JPH0368435A - separation membrane - Google Patents

Abstract

PURPOSE:To enhance selective separation power of the aimed substance in permeated liquid by forming a separation membrane which is made of the membrane constitutional base material with a nitrogen-contg. cyclic compd. bonded thereto and has a membrane structure incorporating many pores capable of permeating liquid. CONSTITUTION:A separation membrane made of material having hydroxyl group and amino group is selected among the separation membranes having a proper structure and pore size. Working is performed wherein nitrogen-contg. cyclic compd. is bonded by chemical reaction while the shape of the membrane is intactly held. Thereby the separation membrane is obtained which has a membrane structure incorporating many pores capable of permeating liquid and is made of membrane base material with nitrogen-contg. cyclic compd. bonded thereto and has a function capable of selectively separating substance in permeated liquid. As a preferable example of the membrane constitutional base material, cellulose and its derivatives and a synthetic organic high polymer, etc., are utilized. As the preferable example of nitrogen-contg. cyclic compd., compds. having imidazole skeleton and pyrazole skeleton are utilized.

Description

[Detailed Description of the Invention] [Field of Industrial Application] This invention relates to a separation membrane, which is used to remove harmful pyrogens from liquids that enter directly into living bodies, such as injection drugs, dialysis fluids, and infusions. It can be used as a film-like pyrodiene adsorbent.

[Prior Art and Problems to be Solved by the Invention] Adsorbents and separation membranes are both used for the purpose of separating substances in liquids. The difficulty of separation technologies that are used in industry varies depending on the type of substance contained in the system, the degree of separation achieved, the amount of processing, etc., but one example of one with particularly high requirements is the removal of pyrogens. Similar technical fields include the removal of nucleic acids.

Liquids from which pyrogen must be removed include liquids that enter the living body directly without passing through the gastrointestinal tract, such as drug solutions for injections, drug solutions for nutritional infusions, drug solutions for hemodialysis, and dilution water for these drugs. Examples include equipment that handles liquids and water for cleaning containers.

Pyrogens (pyrogens) are substances that abnormally raise the body temperature of warm-blooded animals in very small amounts, and when mixed with intravenous fluids and enter the bloodstream, they cause a strong fever independent of the drug's effect, resulting in excessive When this effect occurs, it is said to cause fever accompanied by chills and sometimes death from shock. Pyrogenic substances are known to include bacterial substances, inflammatory substances, plant polysaccharides, and blood type substances, but among these substances, the substances most associated with fever are bacterial substances.
It is called a bacterial toxin and is generally known as an exotoxin (Bxotox).
They are broadly classified into two types: in) and endotoxins. Among these toxins, Durham-negative cell wall phospholipid polysaccharide (Li-polysacchar)
Endotoxin, which is a so-called 0 antigen mainly composed of ide: LPS), has the most powerful pyrogenicity, cannot be inactivated by heat treatment, and is extremely difficult to remove once mixed into liquid. be.

Chemical decomposition methods, membrane separation methods, gel filtration methods, adsorption methods, and the like are known as methods for removing pyrodiene. In chemical decomposition methods, the stability of the treated material against decomposers,
Its applicability is limited due to problems caused by the contamination of decomposers and decomposition products.

The membrane separation method and gel filtration method can be said to be separation methods that take advantage of the difference in size between pyrodiene and the object to be treated.
Regarding the size of pyrodiene, it is necessary to consider its diversity, association, and the presence of lipid A. In other words, even when looking at LPS, which is particularly problematic among pyrogienes, the fatty chain of partial lipid A involved in exothermic action and the polysaccharide attached to it are unique depending on the type of bacteria from which LPS is derived. and are diverse. Also,
LPS with a molecular weight of about 5,000 associates to form a large micelle structure with a molecular weight of several million, while LPS with a molecular weight of about 20
Libido A itself, which is about 0.00, is also a pyrogenic substance.

The membrane-based pyrodiene removal method includes an ultrafiltration membrane ([lF
membrane) and reverse osmosis membrane (RO membrane) are used.

