JP2019136696A - Porous fiber complex, and purification column with built-in porous fiber complex - Google Patents

Abstract

To provide a porous fiber complex having a material having an adsorption capacity stably supported thereon, and a purification column with a built-in porous fiber complex.SOLUTION: A porous fiber complex contains a compound having a chelate functional group and a metal compound in a porous fiber, the compound having a chelate functional group being contained at least on the surface of the porous fiber.SELECTED DRAWING: None

Description

  The present invention relates to a porous fiber composite and a purification column incorporating the porous fiber composite.

  In the fields of water treatment and medical treatment, etc., in order to purify the fluid that is the liquid to be treated, unnecessary ions, organic substances, and proteins contained in the fluid such as raw water and blood, that is, the substance to be removed are efficiently removed. It has been required to be removed. As a method for removing the substance contained in the fluid, there is a method using adsorption in addition to a method using filtration or diffusion using a membrane. In general, the removal by adsorption is characterized in that the selectivity of the substance to be removed, that is, the substance to be adsorbed, is higher than that of filtration or diffusion.

  There are many substances having adsorption ability used for removal by adsorption. Among these metals, metals form, for example, complexes and sparingly soluble salts with the substances to be adsorbed in the fluid. Thereby, the metal can adsorb | suck a to-be-adsorbed substance efficiently, and can be removed.

  On the other hand, when a substance having an adsorbing ability such as a metal is used alone, the substance having an adsorbing ability may be eluted in the fluid, or fine particles may be generated by contact with the fluid. For this reason, a method has been considered in which a specific carrier is loaded with a substance having an adsorption ability. In particular, in medical applications, if a substance having an adsorbing ability is eluted in blood, the biological environment may be significantly disturbed. Therefore, for medical use, it is more important to stably carry a substance having an adsorption ability on a carrier.

  For example, Patent Document 1 discloses an example in which a metal compound is contained in porous particles. By making the carrier porous, it is possible to increase the surface area per volume and improve the adsorption performance.

  Patent Document 2 discloses a base material for removing a toxic substance that is an adsorbed substance. This base material contains a nanostructured material as a substance having an adsorbing ability. The nanostructured material carrier is described as being porous granular. The support is adjusted so that the pore structure allows electrostatic interaction with the nanostructured material. As a result, the nanostructured material is not eluted from the carrier.

  Patent Document 3 describes a substrate for a protein capture material having selectivity. This base material contains a metal ion as a substance having an adsorbing ability. The carrier shape for supporting metal ions is a porous sheet. Metal ions are supported via chelate functional groups on the sheet.

International Publication No. 2017/082423 Special table 2010-512939 gazette JP 2009-101289 A

  However, for example, in Patent Document 1, there is no particular structure that reduces the elution of the metal contained in the carrier.

  Moreover, although the support | carrier of patent document 2 is considered so that a nanostructure may not elute, since the interaction of a nanostructure and a metal is utilized, there exists a possibility that the metal adsorption | suction performance may fall.

  Moreover, the carrier described in Patent Document 3 is not intended for blood purification. Therefore, as in Patent Document 1, there is no idea to actively prevent metal elution. In addition, the metal and the carrier form a chelate, which may reduce the metal adsorption performance.

  Therefore, the present invention provides a porous fiber composite in which a substance having an adsorbing ability is stably supported, and a purification column incorporating the porous fiber composite.

  In order to solve the above problems, the present invention has the following configuration.

That is, a porous fiber composite comprising a porous fiber containing a compound having a chelating functional group and a metal compound,
In the porous fiber composite, the compound having the chelating functional group is contained at least on the surface of the porous fiber.

  ADVANTAGE OF THE INVENTION According to this invention, the purification | cleaning column which incorporated the porous fiber composite and the porous fiber composite with which the substance which has adsorption ability was stably supported can be obtained.

  The present invention is a porous fiber composite comprising a porous fiber containing a compound having a chelating functional group and a metal compound, wherein the compound having the chelating functional group is at least on the surface of the porous fiber. The present invention relates to a porous fiber composite that is included. Moreover, the purification column of the present invention contains the porous fiber composite.

  Hereinafter, the porous fiber composite of the present invention and the purification column incorporating the porous fiber composite will be described in detail.

<Porous fiber and porous fiber composite>
The porous fiber used in the present invention has a three-dimensional pore structure. The three-dimensional pore structure refers to a structure having continuous pores that are three-dimensionally expanded.

  In the present invention, a material containing at least the following substances in the porous fiber is referred to as a porous fiber composite. That is, in the present invention, a compound having at least a compound having a chelating functional group on the surface of the porous fiber and further containing a metal compound is referred to as a porous fiber composite. The porous fiber composite in the present invention contains at least the above-mentioned substances, but may further contain other substances within a range not impeding the effects obtained by the present invention.

  In the present invention, the meaning of carrying a substance having an adsorbing ability will be described by taking as an example the case where the substance having an adsorbing ability is a metal compound. In the present invention, the porous fiber carrying a metal compound mainly refers to a state in which the porous fiber is physically held inside the porous fiber. However, the metal compound is not necessarily limited to a state in which the metal compound is physically held inside the porous fiber, and may be chemically bonded to a constituent molecule inside the porous fiber.

  The metal compound used in the present invention preferably contains one or more kinds selected from carbonates of rare earth elements and Group 4 oxides. These metal compounds have high adsorption performance, low solubility in water, small pH change in the living body, and hardly release inorganic ions when they come into contact with blood, making them suitable for blood purification applications. It has the characteristics.

  Of the Group 4 oxides, titanium oxide is particularly preferable. Titanium oxide has high adsorption performance similar to rare earth element carbonates, has low solubility in water, and has a small pH change, and is therefore suitable for blood purification applications.

  Here, blood purification in the present invention refers to guiding blood in a living body outside the body, removing a predetermined substance, and then returning it to the body again. Examples of the medical device used for blood purification include a dialysis membrane used in artificial dialysis or an adsorption column used for directly contacting blood and adsorbing harmful substances in blood.

