 10 minutes.
- Ra arithmetic mean roughness
- the blood treatment material 2 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the amount of NMCA added was changed to 3.8 g. Since the blood treatment material 2 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 2 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 2 The average roughness (Ra) was calculated by analyzing the blood treatment material 2.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 2 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 3 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the amount of NMCA added was changed to 4.2 g. Since the blood treatment material 3 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 3 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 3 The average roughness (Ra) was calculated by analyzing the blood treatment material 3.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 3 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 4 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the knitted fabric A was changed to the knitted fabric B and the amount of NMCA added was changed to 4.7 g. Since the blood treatment material 4 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 4 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 4 The average roughness (Ra) was calculated by analyzing the blood treatment material 4.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 4 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 5 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the knitted fabric A was changed to the knitted fabric C. Since the blood treatment material 5 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 5 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 5 The average roughness (Ra) was calculated by analyzing the blood treatment material 5.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 5 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 6 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the amount of NMCA added was changed to 2.8 g. Since the blood treatment material 6 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 6 and the arithmetic average of the surface of the water-insoluble material contained in the blood treatment material 6 The roughness (Ra) was calculated by analyzing the blood treatment material 6.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 6 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 7 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the amount of NMCA added was changed to 4.7 g. Since the blood treatment material 7 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 7 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 7 The average roughness (Ra) was calculated by analyzing the blood treatment material 7. The blood treatment material 7 was prepared under the same conditions as the method for producing the tetraethylenepentamine-parachlorophenylated knitted fabric for Example 1 described in Patent Document 3.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 7 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 8 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the amount of NMCA added was changed to 5.6 g. Since the blood treatment material 8 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 8 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 8 The average roughness (Ra) was calculated by analyzing the blood treatment material 8.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 8 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 9 was obtained by performing the same operation as the method for producing the blood treatment material 1 except that the knitted fabric A was changed to the knitted fabric D. Since the blood treatment material 9 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 9 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 9 The average roughness (Ra) was calculated by analyzing the blood treatment material 9.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 9 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- Adacolumn registered trademark: JIMRO Co., Ltd., approval number: 21100BZZ00687000 was disassembled with a pipe cutter, and the beads taken out were used as blood treatment material 12. Since the blood treatment material 12 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 12 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 12 The average roughness (Ra) was calculated by analyzing the blood treatment material 12.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 13 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the blood treatment material 14 was obtained by performing the same operation as the method for producing the blood treatment material 9 except that the amount of NMCA added was changed to 5.6 g. Since the blood treatment material 14 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 14 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 14 The average roughness (Ra) was calculated by analyzing the blood treatment material 14.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 14 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- the knitted fabric A was filtered off using a glass filter to obtain a blood treatment material 15. Since the blood treatment material 15 is composed of a water-insoluble material, the content of amino groups per 1 g of dry weight of the water-insoluble material contained in the blood treatment material 15 and the surface arithmetic of the water-insoluble material contained in the blood treatment material 15 The average roughness (Ra) was calculated by analyzing the blood treatment material 15.
- the blood treatment material 15 was produced under the same conditions as the method for producing the tetraethylenepentamined knitted fabric for Example 2 described in Patent Document 4.
- the arithmetic mean roughness (Ra) of the surface of the blood treatment material 15 was measured by performing the same operation as that of the blood treatment material 1.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) was obtained by analysis in the fiber minor axis direction, and the minimum value (RaB) was obtained by analysis in the fiber major axis direction.
- Table 1 shows the maximum value (RaA), the minimum value (RaB), and the difference between the maximum value (RaA) and the minimum value (RaB).
- Example 1 Measurement of the number of fine particles generated in blood treatment material 1: Blood treatment material 1 is cut into a circle with a diameter of 26 mm, placed in a clean container together with 50 mL of ion-exchanged water (filter water) that has passed through a HEPA filter with a pore size of 0.3 ⁇ m, mixed 10 times, and then the liquid is discharged. , The fiber debris generated from the end face of the knitted fabric was washed. This cleaning operation was repeated once more.