For pyrogen removal techniques, devices that combine multiple membranes have also been proposed to achieve low ultimate concentrations. JP 57-207517 and U.S. Patent No. 4261834
(deWinter) is an example. If the aqueous solution contains only water or a low-molecular-weight drug, a separation membrane can be selected that passes through the object to be treated but does not pass through pyrodiene or microorganisms containing pyrodiene. However, if the molecular weight of the material to be treated is large, it will permeate through the material with a good recovery rate and block pyrogenes, especially those with small molecular weights, to achieve the target low concentration (animals do not generate heat). Although the concentration varies depending on the type of pyrogen, it is not easy to select a separation membrane that achieves a concentration of several 10 pg (picogram')/d! or less for boat fishing. Removal of pyrogenes from liquids containing polymeric substances such as proteins is even more difficult, and it is almost impossible to remove pyrogenes to satisfactorily low levels while maintaining high drug recovery. In general, membrane filtration methods cannot separate substances with similar molecular weights, so they are not suitable for removing substances with a wide molecular weight distribution, such as pyrodiene, from drugs with complex structures.

It is known that activated carbon and ion exchange resins have the ability to adsorb and remove pyrodiene. Further, the material of the porous separation membrane, such as polyolefin, also has the ability to adsorb pyrodiene due to hydrophobic bonding force. However, these substances cannot selectively adsorb pyrodiene from drug-containing liquids to extremely low concentrations, and are not satisfactory as adsorbents for obtaining drug liquids from which pyrogenes have been sufficiently removed. .

Other materials are known that are capable of adsorbing pyrodiene. For example, JP-A-59-112888 discloses a method for removing Gram-negative bacteria and their cell wall components using fibers containing amino groups.

The lowest pyrodiene concentration achieved among the examples described in this publication is 0.014 mg/-1, or 14000 ng ( nanograms)/ml.

In recent years, affinity adsorbents have become commercially available that specifically adsorb pyrodiene and are therefore useful for removing pyrodiene from drug-containing liquids. A typical example of this type of adsorbent is a polysaccharide gel bonded with a nitrogen-containing cyclic compound, which is disclosed in JP-A-57-183712. It has been highly evaluated for its ability to selectively adsorb and remove high molecular weight drugs from aqueous solutions.

The achieved concentration stated in this publication is 0.1 ng (nanogram)/rn! ! It covers the following.

However, even this adsorbent is not a panacea.

The present inventor has recognized that when this type of adsorbent is used for pyrodiene removal treatment, there is a limit to its pressure resistance performance, and sufficient performance cannot be achieved when the adsorbent is used under conditions where the liquid flow pressure is increased. Conventional pyrodiene adsorbents use polysaccharide gel carriers as adsorbent base materials in order to ensure efficient contact between adsorption sites and solutions, and must be used within the pressure range that the gel can withstand. In other words, when using conventional adsorbents, the only way to improve processing speed is to increase the amount of adsorbent, and in order to process large amounts of liquid at high speed with a compact device, It is desired to realize a pyrodiene adsorbent with further improved performance.

Based on such prior art, an object of the present invention is to provide a separation means that can be used to separate drugs with similar molecular weights, is suitable for large-scale processing, and has high separation performance. A specific example of such a separation means is an adsorbent that has excellent pyrodiene selective adsorption performance, can reach a low pyrodiene concentration, and is suitable for high-speed processing of a large amount of liquid.

[Means to solve the problem]

The problems of the present invention as described above are (1) the physical shape of the separation means having a membrane structure with a large number of pores through which liquid can pass, and (2) the base material constituting the membrane containing a nitrogen-containing cyclic compound. The present invention is solved by a separation membrane characterized by: (3) a chemical structure of a separation means in which a substance in the permeate is bound; and (3) a separation means function capable of selectively separating substances in a permeate. More specific embodiments of the separation membrane of the present invention include the following.