  The fiber shape of the porous fiber used in the present invention is a solid shape. By adopting a solid shape, and by making the shape inside the fiber porous suitable for adsorption, it becomes easy to secure a sufficient adsorption area, and thus the substances to be adsorbed in the blood are efficiently adsorbed and removed It becomes easy to do. In the case of a solid fiber, the shape of the fiber cross section is not necessarily limited to a perfect circle, and may be an irregular cross section. Examples of the irregular cross-sectional shape include an ellipse, a triangle, and a multileaf system. By making it an irregular cross section, the surface area per volume of solid fiber can be improved, and improvement in adsorption performance can be expected. On the other hand, in the case of hollow fibers, when the pressure loss is different between the inside and outside of the hollow fiber, there is a difference in the flow rate of the liquid to be treated inside and outside the hollow fiber, resulting in a decrease in the adsorption efficiency of the column. Concerned. Further, in order to equalize the pressure loss between the inside and outside of the hollow fiber, there are significant restrictions on the inner diameter of the hollow fiber and the column packing rate. Furthermore, when blood flows through a column filled with hollow fibers, the hollow portion of the hollow fibers is a closed environment that is fixed compared to the environment outside the hollow fibers in the column (the gap outside the hollow fibers is It is easy to form thrombus etc. which deforms when fiber moves in the column.

  The porous fiber composite of the present invention has at least a compound having a chelating functional group on the surface. The chelating functional group in the present invention is a functional group that can selectively adsorb by interacting with a specific metal ion. Electron donating atoms such as nitrogen, oxygen, sulfur, and phosphorus contained in the chelating functional group coordinate to the metal ion to form a stable chelate such as a 5-membered ring or 6-membered ring. Adsorb selectively. The chelating functional group and the metal ion to be removed are exemplified in the following items, but in the present invention, the combination is not limited to those combinations, and is appropriately selected based on the compatibility with the metal ion to be removed. Can be used. For the metal preferably used in the present invention, a compound containing an amino group, a carboxyl group, a phosphino group or a thiol group is preferably used. However, in the present invention, not only these functional groups but also a functional group containing an element derived from a chelating functional group indicates a chelating functional group.

  Thus, the amount of elution of metal ions can be reduced by including in the fiber a compound that forms a chelate with metal ions. The molecular weight of the compound is not particularly limited, and both a low molecule and a polymer can be used, but a polymer is preferably used in consideration of the viewpoint that it is supported on a fiber and the compound is difficult to elute. Here, the polymer refers to a compound having a weight average molecular weight of 1,000 or more. The weight average molecular weight can be measured using GPC (gel permeation chromatography). The shape of the low molecule or polymer can be appropriately selected from linear, branched, dendritic, cyclic and the like. It is appropriately selected according to the type of porous fiber material and metal ion, but in general, amines such as ethyleneimine, diethylenetriamine, triethylenetetramine, tetraethylenepentamine and the like, high molecular weight substances thereof, and carboxylic acids such as acrylic acid. Acids and their high molecular weight compounds are preferably used.

  As a method of incorporating a compound having a chelating functional group into the porous fiber used in the present invention, it may be performed by imparting a chemical bond such as a covalent bond or an ionic bond, or by physical adsorption. It may be given. As a specific method, it is preferable to modify the surface by irradiation with radiation. Furthermore, it is preferable to crosslink by irradiation of radiation. In order to crosslink by irradiation with radiation, for example, there is a method of irradiating a solution containing a metal compound, a porous fiber, and a compound having a chelating functional group, and crosslinking the compound to the porous fiber. Can be mentioned.

  The radiation used here is appropriately selected depending on the material such as electromagnetic radiation, particle radiation, etc., but γ-ray is particularly preferred because it can also serve as sterilization.

  The liquid used for mixing the metal compound, the porous fiber, and the compound having a chelating functional group is preferably a polar solvent and more preferably water from the viewpoint of radical generation.

  In addition, the order of mixing the compound having a chelating functional group, the porous fiber, and the metal compound in the solution is not particularly limited, but in order to have the compound having the chelating functional group on at least the surface of the porous fiber composite. A method in which a porous fiber containing a metal compound is prepared in advance and a solution containing the compound having a chelating functional group is mixed is preferable. Then, by irradiating with radiation, a porous fiber composite having a compound having a chelating functional group on at least the surface can be efficiently obtained.

  Here, when the compound having a chelating functional group is first mixed with the liquid, it is more preferable to use water for the liquid as described above. At this time, the aqueous solution concentration of the compound having a chelating functional group is preferably 0.01% or more in order to reduce elution of metal ions of the metal compound from the obtained porous fiber composite. It is more preferably 1% or more, and further preferably 0.5% or more. On the other hand, in order for the porous fiber composite to exhibit desirable adsorption performance, it is preferably 10% or less, more preferably 8% or less, and even more preferably 5% or less.

  The dose during irradiation is preferably 10 KGy or more, more preferably 15 KGy or more, and further preferably 20 KGy or more so that the compound is sufficiently immobilized by crosslinking. On the other hand, in order to suppress fiber breakage, it is preferably 100 KGy or less, more preferably 50 KGy or less, and even more preferably 40 KGy or less.

  The porosity of the surface of the porous fiber used in the present invention is preferably in the range of 0.1% to 30.0%.

  The porosity of the surface of the porous fiber is preferably 0.1% or more because the adsorbed substance in the liquid to be treated is easily diffused into the porous fiber composite, and is preferably 0.5% or more. More preferably, it is 1.0% or more. On the other hand, the porosity of the surface of the porous fiber maintains the fiber strength and appropriate surface roughness, elution of metal out of the porous fiber composite, and inside the pores of the porous fiber composite. In order to reduce the outflow of generated fine particles and the like to the outside, it is preferably 30% or less, more preferably 16% or less, and further preferably 12% or less.