- filter water ion-exchanged water
- the washed blood treatment material 1 is placed on a base plate attached to the stirring type ultra holder UHP-25K (manufactured by ADVANTEC), O-rings are stacked, and then sandwiched between cylindrical containers (cells) having a diameter of 18 mm to attach the base. It was fixed with metal fittings.
- the liquid outlet of the base plate was closed with a silicone tube, and 10 mL of filter water was added with the blood treatment material 1 on the bottom side, and it was confirmed that there was no water leakage.
- the stirring set attached to UHP-25K is attached here, and the stirring set is stirred on the magnetic stirrer RCN-7 (manufactured by Tokyo Rika Kikai Co., Ltd.) at a rotation speed of 600 rpm for 5 minutes without contacting the blood treatment material 1. It was.
- This liquid was collected and measured in 3 mL with a light-shielding automatic fine particle measuring device KL-04 (manufactured by Rion), and the number of fine particles of 5 ⁇ m or more per mL was measured, and the number of fine particles of 10 ⁇ m or more per 1 mL was measured. (Unit: piece / mL). The results are shown in Table 2.
- Measurement of activated leukocyte removal rate of blood treatment material 1 By stacking and filling a cylindrical column (inner diameter 1 cm x height 1.2 cm, outer diameter 2 cm, made of polypropylene) cut out in a disk shape with a diameter of 1 cm on the top and bottom. , A blood treatment material 1-filled column was prepared. Blood activated by shaking healthy human volunteer blood to which LPS was added to 70 EU / mL at 37 ° C. for 30 minutes at 65 rpm was passed through the column at a flow rate of 0.63 mL / min, and the column inlet. And blood samples were taken at the outlet.
- the time when blood flowed into the column was set to 0 minutes, and the sample was collected after passing the liquid for 6.5 minutes.
- the collected sample was measured with a multi-item automatic blood cell analyzer, and the activated leukocyte removal rate of the blood treatment material 1 was measured using the following formula 4. The results are shown in Table 2.
- IL-8 adsorption rate measurement of blood treatment material 1 In order to confirm the IL-8 adsorption performance of the blood treatment material 1, the blood treatment material 1 is taken out after impregnating the liquid containing IL-8 for a predetermined time, and IL-8 is adsorbed from the difference in the amount of IL-8 in the liquid before and after impregnation. The rate was measured. The measurement method is shown below.
- the blood treatment material 1 was cut out into a disk shape having a diameter of 6 mm, and then four pieces of each were placed in a polypropylene container.
- fetal bovine serum (FBS) prepared so that the concentration of IL-8 was 2000 pg / mL was added so as to be 88 mL with respect to 1 cm 3 of blood treatment material 1.
- FBS fetal bovine serum
- ELISA enzyme-linked immunosorbent assay
- IL-8 adsorption rate (%) of blood treatment material 1 ⁇ IL-8 concentration before inversion mixing (pg / mL) -IL-8 concentration after inversion mixing (pg / mL) ⁇ / IL- before inversion mixing 8 concentration (pg / mL) x 100 ... Equation 5
- Example 2 Using the blood treatment material 2, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 3 Using the blood treatment material 3, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 4 Using the blood treatment material 4, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 5 Using the blood treatment material 5, the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate were measured by performing the same measurements as in Example 1. The results are shown in Table 2.
- Example 6 Using the blood treatment material 13, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 1 Comparative Example 1 Using the blood treatment material 6, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 2 (Comparative Example 2) Using the blood treatment material 7, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 3 Using the blood treatment material 8, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 4 Using the blood treatment material 9, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- IL-8 adsorption rate measurement of blood treatment material 10 After taking out 50 cm of the blood treatment material 10, the IL-8 removal rate was measured by performing the same measurement as in Example 1. The results are shown in Table 2.
- IL-8 adsorption rate measurement of blood treatment material 11 After taking out 50 ⁇ L of the blood treatment material 11, the IL-8 removal rate was measured by performing the same measurement as in Example 1. The results are shown in Table 2.
- IL-8 adsorption rate measurement of blood treatment material 12 The IL-8 removal rate was measured by performing the same measurement as in Example 1 except that the blood treatment material 12 was changed to 75 mg. The results are shown in Table 2.