(1) The above separation membrane in which the nitrogen-containing cyclic compound has a pi-electron system (2) The above separation membrane in which the pore diameter is ln+n to 20 μm (3) The above separation membrane having a pyrodiene adsorption function (4)
Pyrodiene 11000n/m1. The above-mentioned separation membrane (physical shape) has sufficient pyrodiene removal function to allow an aqueous solution containing the same to permeate at a permeation rate of 101/m''·hr or more, and more than half of the permeate has a pyrodiene concentration of 1 ng/- or less. The first feature of the separation membrane of the invention is that an affinity adsorbent having a membrane structure having a large number of pores, that is, a porous membrane shape is used as a separation means. Examples include microfiltration membranes that maintain their strength and are thick enough to make sufficient contact with the liquid passing through them, so that the liquid containing the drug of interest can come into contact with the membrane without undue resistance. It has many pores that are large enough and continuous enough to pass through.

Other suitable examples of anisotropic ultrafiltration membranes include:
It consists of a thin, dense skin layer with open pores and a thicker core layer with rougher, larger pores. The structures of these membranes are conventionally known in the field of separation membranes. The thickness of one film is usually 10 to 1000 μm, especially 50 μm.
~300 μm, but if necessary, a thicker film can be used or a plurality of films can be stacked. The pore size is within the range commonly referred to as ultrafiltration or microfiltration in the technical field of membrane separation, for example from ln+n to 20 μm, preferably from 10 nm to 5 μm, and particularly frequently used ones are about 50 nm to 1 μm.

When removing pyrodiene from a solution containing a drug with a large molecular weight, such as a protein or polysaccharide, it is a matter of course that a membrane with a pore size that does not block the permeation of the drug should be selected depending on the molecular diameter of the drug.

The pore size of a membrane is, for example, expressed as the particle diameter at which the rejection rate is 90%, because of the relationship between the size of particles that are not adsorbed to the membrane and the rejection rate.

In the present invention, a nitrogen-containing cyclic compound is bonded to the base material constituting such a membrane, and the pyrodiene in the liquid that permeates through the membrane through the pores is absorbed into the adsorbent located at an appropriate distance from the skeleton of the base material. It can come into contact with the body (nitrogen-containing cyclic compound). In the case of an anisotropic membrane, if it is brought into contact with the liquid with the skin layer side upstream, it will come into contact with the ligand as it passes through the skin layer, and can also come into contact with the core portion.

A skin layer is preferable because it prevents particles that would clog the pores from entering the membrane. Of course, the pore size of the skin layer must be such that the drug of interest can pass through. There may be a plurality of skin layers. In the case of a homogeneous membrane, of course, when the liquid passes through its pores, it comes into contact with the ligand and adsorbs pyrodiene.

A simple method to obtain a pyrodiene adsorbent having a homogeneous membrane or anisotropic membrane structure is to select one made of a material containing hydroxyl groups or amino groups from commercially available separation membranes with an appropriate structure and pore size. The process involves selecting a membrane and bonding it with a nitrogen-containing cyclic compound through a chemical reaction while maintaining the shape of the membrane.

Further, a porous membrane having a support can also be cited as an example of the shape of the adsorbent of the present invention. For example, a homogeneous film or an anisotropic film as described above is formed on a synthetic fiber nonwoven fabric. In this case, the strength of the membrane depends primarily on the support, e.g. porous plastic films or textiles (textiles,
The uke is held by knitted fabrics, non-woven fabrics, etc. The main body of the membrane, which is made of a material in which a nitrogen-containing cyclic compound is bonded to an insoluble carrier, has many pores and a certain thickness, allowing the liquid to pass through while ensuring the desired contact without experiencing excessive resistance. This is possible as in the previous example. A membrane in which a porous plastic film is used as a support and is impregnated with a base material can also be used. As a support, for example Duragard (
A porous membrane made of polypropylene with a high porosity, which is commercially available under the name (Trademark), can be used.