  The porosity of the surface of the porous fiber used in the present invention can be measured by the following method. First, the porous fiber is sufficiently moistened and then immersed in liquid nitrogen, and the moisture in the pores is instantaneously frozen with liquid nitrogen. Thereafter, the porous fiber is quickly folded, and in a state where the cross section of the porous fiber is exposed, the water frozen in a vacuum dryer of 0.1 torr or less is removed to obtain a dry sample. Thereafter, a thin film such as platinum (Pt) or platinum-palladium (Pt—Pd) is formed on the surface of the porous fiber by sputtering to obtain an observation sample. The cross section of the sample is observed at 50,000 times with a scanning electron microscope (for example, S-5500, manufactured by Hitachi High-Technologies Corporation), and the image is taken into a computer. The size of the captured image is preferably 640 pixels × 480 pixels. The SEM image is cut into a range of 6 μm × 6 μm at an arbitrary position, and image analysis is performed with image processing software. By binarization processing, a threshold value is determined so that the structure portion has bright luminance and the other portions have dark luminance, and an image is obtained in which the bright luminance portion is white and the dark luminance portion is black. If the structure part and other parts cannot be separated because the contrast difference in the image is small, the image is divided into parts with the same contrast range and binarized, and then the original Connect to and return to a single image. Alternatively, the image analysis may be performed by painting other than the structure portion in black. Since the image contains noise and the dark luminance portion having 5 or less consecutive pixels is indistinguishable from noise and a hole, it is treated as a bright luminance portion as a structure. As a method for eliminating noise, a dark luminance portion having 5 or less consecutive pixels is excluded when measuring the number of pixels. Alternatively, the noise portion may be painted white. The number of pixels in the dark luminance portion is measured, and a percentage with respect to the total number of pixels in the analysis image is calculated to obtain a hole area ratio. The same measurement is performed on 30 images, and an average value is calculated.

  The metal compound used in the present invention preferably has an average particle size in the range of 1 μm to 1,000 μm.

  The average particle diameter of the metal compound is preferably larger than the pore diameter, preferably 1 μm or more, and more preferably 5 μm or more in order to prevent the metal compound from passing through the pores and eluting into the liquid to be treated such as blood. 10 μm or more is more preferable.

  On the other hand, the smaller the average particle diameter of the metal compound, the more powder particles can be packed in the column and the like, and the total specific surface area can be increased, so that the adsorption efficiency can be improved. Further, when spinning, the die is not easily clogged, and the spinning performance is hardly lowered. For this reason, the average particle size of the metal compound is preferably 1,000 μm or less, more preferably 500 μm or less, and even more preferably 300 μm or less.

  When the metal compound is an aggregate of primary particles, the primary particles themselves may have a particle size smaller than the above range, and the aggregate only needs to be within the above range.

  As a method for measuring the average particle diameter, first, an observation sample is prepared using the porous fiber composite by the same method as the method for measuring the porosity of the porous fiber surface. The cross section of the sample is observed with a scanning electron microscope (for example, S-5500, manufactured by Hitachi High-Technologies Corporation). A transparent sheet is overlaid on a printed electron microscope image of an arbitrary fiber cross-section with a scanning electron microscope (400 times), and the metal compound is painted black using a black pen or the like. Using a ruler and a black pen, the scale bar is accurately copied. Thereafter, by copying the transparent sheet onto a white paper, the metal compound can be clearly distinguished from black and the non-metal compound portion can be clearly distinguished from white. Thereafter, a scale bar is attached using image analysis software “Image J” to determine the particle size of the metal compound. For the particle diameter, the maximum diameter in two orthogonal directions is obtained, and the average value is calculated as the particle diameter. In addition, the electron microscope image of the cross section of the porous fiber composite is obtained by photographing 30 arbitrary cross sections of the porous fiber composite and calculating the average value.

In the present invention, for the metal compound supported inside the porous fiber composite, the area occupancy of the metal compound in the fiber cross section of the porous fiber composite is 3% or more from the viewpoint of the column volume. Is preferred. It is more preferably 5% or more, further preferably 10% or more, and further preferably 20% or more. When the area occupancy of the metal compound is 3% or more, the amount of the porous fiber composite necessary for exhibiting sufficient adsorption performance when columned can be reduced. As a result, the column volume can be reduced.
On the other hand, the area occupancy of the metal compound is preferably 80% or less, more preferably 70% or less, and further preferably 60% or less from the viewpoint of fiber strength. When the area occupancy of the metal compound is 80% or less, sufficient fiber strength of the porous fiber composite can be obtained. As a result, spinning becomes easier. In addition, since the metal compound is supported on the fiber material, it is easy to prevent the metal compound from peeling from the fiber cross section when the fiber is damaged by external pressure.

  The area occupation ratio in the cross-section of the porous fiber composite of the metal compound can be measured by the following method.

First, an observation sample is prepared by the same method as the method for measuring the surface area ratio. The cross section of the sample is observed with a scanning electron microscope (for example, S-5500, manufactured by Hitachi High-Technologies Corporation). A transparent sheet is overlaid on a printed electron microscope image of an arbitrary fiber cross-section with a scanning electron microscope (400 times), and the metal compound is painted black using a black pen or the like. Using a ruler and a black pen, the scale bar is accurately copied. Thereafter, by copying the transparent sheet onto a white paper, the metal compound can be clearly distinguished from black and the non-metal compound portion can be clearly distinguished from white. Thereafter, a scale bar is attached using image analysis software “Image J”, and the total area of the metal compound is obtained by Analyze Particles. Then, the area ratio which a metal compound occupies is calculated | required by Formula 1 below. In addition, the electron microscope image of the cross section of the porous fiber composite is obtained by photographing 30 arbitrary cross sections of the porous fiber composite and calculating the average value.
Formula 1 Area occupation ratio (%) of metal compound = total area of metal compound / fiber cross-sectional area × 100%
The material of the porous fiber used in the present invention is not particularly limited, but an organic material is preferably used from the viewpoint of ease of molding and cost. Accordingly, the porous fibers used in the present invention include polymethyl methacrylate (hereinafter referred to as PMMA), polyacrylonitrile (hereinafter referred to as PAN) polysulfone (hereinafter referred to as PSf), polyether sulfone (hereinafter referred to as PES), and cellulose. It is preferable that 1 or more types of compounds chosen from are included. More specifically, PMMA, PAN, PSf, PES, polyaryl ether sulfone, polypropylene, polystyrene, polycarbonate, cellulose, cellulose triacetate, ethylene-vinyl alcohol copolymer and the like are preferably used. Among them, it is preferable to include a material that is an amorphous polymer and has a property of adsorbing protein, and examples thereof include PMMA and PAN. PMMA and PAN are also representative examples of fibers having a uniform structure in the thickness direction, and are preferable because a structure having a uniform structure and a sharp pore size distribution can be easily obtained. PMMA is particularly preferable because it has excellent biocompatibility and is less likely to cause various shocks when used for blood purification. Moreover, since it is excellent in moldability and cost, and has high transparency, it is preferable that the inside of the fiber is relatively easily observed when the porous fiber is viewed from the outside, and the fouling state is easily evaluated. Here, fouling means that proteins and organic compounds adhere to the fiber surface or inside.