- Example 8 Using the blood treatment material 14, the same measurements as in Example 1 were carried out to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- Example 9 Using the blood treatment material 15, the same measurement as in Example 1 was performed to measure the number of fine particles generated, the activated leukocyte removal rate, and the IL-8 adsorption rate. The results are shown in Table 2.
- the maximum value (RaA) of the arithmetic mean roughness (Ra) indicates the maximum value (RaA) of the arithmetic mean roughness (Ra) on the surface of the water-insoluble material, and the minimum value of the arithmetic mean roughness (Ra).
- the value (RaB) indicates the minimum value (RaB) of the arithmetic mean roughness (Ra) of the surface of the water-insoluble material, and the difference between RaA and RaB (RaA-RaB) is the arithmetic mean roughness of the surface of the water-insoluble material.
- the difference between the maximum value (RaA) and the minimum value (RaB) of (Ra) is shown.
- the number of fine particles generated having a particle size of 5 ⁇ m or more indicates the number of fine particles generated from the blood treatment material having a size of 5 ⁇ m or more per unit volume
- the number of fine particles having a particle size of 10 ⁇ m or more is
- the activated leukocyte removal rate indicates the removal rate of activated leukocytes adsorbed and removed by the blood treatment material.
- IL-8 adsorption rate indicates the adsorption rate of IL-8, which is a kind of inflammatory cytokine adsorbed and removed by the blood treatment material.
- the difference between the maximum value (RaA) and the minimum value (RaB) of the arithmetic mean roughness (Ra) of the surface of the water-insoluble material is less than 0.30 ⁇ m or more than 1.50 ⁇ m. It was clarified that blood components such as activated leukocytes and IL-8 can be adsorbed and removed more efficiently than blood treatment materials. Then, it became clear that the number of fine particles generated could be suppressed, and that it had high safety.
- the blood treatment material of the present invention can adsorb and remove blood components such as activated leukocytes and inflammatory cytokines with high efficiency, it can be used as an adsorption carrier for extracorporeal circulation.
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Abstract
Description
[1] 繊維形状又は粒子形状の水不溶性材料を含み、レーザー顕微鏡を用いて算出された上記水不溶性材料の表面の算術平均粗さ(Ra)の最大値(RaA)と最小値(RaB)の差分が0.30~1.50μmである、血液処理材料。
[2] 上記差分は、0.33~1.00μmである、[1]記載の血液処理材料。
[3] 上記最大値(RaA)は、0.50μm以上である、[1]又は[2]記載の血液処理材料。
[4] 上記水不溶性材料の表面にアミノ基を含むリガンドが結合し、上記アミノ基の含量は、上記水不溶性材料の乾燥重量1g当たり0.20~3.00mmolである、[1]~[3]のいずれかに記載の血液処理材料。