An example of a manufacturing method for these membranes is to form a doped solution of a polymeric substance into a desired shape such as a hollow fiber or flat membrane using a nozzle or Giesser, and then remove the solvent by washing or evaporation. This is a membrane containing pores. The step of bonding the nitrogen-containing cyclic compound to the base material constituting the membrane may be performed before or after forming the membrane.

A membrane-like pyrodiene adsorbent having pores with a size that balances the liquid passage performance and the contact performance with the adsorbent can also be obtained by other manufacturing methods. For example, a very fine (1 μm or less) diameter 41
A sheet is formed using a fibrous base material. The membrane-forming method itself is similar to papermaking, but because it uses minute fibers, unlike ordinary filter paper, it has a pore size that ensures good contact with the liquid, which is essential in the case of the present invention. A precision filtration membrane is obtained. The thickness of the film varies depending on the density of the film structure, but is usually the same as in the previous example.

The separation membrane of the present invention can also be obtained by bonding a nitrogen-containing cyclic compound through a chemical reaction using a previously prepared membrane having an appropriate material and structure, such as a cellulose microfilter, as a base material.

The shape of the membrane is not particularly limited, such as a flat membrane, hollow fiber membrane, or tubular membrane. These membranes can be suitably applied in the form of membrane modules. Examples of membrane modules include spiral type, pleated type, plate and frame type, tubular type, and hollow fiber type.

(Substrate constituting the membrane) The separation membrane of the present invention is composed of a substance in which a nitrogen-containing cyclic compound is bonded to a base material constituting the membrane.

The substrate is generally insoluble, ie, does not dissolve in the liquid with which it is handled. The solvent is usually water, but in special cases it may be a nonaqueous solvent such as alcohol, acetone, acetate, tonitrile, DMSO, chloroform, or an aqueous solution thereof. It is sufficient that the nitrogen-containing cyclic compound becomes insoluble in the final adsorbent to which it is bonded, and it does not matter whether it is insoluble at intermediate stages. Many of the polysaccharide base materials that are insoluble in water are also insoluble in organic solvents.

The base material is generally a polymeric substance, often a linear organic polymer, which is assembled by intermolecular forces. Since it is membrane-like, it appears to be mainly two-dimensional in appearance, but because of the thickness of the membrane, it is essentially three-dimensional. The base material has a structure that can directly or indirectly fix the nitrogen-containing cyclic compound. For example, it has a functional group such as a hydroxyl group or an amino group, or an active position (eg, active hydrogen) that can react with other substances.

Specifically, polysaccharides (including derivatives thereof such as aminoalkylated polysaccharides and carboxyalkylated polysaccharides; examples: cellulose and its derivatives, agarose and its derivatives, crosslinked dextran and its derivatives, chitosan, etc.)
JP-A-57-183712), synthetic organic polymers (e.g., polyacrylonitrile, polysulfone, polyamide, polyvinyl alcohol, polystyrene, polyacrylic acid, hydroxyalkylated, aminoalkyl) Examples include polystyrene resins and polyacrylamide resins which have been halogenated or halogenoalkylated), inorganic polymers (eg, Nisilica gel, alumina, glass, such as aminopropyl porous glass, various ceramics), and the like.

Further, it can be selected from among the water-insoluble carriers described in JP-A-57-183712. These base materials include copolymerization,
Functional groups such as hydroxyl groups and amino groups that are useful for forming bonds with ligands can be introduced by various methods such as methylolation and reduction.

Such a base material constitutes a membrane with a three-dimensional structure,
It is bonded directly or via a B2 spacer to a nitrogen-containing cyclic compound. The molecular structure composed of the base material, ligand, and spacer has an important influence on the higher-order structure, which is the association of molecules and the formation of pores, as well as the contact between the liquid and the adsorbent.

In carrying out the present invention, selection of an appropriate substrate is extremely important.

(Nitrogen-containing cyclic compound) The nitrogen-containing cyclic compound in the present invention is
Those similar to those described in No. 3712 can be applied, and those having a pi-electron system are preferable.