The porous fiber composite of the present invention preferably has an elution amount of metal ions of 0.1 mg / cm ³ or less. This unit means that the elution amount of metal ions per 1 cm ³ of the porous fiber composite is 0.1 mg or less. The elution amount of metal ions in the present invention is defined as a value when measured as described later. The elution amount of metal ions is more preferably 0.5 mg / cm ³ or less, further preferably 0.3 mg / cm ³ or less, still more preferably 0.2 mg / cm ³ or less, 0 Particularly preferred is 1 mg / cm ³ or less. When the elution amount of metal ions from the porous fiber composite is 0.1 mg / cm ³ or less, the biological environment is reduced by elution of metal ions from the porous fiber composite when used for medical purposes such as a purification column. The possibility of being disturbed can be reduced.

The measuring method of the elution amount of the metal ion of the porous fiber composite in the present invention is as follows. Bovine plasma is prepared by centrifugation from bovine blood supplemented with disodium ethylenediaminetetraacetate. The bovine plasma was adjusted so that the total protein amount (TP) was 6.5 ± 0.5 g / dL. The bovine plasma used was within 5 days after blood collection. 3400 mg sodium monohydrogen phosphate (Na ₂ HPO ₄ ) and 13.8 mg potassium dihydrogen phosphate (KH ₂ PO ₄ ) were dissolved per 400 mL of the bovine plasma to prepare a solution.

The porous fiber composite was cut to 11 cm, and 200 pieces were inserted into a cylindrical plastic case having a dialysate inlet and a dialysate outlet. Both ends were sealed with an epoxy resin to create a minimodule, and γ-ray treatment was performed by various methods described below. 30 mL of bovine plasma prepared by the above method was circulated through the obtained minimodule at 37 ° C. for 4 hours at a flow rate of 2 mL / min. After circulation for 4 hours, the circulating bovine plasma was collected and stirred. Thereafter, the bovine plasma was sent to Toray Research Center, Inc., and the measurement of neodymium ion concentration in the plasma was entrusted. Using the metal ion concentration in plasma calculated by inductively coupled plasma-mass spectrometry (ICP-MS), the amount of elution neodymium per unit volume (elution amount metal ion amount) was calculated by the following formula 1.
Formula 1: Eluted metal ion amount of porous fiber composite [mg / cm ³ ] = Metal ion concentration in plasma [mg / L] × Plasma volume [L] / Porous fiber composite volume [cm ³ ]
In the porous fiber composite of the present invention, the adsorption performance of the substance to be adsorbed is preferably 3.0 mg / cm ³ or more, more preferably 3.5 mg / cm ³ or more, and 4.0 mg / cm ^3. more preferably cm ³ or more, even more preferably at 7.0 mg / cm ³ or more, and particularly preferably 15.0 mg / cm ³ or more. When the adsorption performance of the porous fiber composite is 3.0 mg / cm ³ or more, it is possible to sufficiently remove the substance to be adsorbed, and the amount of the porous fiber composite filled in the purification column can be reduced. Therefore, in medical use, it becomes easy to reduce the amount of blood taken out of the body.

The method for measuring the adsorption performance of the porous fiber composite in the present invention is as follows. An appropriate amount of the porous fiber composite is shaken at 37 ° C. for 4 hours to be reacted. After the reaction for 4 hours, the reaction solution is centrifuged at 9000 rpm for 5 minutes, and the supernatant is recovered. The supernatant is measured by the molybdate direct method. The molybdate direct method is a method of calculating the phosphorus concentration in plasma from the amount of absorption utilizing the fact that phosphorus and molybdate in plasma are combined to form phosphomolybdic acid having ultraviolet absorption. In this way, the phosphorus concentration in the supernatant is measured to obtain the final concentration Ce (mg / dL). The phosphorus concentration of the solution at the start of the experiment is similarly measured. Thereafter, the phosphorus adsorption performance per 1 cm ^{3 of the} porous fiber composite is calculated by the following formula 2. In addition, the phosphorus adsorption | suction performance calculated | required from this type | formula becomes a value when adsorption | suction is not saturated.
Formula 2: Phosphorus adsorption performance of porous fiber composite [mg / cm ³ ] = [(Cs (mg / dL) −Ce (mg / dL)) × 0.5 (dL)] / porous fiber composite volume (Cm ³ )
Here, the adsorbed substance refers to a substance that exists in blood in the case of medical use as an example, and is a substance that is harmful to the nature of the substance and a substance that exhibits a harmful action when present in an excessive amount. . Examples of the low molecular weight compound include phosphoric acid, urea, creatinine and the like. As the polymer compound, a cytokine, HMGB1, tumor-producing protein, beta _{2-microglobulin} (32MG), it can be cited α1 microglobulin (α1MG) or the like. The porous fiber composite of the present invention is particularly suitably used for adsorption removal of phosphorus in blood.

When the porous fiber composite of the present invention is used for adsorption removal of phosphorus, it is preferable to satisfy the following relationship. That is, the porous fiber composite of the present invention preferably has an elution amount of the metal ions in the range of 0.01 mg / cm ³ or less when the phosphorus adsorption performance is 1 mg / cm ³ . In the present invention, the phosphorus adsorption performance is defined as a value when measured as described later.

  The ratio of the amount of eluted metal ions and phosphorus adsorption performance (the amount of eluted metal ions / phosphorus adsorption performance) is 0.1 or less, more preferably 0.05 or less, and still more preferably 0.01 or less. When the ratio of the eluted metal ion amount and the phosphorus adsorption performance of the porous fiber composite is 0.05 or less, the porous fiber composite is used in the purification column incorporating the porous fiber composite of the present invention. The ecological environment is less likely to be disturbed by the elution of metal ions from the metal, and a sufficient effect of removing and adsorbing phosphorus can be easily obtained without filling a large amount of the porous fiber composite. Therefore, it is easy to reduce the amount of blood that can be used for blood purification and brought out of the body for sufficient phosphorus removal, and a column suitable for blood purification can be produced. The method for measuring the phosphorus adsorption performance of the porous fiber composite in the present invention is as described above.

  In the present invention, the amount of the chelating functional group contained in the porous fiber composite can be quantified by a staining method using a dye having a negatively charged or positively charged functional group. This method can be confirmed in Table 2014/168198 and Table 2016/190407.