[5] 上記水不溶性材料の形状が、繊維であり、上記水不溶性材料の表面の算術平均粗さ(Ra)が最小となるレーザー顕微鏡の測定方向が、繊維長軸方向である、[1]~[4]のいずれかに記載の血液処理材料。
[6] 上記水不溶性材料の形状が、海島複合繊維であり、該海島複合繊維の海成分が、ポリスチレン、ポリスチレンの誘導体、ポリスルホン及びポリスルホンの誘導体並びにそれらの混合物からなる群から選択され、該海島複合繊維の島成分が、ポリプロピレン、ポリエチレン及びポリプロピレン/ポリエチレン共重合体並びにそれらの混合物からなる群から選択される、[1]~[5]のいずれかに記載の血液処理材料。
[7] 活性化白血球及び/又は炎症性サイトカインの吸着除去用である、[1]~[6]のいずれかに記載の血液処理材料。
[8] [1]~[7]のいずれかに記載の血液処理材料を備える、血液浄化カラム。
海成分として、メルトフローレート(単位:g/10min、以下MFR)が18g/10minのポリスチレン(重量平均分子量18万、PSジャパン株式会社製)、島成分として、MFRが12g/10minのポリプロピレン(株式会社プライムポリマー製)を用いて別々に溶融計量し、1つの吐出孔当たり700の島成分用分配孔が穿設された海島複合口金が組み込まれた紡糸パックに流入させて、海島複合流とし、溶融吐出した。島比率を50wt%に制御し、単繊度3.0dtex、繊維径20μm、島数700個、フィラメント数36本である、海島複合繊維A(以下、繊維A)を得た。
海成分として、MFRが2g/10minのポリスチレン(重量平均分子量26万、PSジャパン株式会社製)、島成分として、MFRが12g/10minのポリプロピレン(株式会社プライムポリマー製)を用いて別々に溶融計量し、1つの吐出孔当たり700の島成分用分配孔が穿設された海島複合口金が組み込まれた紡糸パックに流入させて、海島複合流とし、溶融吐出した。島比率を50wt%に制御し、単繊度3.0dtex、繊維径20μm、島数700個、フィラメント数36本である、海島複合繊維B(以下、繊維B)を得た。
海成分として、MFRが18g/10minのポリスチレン(重量平均分子量18万、PSジャパン株式会社製)90質量%及びMFRが12g/10minのポリプロピレン(株式会社プライムポリマ―製)10質量%の混合物、島成分として、MFRが12g/10minのポリプロピレン(株式会社プライムポリマー製)を用いて別々に溶融計量し、1つの吐出孔当たり700の島成分用分配孔が穿設された海島複合口金が組み込まれた紡糸パックに流入させて、海島複合流とし、溶融吐出した。島比率を50wt%に制御し、単繊度3.0dtex、繊維径20μm、島数700個、フィラメント数36本である、海島複合繊維C(以下、繊維C)を得た。
島成分が、芯成分と鞘成分とからなり、上記芯成分として、MFRが12g/10minのポリプロピレン(株式会社プライムポリマー製)、上記鞘成分として、MFRが18g/10minのポリスチレン(重量平均分子量18万、PSジャパン株式会社製)、海成分として、5-ナトリウムスルホイソフタル酸8.0モル%および数平均分子量1000のポリエチレングリコール10wt%が共重合したポリエチレンテレフタレート(共重合PET1 溶融粘度:45Pa・s)を用いて別々に溶融計量し、各ポリマー成分を計量する複数の計量孔を有する計量プレート、計量孔からの吐出ポリマーを合流する合流溝に複数の分配孔が穿設されている分配プレートで構成されており、島成分中の鞘成分がスリット形状になるよう加工された海島複合口金が組み込まれた紡糸パックに流入させて、海島複合流とし、溶融吐出した。芯/鞘比率を50/50(v/v)、海/島比率を30/70(v/v)に制御し、単繊度5.0dtex、繊維径30μm、フィラメント数24本である、海島複合繊維を得た。続いて、得られた海島複合繊維1gを、室温でクロロホルム50cm3に浸漬させ、一晩静置して海島複合繊維の海成分を溶解させた後、メタノール、イオン交換水の順で洗浄することで、海島複合繊維の芯鞘成分として、スリット数16本、スリット間隙2μmである、芯鞘複合スリット繊維D(以下、繊維D)を得た。
繊維Aを用いて、筒編み機(機種名:丸編み機 MR-1、丸善産業株式会社)の度目調整目盛りを調整し、目付けが56g/m2、嵩密度が0.20g/cm3の筒編み編地A(以下、編地A)を作製した。
繊維Bを用いて、筒編み機(機種名:丸編み機 MR-1、丸善産業株式会社)の度目調整目盛りを調整し、目付けが55g/m2、嵩密度が0.20g/cm3の筒編み編地B(以下、編地B)を作製した。
繊維Cを用いて、筒編み機(機種名:丸編み機 MR-1、丸善産業株式会社)の度目調整目盛りを調整し、目付けが54g/m2、嵩密度が0.19g/cm3の筒編み編地C(以下、編地C)を作製した。
繊維Dを用いて、筒編み機(機種名:丸編み機 MR-1、丸善産業株式会社)の度目調整目盛りを調整し、目付けが70g/m2、嵩密度が0.22g/cm3の筒編み編地D(以下、編地D)を作製した。
N-ヒドロキシメチル-2-クロロアセトアミド(以下、NMCA)3.3gをニトロベンゼン26cm3と98重量%硫酸17cm3混合液に添加後、NMCAが溶解するまで10℃で攪拌して、NMCA溶液を調製した。次に、ニトロベンゼン2cm3、98重量%硫酸1.3cm3の混合液にパラホルムアルデヒド(以下、PFA)0.2gを添加し、PFAが溶解するまで20℃で攪拌し、PFA溶液を調製した。該PFA溶液3.3cm3を5℃に冷却後、上記NMCA溶液43cm3に混合した。該混合液を5分間攪拌したのちに、編地A1gを添加して2時間含浸させた。含浸後の編地Aを10℃のニトロベンゼン43cm3中に浸して反応を停止させた後、該編地Aに付着しているニトロベンゼンをメタノールで洗浄した。