Specifically, imidazole skeleton, pyrazole skeleton, pyrimidine skeleton, pyridazine skeleton, pyrazine skeleton, purine skeleton, acridine skeleton, triazole skeleton, oxadiazole skeleton, tetrazole skeleton, indazole skeleton, benzotriazole skeleton, benzopyridazine skeleton, benzopyrimidine Examples include compounds represented by the formula R-^-X containing a nitrogen-containing cyclic group R having a skeleton, a benzopyrazine skeleton, a naphthyridine skeleton, or the like.

A is a single bond, alkylene (ethylene, butylene, C1
2 etc.) group, alkenylene group, X is a hydrogen atom, a,
It represents a mino group, a hydroxyl group, a carboxyl group, etc., and the nitrogen-containing cyclic group and alkylene group may have a substituent (carboxyl, oxo, alkyl, hydroxyl, amino, alkoxy, etc.).

Specific examples of heterocyclic compounds include histidine, histamine, urocanic acid, uracil, orotic acid, cytosine, 5-methylcytosine, 2-amino-4,6-dimethylpyrimidine, 2-amino-4-hydroxy- Examples include 6-methylpyrimidine, adenine, and 6,9-diamino-2-ethoxyacridine, and particularly preferred compounds are compounds having an imidazole skeleton, such as histamine and histidine.

<Bonding of the substrate and the nitrogen-containing cyclic compound> The bonding methods of the ligand, which is a nitrogen-containing cyclic compound, and the substrate constituting the membrane include - carrier bonding, cross-linking, and inclusion (e) for boat fishing.
ntrapping (lattice type, microcapsule type), etc., but carrier binding method is usually selected.

The crosslinking method has problems in expressing affinity and securing a sufficient flow rate.

The base material and the nitrogen-containing cyclic compound may be bonded directly or may be bonded via a spacer.

As the spacer, a spacer similar to that described in JP-A-57-183712 can be used. A typical example is Nl2(['1
12)l, N)1. ,l100c(CH2),,CD
DH (or corresponding acid anhydride), NL(CH2)l
, C00II, N)1. (CH2), DH (wherein represents an integer from 1 to 12). The presence of a spacer is particularly useful when the network constituted by the substrate is so dense as to prevent access of the pyrodiene to the adsorption sites.

Immobilization methods for directly or indirectly binding a ligand to a base material constituting a membrane as a carrier include covalent bonding, ionic bonding, hydrophobic bonding, coordinate bonding, and the like.

Among these, preferable is immobilization by covalent bonding, which is less likely to detach the nitrogen-containing cyclic compound. Examples of covalent bonds include amide bonds, ester bonds, ether bonds,
Examples include amino bonds, imino bonds, sulfide bonds, disulfide bonds, and sulfone bonds.

The method for attaching the ligand or spacer to the substrate is as follows:
For example: Cyanogen halides (e.g. nibromcyan), epoxy compounds (e.g. epichlorohydrin,
After activating the base material using halogenated organic acid halides (e.g. chloroacetyl chloride, tresyl chloride), dialdehyde (e.g. nigertaraldehyde), benzoquinone, etc., amino groups, hydroxyl groups, thiol groups, A nitrogen-containing cyclic compound having a carboxyl group or a spacer is attached.

Examples of indirect ligand immobilization methods using spacer carriers include epoxidation method (e.g. epichlorohydrin, bisoxirane), dehydration condensation method (WSC, BEDO), reductive amination method (NaCN + borane, dimethylamine + borane), thiol There are activation methods (PySSPy), etc.

These are made by using carrier spacer derivatives with groups such as epoxy, carboxyl, amino, hydrazino, formyl, thiol, etc. as active intermediates using condensing agents and activating agents (examples are given in parentheses after each method). , amino, carboxyl, aldehyde, thiol, etc.

The adsorbent prepared by the epoxy method is superior to the bromcyan method, which is the most commonly used method, in that the ligand is stably immobilized and nonspecific adsorption is low, making it the preferred binding method in the present invention. .