  The kind of the dye having a negatively charged functional group to be used is not particularly limited, but is preferably water-soluble, orange II, methyl orange, methyl red, thymol blue, disulfin blue, lumogalion, hydroxy Examples include naphthol blue and Coomassie brilliant blue.

  The kind of the dye having a positively charged functional group to be used is not particularly limited, but is preferably water-soluble, and examples thereof include toluidine blue O, malachite green, methylene blue, crystal violet, and methyl violet.

Specifically, a staining method using Orange II as a dye having a negatively charged functional group in the present invention will be described below.
A sample mass of 10 mg was stained with 0.5 mL of orange II acetic acid interference solution (pH 4.0) at 37 ° C. for 1 hour. Excess orange II solution was wiped off and washed with 1 mL of acetic acid interference solution (pH 4.0) at 37 ° C. for 10 minutes. Washing was performed twice with 1 mL of water at 37 ° C. for 10 minutes. By treating with a 30 mM aqueous sodium hydroxide solution at 37 ° C. for 30 minutes, a dye having a negatively charged functional group ion-bonded to the positively charged functional group was extracted. The extract was neutralized with 35 mM hydrochloric acid, and the absorbance at 482 nm and 550 nm was measured with an ultraviolet / visible spectrophotometer (U-3900, Hitachi High-Tech Science), and the absorbance at 482 nm and 550 nm was subtracted. Using a separately prepared calibration curve, the amount of the positively charged functional group of the sample was quantified from the absorbance. When dilution was required, the same amount of 35 mM hydrochloric acid as the extract was added, and then a mixed solution of 30 mM aqueous sodium hydroxide / 35 mM hydrochloric acid = 1: 1 was added. Here, assuming that 1 mol of orange II is bonded to 1 mol of the positively charged functional group, in the present invention, the quantitative mole number of orange II is defined as the amount of the positively charged functional group.

  The amount of the chelating functional group contained in the porous fiber composite is preferably 5 mmol / g or more in order to reduce elution of metal ions of the metal compound from the obtained porous fiber composite. More preferably, it is more preferably 15 mmol / g or more. On the other hand, it is preferably 30 mmol / g or less, preferably 25 mmol / g or less, in order to reduce the amount of the porous fiber composite to be packed in the purification column and to easily reduce the amount of blood taken out of the body. More preferably, it is more preferably 20 mmol / g or less.

The porous fiber composite of the present invention is preferably in a form in which a metal compound is mixed with a polymer because it is physically stable and can be easily produced. In this case, the addition ratio of the metal compound is preferably 5% by mass or more, more preferably 20% by mass or more, and further preferably 40% by mass or more based on the polymer to be mixed. Moreover, it is preferable that the addition rate of a metal compound is 80 mass% or less, It is more preferable that it is 70 mass% or less, It is further more preferable that it is 60 mass% or less. When the addition rate of the metal compound is 5% by mass or more, more preferably 20% by mass or more, and still more preferably 40% by mass or more, the porous fiber composite required for sufficient phosphorus adsorption when columned The volume can be reduced, and as a result, the column volume can be reduced and the amount of blood taken out of the body can be reduced. On the other hand, when the addition rate of the metal compound is 80% by mass or less, more preferably 70% by mass or less, and still more preferably 60% by mass or less, sufficient fiber strength of the porous fiber composite can be obtained, and spinnability is obtained. Tends to be good. The addition rate of the metal can be calculated by the following formula 3.
Formula 3: Rate of addition%: [mass of added metal compound] / (mass of added metal compound + mass of raw material polymer) × 100
The porous fiber composite used in the present invention preferably supports a metal compound inside the porous fiber in order to increase the adsorption efficiency, but may be supported on the surface of the porous fiber. When the porous fiber composite of the present invention is used for blood purification, it is necessary to reduce the amount of blood circulating outside the body as much as possible in order to prevent a decrease in blood pressure during use. Therefore, it is preferable that the adsorption performance per unit volume of the porous fiber is high. In addition to the surface of the porous fiber, the metal compound is also supported inside, so that the blood containing the substance to be adsorbed and the metal compound efficiently contact each other, increasing the adsorption performance per unit volume and efficiently. It can be removed.

  Examples of the method for supporting the metal compound inside the porous fiber include a method in which the metal compound is added to a polymer solution prepared at a predetermined concentration and mixed at a constant rotational speed. Alternatively, there is a method in which a polymer raw material, a metal compound, and a solvent for dissolving the polymer raw material are put in the same container from the beginning and mixed while rotating the rotor. Alternatively, a method of adding a metal compound while spraying a polymer solution already dissolved at a predetermined concentration can be mentioned. The method is not limited to the above as long as the metal compound can be uniformly dispersed in the polymer. In the case of a polymer that gels at room temperature, in order to increase the dissolution efficiency of the polymer, it is preferable to heat in a temperature range that suppresses gelation.

  The solid fibers used in the porous fiber composite of the present invention preferably have a solid fiber diameter (fiber diameter) of 50 to 1000 μm. The fiber diameter is preferably 50 μm or more, more preferably 100 μm or more, and still more preferably 150 μm or more. The fiber diameter is preferably 1000 μm or less, more preferably 800 μm or less, and still more preferably 500 μm or less. When the fiber diameter is 50 μm or more, more preferably 100 μm or more, and even more preferably 150 μm or more, even if the particle addition rate is increased, the fiber strength is not easily lowered, and the productivity is easily improved. On the other hand, when the fiber diameter is 1000 μm or less, more preferably 800 μm or less, and even more preferably 500 μm or less, the packing rate of the porous fiber composite packed in the column can be easily increased, and the adsorption performance can be easily improved.

The measuring method of the fiber diameter of the solid fiber used for the porous fiber composite of the present invention is as follows. That is, arbitrarily 50 of the solid fibers packed in the column are extracted and washed. After washing, the washing solution is completely replaced with pure water. A solid fiber is sandwiched between a slide glass and a cover glass. Using a projector (for example, Nikon Corporation V-10A), the outer diameter (outermost diameter) of the solid fibers is measured at arbitrary two positions for the same solid fibers. Take the average of the two outer diameters and round off to the first decimal place. When the number of filled solid fibers is less than 50, all the fibers are measured and the average value is similarly taken. When the cross section of the solid fiber of the porous fiber is other than a perfect circle, the diameter of the circle inscribed in the shape of the cross section of the solid fiber is a, and the diameter of the circumscribed circle is b. ) ^0.5 is the diameter of the fiber.