血液処理材料1に含まれるアミノ基の含量は、該血液処理材料1に含まれるアミノ基の含量を、酸塩基逆滴定することより決定した。200cm3ナスフラスコに血液処理材料1を1.5g、乾燥機にて常圧下、80℃で48時間静置することで乾燥処理をした血液処理材料1を得た。次に、ポリプロピレン製容器に、上記血液処理材料1を1.0g、6M水酸化ナトリウム水溶液50cm3を添加して30分攪拌し、濾紙を用いて血液処理材料1をろ別した。次にイオン交換水50cm3に上記血液処理材料1を添加して30分間攪拌し、濾紙を用いてろ別した。上記血液処理材料1をイオン交換水に添加、洗浄及びろ別操作を、添加したイオン交換水のろ別後の洗浄液のpHが7になるまで繰り返すことで脱塩後の血液処理材料1を得た。該脱塩後の血液処理材料1を30℃に設定した真空乾燥機で真空条件下、8時間静置した。続いて、ポリプロピレン製容器に、上記血液処理材料1を1.0gと0.1M塩酸を30cm3添加し、10分間攪拌した。攪拌後、溶液のみを5cm3抜き取って、ポリプロピレン製容器に移した。次に、抜き取った溶液に対して、0.1Mの水酸化ナトリウム水溶液を0.1cm3滴下した。滴下後10分間攪拌し、溶液のpHを測定した。0.1Mの水酸化ナトリウム水溶液の滴下後10分間の攪拌、pHの測定操作を同様に100回繰り返した。溶液のpHが8.5を越えた際の0.1Mの水酸化ナトリウム水溶液滴下量を1g当たりの滴定量とした。1g当たりの滴定量と以下の式2を用いて、血液処理材料1の1g当たりのアミノ基の含量を算出した。結果を表1に示す。
血液処理材料1を1枚、2cm×2cmの大きさに切り出し、25℃、16時間真空乾燥した。乾燥させた該血液処理材料1を、レーザー顕微鏡(キーエンス社製;超深度3D形状測定顕微鏡VK-9710)を用いて、対物レンズ50倍の倍率で画像を撮影し、得られた画像の単糸の輪郭曲線から基準長lを20μmとして、10箇所の線分をそれぞれが平行の位置関係にならないようランダムに抜き取り、VK9710搭載の解析ソフトを用いて線粗さモードにより解析することで、10箇所それぞれの表面の算術平均粗さ(Ra)を測定した(JIS B 0601:2001準拠)。この操作を異なる3視野の画像でそれぞれ行い、3視野の画像から抜き取った合計30箇所の線分についてRaをそれぞれ算出し、これら30箇所のRaから、最大値(RaA)と、最小値(RaB)を得た。ここで、上記RaAは繊維短軸方向の解析により得られ、上記RaBは繊維長軸方向の解析により得られた。また、得られたRaAとRaBの差分を以下の式3を用いて算出した。結果を表1に示す。なお表1中、RaAとRaBの値は、それぞれ小数第3位を四捨五入した値であり、RaA-RaBの値は、RaAとRaBの差分をとった後に小数第3位を四捨五入した値である。
NMCAの添加量を3.8gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料2を得た。血液処理材料2は水不溶性材料で構成されているため、血液処理材料2に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料2に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料2を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料2に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料2表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を4.2gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料3を得た。血液処理材料3は水不溶性材料で構成されているため、血液処理材料3に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料3に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料3を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料3に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料3表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
編地Aを編地Bに変更し、NMCAの添加量を4.7gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料4を得た。血液処理材料4は水不溶性材料で構成されているため、血液処理材料4に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料4に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料4を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料4に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料4表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
編地Aを編地Cに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料5を得た。血液処理材料5は水不溶性材料で構成されているため、血液処理材料5に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料5に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料5を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料5に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料5表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を2.8gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料6を得た。血液処理材料6は水不溶性材料で構成されているため、血液処理材料6に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料6に含まれる水不溶性材料表面の算術平均粗さ(Ra)は、血液処理材料6を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料6に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料6表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を4.7gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料7を得た。血液処理材料7は水不溶性材料で構成されているため、血液処理材料7に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料7に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料7を分析することで算出した。なお、血液処理材料7は、特許文献3に記載の実施例1用のテトラエチレンペンタミン-パラクロロフェニル化編地の作製方法と同じ条件で作製した。