An example of immobilization other than a covalent bond is, for example, a nitrogen-containing cyclic compound having a strong basic substituent on a carrier with a strongly acidic group bonded to the surface (commercially available as a packing material for anion chromatography). Immobilizing a ligand with ionic bonds, or holding a base material whose surface has been made hydrophobic with octadecyl, octyl, phenyl, etc. and a ligand bonded with a long-chain alkyl group or phenyl group through hydrophobic bonds (dynamic coating method) is also possible.

The immobilization method for bonding the substrate, spacer, and nitrogen-containing cyclic compound is explained in detail in the above publication, and in the present invention, the immobilization of the ligand is carried out by applying such already disclosed technology. can do.

These ligand immobilization techniques can be applied to the processing of a material in the shape of a membrane as shown in Example 1, as well as to the processing of a material before it becomes a membrane as shown in Example 3.

(Separation Function) As is understood from the above description, the separation membrane of the present invention has a function of adsorbing and separating pyrodiene by contacting the liquid passing through the pores.

The thickness of the membrane is thin as described above, and therefore the contact time is extremely short compared to the column method as well as the batch method used with conventional adsorbents. For example, the film thickness is 1100j
J (10-'cm), flow rate 504! /m'・hour, the value corresponding to SV (volumetric velocity, apparent value) in the column method is 500 (per hour), so the contact time (apparent value) is 7.2 seconds (1/500th of an hour). This is less than 1/100 of the SV3 in the affinity chromatography column method, that is, the contact time of about 20 minutes.

Nevertheless, by selecting an appropriate substrate and a nitrogen-containing cyclic compound as a ligand (and in some cases a spacer), we can construct three-dimensional molecular structures, molecular association structures, and even larger three-dimensional structures. The membrane configuration with certain pores provides satisfactory contact between the liquid and the adsorbent. The separation membrane of the present invention has pores large enough to allow drugs to permeate, and at a permeation flow rate of 101/m'·hr or more, for example, pyrodiene 1000 to 1
1 ng of pyrodiene from an aqueous solution containing 100 n/-
/- or less, even reaching 0.01 ng/- or less,
A selective separation function is provided to obtain a permeate virtually completely free of pyrogenes.

The separation membrane of the present invention can also be used to remove O pyrodiene from liquids containing higher concentrations of pyrodiene. in this case,
Although the achieved concentration may not reach the above-mentioned virtually complete removal, a high value of, for example, 99%, can be obtained in terms of pyrodiene removal rate from the feed solution, despite the short contact time. It is quite useful depending on the purpose of use.

In addition to its physical shape and chemical structure, the separation membrane of the present invention is characterized by having a function of selectively separating substances in a liquid by a permeation method, for example, a function of removing pyrodiene from a permeate liquid. can be distinguished from other separation methods. For example, a filter paper made of fibers with pyrodiene adsorption function may function as an adsorbent if packed in a column and given sufficient contact time, but if a permeation method with an extremely short contact time is applied, It is not possible to demonstrate sufficient removal function.

〔Effect of the invention〕

The separation membrane of the present invention has a membrane shape with a porous structure, in contrast to the gel-structured particulate adsorbent of the prior art. The device for contacting the liquid with the separation means is therefore usually a membrane module rather than a packed column. In this case, the resistance when the liquid passes through is mainly the membrane resistance, and pressure loss caused by the flow between particles is avoided. Membrane resistance varies depending on the pore diameter, membrane thickness, etc., which are used depending on the properties of the processing liquid, but it can be used in the area of microfiltration membranes and ultrafiltration membranes, so no special pressure-resistant equipment is required.

Furthermore, even when using a membrane that requires pressure to be applied to the RO membrane region, the membrane itself can have sufficient pressure resistance.

As described above, the separation membrane of the present invention solves the problems of particulate adsorbents with a gel structure by reducing liquid flow resistance and increasing pressure resistance, but the effects of having a membrane structure end there. Not. Hereinafter, a calculation example will be used to explain how pyrogen removal equipment that processes a large amount of liquid can be realized on a compact scale according to the present invention.