<Metal compound>
What is necessary is just to have a metal element with the metal compound of this invention, for example, an oxide, a hydroxide, a carbonate compound etc. are contained. Components other than the rare earth element carbonates or Group 4 oxides may include rare earth oxides, rare earth hydrated oxides, and the like. These metals may be used alone or as a mixture of two or more.

  In the metal compound of the present invention, the rare earth element preferably contains one or more elements selected from lanthanum, cerium, praseodymium, samarium, and neodymium. In this case, the rare earth element carbonates are lanthanum carbonate, cerium carbonate, praseodymium carbonate, neodymium carbonate and samarium carbonate. Further preferred are neodymium carbonate and samarium carbonate, which have high adsorption performance.

  The metal compound of the present invention preferably has a solubility in 100 g of water at 20 ° C. of 10 mg or less. The solubility is preferably 5 mg or less, more preferably 2 mg or less, and even more preferably 1 mg or less.

  The metal compound of the present invention preferably has an average particle size of more than 1 μm and 1000 μm or less. The average particle diameter is preferably 1000 μm or less, more preferably 800 μm or less, and particularly preferably 500 μm or less because the metal compound is preferably as small as possible. When the average particle size is 1000 μm or less, for example, when a metal is supported inside a porous fiber and used, it is preferable that the die is not clogged during spinning and the spinning performance is not easily lowered. In addition, the smaller the average particle size, the larger the specific surface area, and the higher the adsorption efficiency. However, when the average particle size is smaller than the pores of the porous fiber, the metal may pass through the pores and elute into the liquid to be treated such as blood. It can be said that it is preferable to exceed. However, when the metal compound is an aggregate of primary particles, the primary particles are not limited to this.

  The particle size in the present invention can be determined by the same method as the measurement method described above.

  The metal compound of the present invention is particularly preferably used as an adsorbent for the purpose of removing phosphate from blood in blood purification applications. Here, the adsorbent is preferably a compound having an adsorption performance, that is, an adsorbent capable of reducing the concentration of an adsorbed substance in a solution in the measurement of the adsorption performance described later.

  In addition, as a processing method when processing a polymer mixed with such a metal compound into a fiber shape, there are a dry spinning method, a wet spinning method, or a dry and wet spinning method that combines dry and wet methods. Absent. The shape of the fiber formed by solidification is determined by the shape of the cap used, and the main shape includes a hollow fiber shape and a solid fiber shape.

  The metal compound of the present invention is preferably used while being supported inside the porous fiber described above.

<Adsorption column>
The adsorption column of the present invention contains the porous fiber composite of the present invention. In particular, it is suitably used for removing phosphate from the blood.

  Next, the example of preparation of the porous fiber composite used for this invention is given.

<Spinning method>
After dissolving a polymer as a raw material of the porous fiber in an appropriate solvent, a predetermined amount of selected metal particles are added to prepare a spinning dope. The solvent is appropriately selected according to the polymer to be dissolved, but dimethylformamide, dimethyl sulfoxide, hexanone, xylene, tetralin, cyclohexanone, carbon tetrachloride, etc. are generally used. For example, when PMMA is used as the polymer, dimethyl sulfoxide (DMSO) is preferably used.

  If the spinning stock viscosity is too low, the stock solution may be highly fluid and difficult to maintain its intended shape. Therefore, the lower limit of the stock solution viscosity at the temperature of the spinning outlet is preferably 10 poise, more preferably 90 poise, still more preferably 400 poise, and particularly preferably 800 poise. On the other hand, when the viscosity of the spinning solution is too high, the discharge stability tends to decrease due to an increase in pressure loss during discharging the stock solution, and mixing of the stock solution may be difficult. Therefore, the upper limit of the stock solution viscosity at the temperature of the spinneret is preferably 100,000 poise, more preferably 50,000 poise.

  The spinning dope is discharged from a die having a circular stock solution discharge port, or in the case of spinning a modified cross-section fiber, from a die having a stock solution discharge port shaped to match the cross-sectional shape, and in a solid fiber shape in a coagulation bath To solidify. The coagulation bath usually comprises a coagulant such as water or alcohol, or a mixture of a solvent and a coagulant constituting the spinning dope. Further, the porosity of the porous fiber can be changed by controlling the temperature of the coagulation bath. Since the porosity can be affected by the type of spinning dope, etc., the temperature of the coagulation bath is also appropriately selected. In general, the porosity can be increased by increasing the coagulation bath temperature. Although this mechanism is not exactly clear, it is thought that the solvent reaction in the high temperature bath is fast and the solvent is solidified and fixed before shrinkage due to the competitive reaction between the solvent removal from the stock solution and the solidification shrinkage. However, if the coagulation bath temperature becomes too high, the pore diameter becomes excessive. For example, the solidification bath temperature is preferably 39 ° C. or more when solid gas containing PMMA is used as the base material and gas is put into the inner tube. 42 ° C. or higher is more preferable. On the other hand, the coagulation bath temperature is preferably 50 ° C. or lower, more preferably 46 ° C. or lower.

  Next, a step of washing the solvent adhering to the solidified solid fibers is passed. The means for washing the solid fibers is not particularly limited, but a method of allowing the solid fibers to pass through a multi-staged water bath (referred to as a washing bath) is preferably used. What is necessary is just to determine the temperature of the water in a water-washing bath according to the property of the polymer which comprises a fiber. For example, in the case of a fiber containing PMMA, 30 to 50 ° C. is used.

  Moreover, in order to maintain the pore diameter in the solid fiber after passing through the washing bath, a step of applying a moisturizing component may be added. The term “moisturizing component” as used herein refers to a component capable of maintaining the humidity of the solid fiber or a component capable of preventing a decrease in the humidity of the solid fiber in the air. Typical examples of moisturizing ingredients include glycerin and its aqueous solutions.