血液処理材料1と同様の操作を行うことで、血液処理材料7に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料7表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を5.6gに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料8を得た。血液処理材料8は水不溶性材料で構成されているため、血液処理材料8に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料8に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料8を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料8に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料8表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
編地Aを編地Dに変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料9を得た。血液処理材料9は水不溶性材料で構成されているため、血液処理材料9に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料9に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料9を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料9に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料9表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
SepXiris(登録商標:バクスター株式会社、医療機器承認番号:22500BZX00401000)をパイプカッターにより解体し、取り出した中空糸を血液処理材料10とした。血液処理材料10は水不溶性材料で構成されているため、血液処理材料10に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料10に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料10を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料10に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料10を5cmの長さに1本切り出した後、血液処理材料1と同様の操作を行うことで、血液処理材料10表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
Cytosorb(登録商標:CytoSorbents Corporation)をパイプカッターにより解体し、取り出したビーズを血液処理材料11とした。血液処理材料11は水不溶性材料で構成されているため、血液処理材料11に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料11に含まれる水不溶性材料表面の算術平均粗さ(Ra)は、血液処理材料11を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料11に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料11を1粒取り出し、血液処理材料1と同様の操作を行うことで、血液処理材料11表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の解析により得られた最大値(RaA)と最小値(RaB)、該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
アダカラム(登録商標:株式会社JIMRO、承認番号:21100BZZ00687000)をパイプカッターにより解体、取り出したビーズを血液処理材料12とした。血液処理材料12は水不溶性材料で構成されているため、血液処理材料12に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料12に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料12を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料12に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料12を1粒取り出し、血液処理材料1と同様の操作を行うことで、血液処理材料12表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の解析により得られた最大値(RaA)と最小値(RaB)、該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を4.7gに変更し、編地AをNMCA溶液及びPFA溶液の混合液に含浸させる時間を90分に変更した以外は、血液処理材料1の作製方法と同様の操作を行うことで、血液処理材料13を得た。