  After washing with water and applying moisturizing components, it is possible to pass through a bath (called heat treatment bath) filled with an aqueous solution of heated moisturizing components to increase the dimensional stability of solid fibers with high shrinkage. is there. The heat treatment bath is filled with a heated aqueous solution of the moisturizing component, and the solid fibers pass through this heat treatment bath and shrink due to thermal action, making it difficult to shrink in the subsequent steps, and the fiber structure Can be stabilized. Although the heat processing temperature at this time changes with the raw materials of a porous fiber, in the case of the fiber containing PMMA, 75 degreeC or more is preferable and 82 degreeC or more is more preferable. Moreover, 90 degrees C or less is preferable and 86 degrees C or less is set as a more preferable temperature.

  An example of an embodiment of the present invention is shown in the following examples.

(1) Measuring method of elution amount of substance having adsorption ability In the present invention, the elution amount of metal ion which is a substance having adsorption ability was measured as follows. In this example, the amount of neodymium ions eluted (the amount of solute neodymium) was determined by the following method as the amount of metal ions eluted.

  Bovine plasma was obtained by centrifugation from bovine blood supplemented with disodium ethylenediaminetetraacetate. The bovine plasma was adjusted so that the total protein amount (TP) was 6.5 ± 0.5 g / dL. The bovine plasma used was within 5 days after blood collection.

3400 mg sodium monohydrogen phosphate (Na ₂ HPO ₄ ) and 13.8 mg potassium dihydrogen phosphate (KH ₂ PO ₄ ) were dissolved per 400 mL of the bovine plasma to prepare a solution. Various porous fiber composites and porous fibers shown in Example 1 and Comparative Examples 1 and 2 were cut into 11 cm, and 200 pieces were inserted into a cylindrical plastic case having a dialysate inlet and a dialysate outlet. Both ends were sealed with an epoxy resin to create a minimodule, and γ-ray treatment was performed by various methods described below. 30 mL of bovine plasma prepared by the above method was circulated through the obtained minimodule at 37 ° C. for 4 hours at a flow rate of 2 mL / min. After circulation for 4 hours, the circulating bovine plasma was collected and stirred. Thereafter, the neodymium ion concentration in the bovine plasma was measured. Using the metal ion concentration in plasma calculated by inductively coupled plasma-mass spectrometry (ICP-MS), the amount of elution neodymium per unit volume (the elution amount of metal ions) was calculated by the following formula 4.
Formula 4: Dissolved metal ion amount of porous fiber composite [mg / cm ³ ] = Metal ion concentration in plasma [mg / L] × Plasma volume [L] / Porous fiber composite volume [cm ³ ]
(2) Evaluation of adsorption performance of porous fiber composite (Method of measuring phosphorus adsorption performance)
In order to evaluate the adsorption performance of the porous fiber composite of the present invention, phosphorus was selected as the substance to be adsorbed, and the phosphorus adsorption performance was measured by the following method. The phosphorus adsorption performance is preferably 3.0 mg / cm ³ or more, more preferably 3.5 mg / cm ³ or more, still more preferably 4.0 mg / cm ³ or more, and 7.0 mg / cm ^3. still more preferred ³ or more, and particularly preferably 15.0 mg / cm ³ or more. When the adsorption performance of the porous fiber composite is 3.0 mg / cm ³ or more, it is possible to sufficiently remove the substance to be adsorbed, and the amount of the porous fiber composite filled in the purification column can be reduced.

Various porous fiber composites and porous fibers 50 cm shown in Example 1 and Comparative Examples 1 and 2 were shaken and reacted in the bovine plasma prepared by the above method at 37 ° C. for 4 hours. After the reaction for 4 hours, the reaction solution was centrifuged at 9000 rpm for 5 minutes, and the supernatant was collected. The supernatant was measured by the molybdate direct method. The phosphorus concentration in the supernatant is measured and set as the final concentration Ce (mg / dL). The phosphorus concentration of the solution at the start of the experiment was similarly measured. Actual measurements were entrusted to the Nagahama Life Science Laboratory.
Thereafter, the phosphorus adsorption performance per 1 cm ^{3 of the} porous fiber composite was calculated by the following formula 5. In addition, the phosphorus adsorption | suction performance calculated | required from this type | formula becomes a value when adsorption | suction is not saturated.
Formula 5: Phosphorus adsorption performance of porous fiber composite [mg / cm ³ ] = [(Cs (mg / dL) −Ce (mg / dL)) × 0.5 (dL)] / porous fiber composite volume (Cm ³ )
(3) Measuring method of amount of chelating functional group contained in porous fiber composite
A sample mass of 10 mg was stained with 0.5 mL of an orange II acetic acid interference solution (Fujifilm Wako Pure Chemical Industries, Ltd.) (pH 4.0) at 37 ° C. for 1 hour. Excess orange II solution was wiped off and washed with 1 mL of acetic acid interference solution (pH 4.0) at 37 ° C. for 10 minutes. Washing was performed twice with 1 mL of water at 37 ° C. for 10 minutes. By treating with a 30 mM aqueous sodium hydroxide solution at 37 ° C. for 30 minutes, a dye having a negatively charged functional group ion-bonded to the positively charged functional group was extracted. The extract was neutralized with 35 mM hydrochloric acid, and the absorbance at 482 nm and 550 nm was measured with an ultraviolet / visible spectrophotometer (U-3900, Hitachi High-Tech Science), and the absorbance at 482 nm and 550 nm was subtracted. Using a separately prepared calibration curve, the amount of the positively charged functional group of the sample was quantified from the absorbance. When dilution was required, the same amount of 35 mM hydrochloric acid as the extract was added, and then a mixed solution of 30 mM aqueous sodium hydroxide / 35 mM hydrochloric acid = 1: 1 was added. Here, assuming that 1 mol of orange II is bonded to 1 mol of the positively charged functional group, in the present invention, the quantitative mole number of orange II is defined as the amount of the positively charged functional group.

[Example 1]
<Preparation of core liquid spinning dope>
First, 18 mass% PMMA stock solution was prepared. 40.7 parts by mass of syndiotactic-PMMA (syn-PMMA, manufactured by Mitsubishi Rayon Co., Ltd., “Dynar” (registered trademark) BR-85) having a mass average molecular weight of 400,000, and a syn having a mass average molecular weight of 1.4 million -PMMA (Sumitomo Chemical Co., Ltd., "Sumipex" (registered trademark) AK-150) 25.9 parts by mass, isotactic PMMA (iso-PMMA, manufactured by Toray Industries, Inc.) having a mass average molecular weight of 500,000. 13.4 parts by weight were mixed with 420 parts by weight of dimethyl sulfoxide (DMSO). 250 g of neodymium carbonate was added to 500 g of the obtained spinning stock solution to prepare a neodymium carbonate / PMMA stock solution containing 33.3% by mass of the metal compound, and stirred at 110 ° C. for 5 hours to obtain a core solution.

<Preparation of sheath liquid spinning dope>
122.1 parts by mass of syn-PMMA having a weight average molecular weight of 400,000, 77.8 parts by mass of syn-PMMA having a weight average molecular weight of 1,400,000, and 40.1 parts by mass of iso-PMMA having a weight average molecular weight of 500,000 The mixture was mixed with 760 parts by mass of sulfoxide and stirred at 110 ° C. for 8 hours to prepare a spinning dope.

<Spinning>
An annular slit die having an outer diameter / inner diameter of 2.1 / 1.95 mmφ was used. The base was heated to 100 ° C., and the sheath liquid was discharged from the slit part at a rate of 1.65 g / min, and the core liquid was discharged from the center part at a rate of 2.76 g / min. The discharged stock solution was guided to a coagulation bath after traveling in the air for 500 mm. Water was used for the coagulation bath, and the water temperature (coagulation bath temperature) was 42 ° C. The fiber was washed in a water-washing bath, led to a bath made of an aqueous solution containing 70% by mass of glycerin as a moisturizing agent, and then passed through a heat treatment bath at a temperature of 84 ° C. and wound around a cake at 30 m / min. .

  After washing the obtained core-sheath type fiber, the washing solution is completely replaced with pure water, sandwiched between a slide glass and a cover glass, and the same fiber is used using a projector (for example, V-10A manufactured by Nikon). The outer diameter (outermost diameter) of the fiber was arbitrarily measured at two places, the average value was taken, and the first decimal place was rounded off to obtain the fiber diameter. A solid porous fiber having a cross-sectional outer diameter of φ185 μm and containing neodymium carbonate as a metal compound was obtained.

  A minimodule was produced by the above-described method using the porous fiber composite obtained above. Thereafter, a 1% by mass polyethyleneimine (PEI, mass average molecular weight 10,000, manufactured by Wako Pure Chemical Industries, Ltd.) aqueous solution was filled and irradiated with γ rays at 25 kGy. The radiation-treated membrane was washed again with distilled water. The amount of eluted ions was evaluated using the minimodule containing the porous fiber composite obtained above. The neodymium ion concentration was measured by the same method as (1) shown above. The results are shown in Table 1.

  The phosphorus adsorption performance of the porous fiber composite obtained above was evaluated. The phosphorus adsorption performance was measured by the same method as (2) shown above. The results are shown in Table 1.

  The amount of chelating functional group of the porous fiber composite obtained above was evaluated. The amount of the chelating functional group was measured in the same manner as (3) shown above. The results are shown in Table 1.

[Comparative Example 1]
Spinning was performed using the same stock solution composition and base as in Example 1. A minimodule containing solid-state porous fibers containing neodymium carbonate as a metal compound was prepared, filled with pure water, and irradiated with γ rays at 25 kGy. The radiation-treated membrane was washed again with distilled water.

  About the minimodule obtained above, the neodymium ion density | concentration was measured by the method similar to (1) shown by the measurement example like Example 1. FIG. The results are shown in Table 1.

  Moreover, phosphorus adsorption | suction performance was measured by the method similar to (2) shown above, and the amount of chelating functional groups was measured by the method similar to (3). The results are shown in Table 1.

[Comparative Example 2]
Spinning was performed using the same stock solution composition and base as in Example 1. At that time, the discharge amount of the core discharged from the base slit portion was set to 0 g / min. The obtained porous fiber was subjected to γ-ray treatment in the same manner as in Example 1.

  About the obtained PMMA fiber, the phosphorus adsorption | suction performance was measured by the method similar to (2) shown above. The results are shown in Table 1.

Claims (15)

A porous fiber composite comprising a porous fiber containing a compound having a chelating functional group and a metal compound,
A porous fiber composite, wherein the compound having a chelating functional group is contained at least on the surface of the porous fiber.   The porous fiber composite according to claim 1, wherein the porosity of the surface of the porous fiber is in the range of 0.1% to 30.0%.   The porous fiber composite according to claim 1 or 2, wherein the metal compound includes one or more selected from a rare earth element carbonate and a Group 4 oxide.   The porous fiber composite according to claim 3, wherein the rare earth element includes one or more elements selected from lanthanum, cerium, praseodymium, samarium, and neodymium.   The porous fiber composite according to any one of claims 1 to 4, wherein an average particle diameter of the metal compound is in a range of 1 µm to 1000 µm.   The porous fiber composite containing the metal compound in any one of Claims 1-5 whose area occupation rate of the said metal compound in the cross section of the said porous fiber is 3% or more.   The porous fiber composite according to any one of claims 1 to 6, wherein the chelating functional group contains one or more elements selected from nitrogen, oxygen, sulfur and phosphorus.   The porous fiber composite according to any one of claims 1 to 7, wherein the porous fiber includes one or more compounds selected from polymethyl methacrylate, polyacrylonitrile, polysulfone, polyethersulfone, and cellulose. The porous fiber composite according to any one of claims 1 to 8, wherein an elution amount of metal ions contained in the metal compound is 0.1 mg / cm ³ or less. The porosity according to any one of claims 1 to 9, wherein an elution amount of metal ions contained in the metal compound when a phosphorus adsorption performance is 1 mg / cm ³ is in a range of 0.01 mg / cm ³ or less. Fiber composite.   The porous fiber composite according to any one of claims 1 to 10, wherein the compound having a chelating functional group is contained within a range of 5 mmol / g to 30 mmol / g. A method for producing the porous fiber composite according to claim 1,
The manufacturing method of a porous fiber composite including the process of performing radiation irradiation to the solution containing the said metal compound, the said porous fiber, and the compound which has the said chelating functional group. A method for producing the porous fiber composite according to claim 1,
The manufacturing method of a porous fiber composite including the process of performing radiation irradiation, after mixing the porous fiber containing the said metal compound, and the solution containing the compound which has the said chelating functional group.   The purification | cleaning column in which the porous fiber composite_body | complex in any one of Claims 1-11 was incorporated.   The purification column according to claim 14, which is for medical use.