血液処理材料13は水不溶性材料で構成されているため、血液処理材料13に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料13に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料13を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料13に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料13表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCAの添加量を5.6gに変更した以外は、血液処理材料9の作製方法と同様の操作を行うことで、血液処理材料14を得た。血液処理材料14は水不溶性材料で構成されているため、血液処理材料14に含まれる水不溶性材料の乾燥重量1g当たりのアミノ基の含量や血液処理材料14に含まれる水不溶性材料の表面の算術平均粗さ(Ra)は、血液処理材料14を分析することで算出した。
血液処理材料1と同様の操作を行うことで、血液処理材料14に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料14表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
NMCA4.7gをニトロベンゼン26cm3と98重量%硫酸17cm3混合液に添加後、NMCAが溶解するまで10℃で攪拌して、NMCA溶液を調製した。次に、ニトロベンゼン2cm3、98重量%硫酸1.3cm3の混合液にPFA0.2gを添加し、PFAが溶解するまで20℃で攪拌し、PFA溶液を調製した。該PFA溶液3.3cm3を5℃に冷却後、上記NMCA溶液43cm3に混合した。該混合液を5分間攪拌したのちに、編地A1gを添加して2時間含浸させた。含浸後の編地Aを10℃のニトロベンゼン43cm3中に浸して反応を停止させた後、該編地Aに付着しているニトロベンゼンをメタノールで洗浄した。
血液処理材料1と同様の操作を行うことで、血液処理材料15に含まれるアミノ基の含量を測定した。結果を表1に示す。
血液処理材料1と同様の操作を行うことで、血液処理材料15表面の算術平均粗さ(Ra)を測定した。その算術平均粗さ(Ra)の最大値(RaA)は繊維短軸方向の解析により得られ、最小値(RaB)は繊維長軸方向の解析により得られた。最大値(RaA)、最小値(RaB)及び該最大値(RaA)と該最小値(RaB)の差分を表1に示す。
血液処理材料1の微粒子発生数測定:
血液処理材料1を直径26mmの円形に切り出し、孔サイズ0.3μmのHEPAフィルターを通過させたイオン交換水(フィルター水)50mLとともに清浄な容器に入れて10回転倒混和してから液を排出し、編地端面から生じた繊維屑を洗浄した。この洗浄操作をさらにもう1回繰り返した。洗浄した該血液処理材料1を攪拌型ウルトラホルダーUHP-25K(ADVANTEC社製)付属のベースプレートに載せてO-リングを重ねたのち直径18mmの円筒状容器(セル)の間に挟みこみ、ベース取付金具により固定した。ベースプレートの液出口をシリコーンチューブで塞ぎ、該血液処理材料1を底面側にして10mLのフィルター水を加え、水漏れがないことを確認した。ここにUHP-25K付属の攪拌セットを取りつけ、マグネティックスターラーRCN-7(東京理化器械社製)上で、攪拌セットが該血液処理材料1に接触しない状態で回転数600rpmにて5分間攪拌を行った。この液を採取し、光遮蔽型自動微粒子測定装置KL-04(リオン社製)で3mL測定し、1mL当たりの5μm以上の微粒子数、1mL当たりの10μm以上の微粒子数を測定し、微粒子発生数(単位:個/mL)とした。結果を表2に示す。
上下に溶液の出入り口のある円筒状カラム(内径1cm×高さ1.2cm、外径2cm、ポリプロピレン製)に、直径1cmの円板状に切り抜いた血液処理材料1を積層して充填することで、血液処理材料1充填カラムを作製した。LPSを70EU/mLになるよう添加した健常ヒトボランティア血液を37℃、30分間、65rpmで振とうして活性化させた血液を、当該カラムに流量0.63mL/minで通液し、カラム入口及び出口で血液のサンプル採取を行った。カラム出口のサンプルはカラム内に血液が流入した時点を0分とし、6.5分間通液したものを採取した。採取したサンプルを多項目自動血球分析装置で測定し、以下の式4を用いて、血液処理材料1の活性化白血球除去率を測定した。結果を表2に示す。
血液処理材料1のIL-8吸着性能を確認するため、IL-8を含む液体に血液処理材料1を所定時間含浸後に取り出し、含浸前後の液体中のIL-8量の差分からIL-8吸着率を測定した。以下に測定方法を示す。
血液処理材料2を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料3を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料4を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料5を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料13を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料6を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料7を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料8を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料9を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料10の微粒子発生数測定:
血液処理材料10を10cm×39本切り出した後、実施例1と同様の測定を行うことで微粒子発生数を測定した。結果を表2に示す。
血液処理材料10を10cm×157本切り出した後、円筒状カラム(内径0.5cm×高さ10cm、内容積1.9cm3、ポリカーボネート製)に変更した以外は、実施例1と同様の測定を行うことで活性化白血球除去率を測定した。結果を表2に示す。
血液処理材料10を50cm分取り出した後、実施例1と同様の測定を行うことでIL-8除去率を測定した。結果を表2に示す。
血液処理材料11の微粒子発生数測定:
血液処理材料11を0.28mL取り出した後、実施例1と同様の測定を行うことで微粒子発生数を測定した。結果を表2に示す。
血液処理材料11を1.13mL取り出した後、実施例1と同様の測定を行うことで活性化白血球除去率を測定した。結果を表2に示す。
血液処理材料11を50μL取り出した後、実施例1と同様の測定を行うことでIL-8除去率を測定した。結果を表2に示す。
血液処理材料12の微粒子発生数測定:
血液処理材料12を0.40gに変更した以外は、実施例1と同様の測定を行うことで微粒子発生数を測定した。結果を表2に示す。
血液処理材料12を1.63g取り出した後、実施例1と同様の測定を行うことで活性化白血球除去率を測定した。結果を表2に示す。
血液処理材料12を75mgに変更した以外は、実施例1と同様の測定を行うことでIL-8除去率を測定した。結果を表2に示す。
血液処理材料14を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
血液処理材料15を用いて、実施例1と同様の測定を行うことで微粒子発生数、活性化白血球除去率、IL-8吸着率を測定した。結果を表2に示す。
2.単糸径(繊維径)
Claims (8)
- 繊維形状又は粒子形状の水不溶性材料を含み、
レーザー顕微鏡を用いて算出された前記水不溶性材料の表面の算術平均粗さ(Ra)の最大値(RaA)と最小値(RaB)の差分が0.30~1.50μmである、血液処理材料。 - 前記差分は、0.33~1.00μmである、請求項1記載の血液処理材料。
- 前記最大値(RaA)は、0.50μm以上である、請求項1又は2記載の血液処理材料。
- 前記水不溶性材料の表面にアミノ基を含むリガンドが結合し、
前記アミノ基の含量は、前記水不溶性材料の乾燥重量1g当たり0.20~3.00mmolである、請求項1~3のいずれか一項記載の血液処理材料。 - 前記水不溶性材料の形状が、繊維であり、
前記水不溶性材料の表面の算術平均粗さ(Ra)が最小となるレーザー顕微鏡の測定方向が、繊維長軸方向である、請求項1~4のいずれか一項記載の血液処理材料。 - 前記水不溶性材料の形状が、海島複合繊維であり、
該海島複合繊維の海成分が、ポリスチレン、ポリスチレンの誘導体、ポリスルホン及びポリスルホンの誘導体並びにそれらの混合物からなる群から選択され、
該海島複合繊維の島成分が、ポリプロピレン、ポリエチレン及びポリプロピレン/ポリエチレン共重合体並びにそれらの混合物からなる群から選択される、請求項1~5のいずれか一項記載の血液処理材料。 - 活性化白血球及び/又は炎症性サイトカインの吸着除去用である、請求項1~6のいずれか一項記載の血液処理材料。
- 請求項1~7のいずれか一項記載の血液処理材料を備える、血液浄化カラム。
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WO2023167184A1 (ja) * | 2022-03-03 | 2023-09-07 | 東レ株式会社 | 好中球除去材料及び好中球除去材料の製造方法 |
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WO2008026667A1 (fr) * | 2006-08-31 | 2008-03-06 | Toray Industries, Inc. | Support d'adsorption contenant une fibre composite |
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US10262371B2 (en) | 2017-02-06 | 2019-04-16 | Idealratings, Inc. | Automated compliance scoring system that analyzes network accessible data sources |
KR20200051586A (ko) * | 2017-09-08 | 2020-05-13 | 도레이 카부시키가이샤 | 면역 억제성 단백질 흡착 재료 및 흡착 칼럼 |
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WO2022220292A1 (ja) * | 2021-04-15 | 2022-10-20 | 東レ株式会社 | 血液処理材料 |
WO2023167184A1 (ja) * | 2022-03-03 | 2023-09-07 | 東レ株式会社 | 好中球除去材料及び好中球除去材料の製造方法 |
WO2024158046A1 (ja) * | 2023-01-27 | 2024-08-02 | 東レ株式会社 | 活性化血小板除去用水不溶性担体 |
Also Published As
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JP7497682B2 (ja) | 2024-06-11 |
CN114423470A (zh) | 2022-04-29 |
EP4039327A1 (en) | 2022-08-10 |
KR20220074852A (ko) | 2022-06-03 |
CA3156253A1 (en) | 2021-04-08 |
EP4039327A4 (en) | 2023-11-29 |
JPWO2021066152A1 (ja) | 2021-04-08 |
US20220362742A1 (en) | 2022-11-17 |
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