When using a column filled with particulate adsorbent 11 having a gel structure, the amount of liquid passed is usually from about 3 to 1017 hours, assuming a pressure of 1 kg/cnfG. In the case of the adsorbent of the present invention, a membrane with an area of about 1 to 2 m" can be provided in a module with a volume of 11. Therefore, if the permeation rate is 501/m"/hr, the liquid flow rate is 50 to 2 m. 1001/
In addition, a throughput of about 10 times that of a particulate adsorbent can be achieved with equipment of the same volume. If the operating pressure is further increased, the throughput can be expected to increase by more than 100 times.

As explained above, the separation membrane of the present invention has extremely excellent separation ability not only in terms of volumetric efficiency but also in terms of ultimate concentration and removal rate. Since the separation membrane of the present invention has a membrane shape, it also works as a membrane separation effect and helps function as an adsorbent. Due to these effects, the present invention can remove pyrodiene and nucleic acids (DNA, RNA) from solutions containing a wide range of drugs ranging from large molecular weights such as proteins to low molecular weights, and even from the solvent itself.
) is useful for selectively separating and removing substances that have affinity with nitrogen-containing cyclic compounds with high efficiency.

〔Example〕

In the following explanation, (Net) represents wet weight.

Example 1. Preparation of histidine-immobilized PVA membrane Three polyvinyl alcohol (PVA) hollow fiber membranes (Cla-5F-401, homogeneous membrane with pore size of approximately 0.1 μm, inner diameter 330 μm, membrane thickness 125 μm, effective length 5.5 cm) were placed in a glass tube using epoxy resin. Create a mini module fixed with resin. Below, using this module, the hollow fiber membrane is brought into contact with the liquid in the order of ① to O below, and the membrane is subjected to a treatment that includes a chemical reaction of the materials that make up the membrane, and the old sPV^ membrane adsorbent of the present invention is obtain. The method of contacting the membrane with the liquid is to apply the liquid at a flow rate of 20 to 50
Circulate in and out of the hollow fiber membrane at m1/min.

The temperature is regulated by submerging the entire module in a water bath.

■Cleaning (IM NaC1, pure 7k), ■Epoxidation (
60℃, IN NaOH, 90mj! , further adding Ebiku OJL/Hydrin 1Ord for 2 hours), ■ Washing (pure water), ■ Spacer binding (0,625% hexamethylene diamine aqueous solution 40mj!, 60°C, 2 hours), ■
Washing (pure water), ■Epoxidation (same as ■), ■Washing (pure water), ■Histidine (His) immobilization (1mM) 1is
40ml! , pH 13, 60°C, 2 hours>, ■ Washing (I M NaCl, pure water), ■ Making the membrane itself pyrogen-free (0.2N using 20% ethanol as a solvent).
(NaOH) In this way, a histidine-immobilized PVA membrane (HisPVA membrane), which is the adsorbent of the present invention, is obtained.

The elemental analysis value (%) of this old 5 PVA membrane was calculated based on the raw material PVA membrane and the intermediate treated membrane (AH-PVA membrane) obtained in the process up to
A comparison is shown with the elemental analysis values of the film).

Sample name Carbon Hydrogen Nitrogen raw material PVA membrane 55,14 7.92 0.028H-PV
A membrane 54.92 8.0G
O,17H1sPVAM 54.27
7.87 0.40 Example 2. l1sPVA membrane incorporated into pyrodiene removal mini-module (Example 1,
pyrodiene (B, coli
olll: 84 origin) 42rnl of raw water with an S degree of 1100n/rnl was circulated at a rate of 13rd/min, and the membrane permeation rate was 0.2mA! /min (701/m”・hour). Supply pressure is approximately 0.2 kg/min.
The pyrodiene concentration of the caf G 0 permeate is measured using Limulus BS-Test, Wako (trademark), and a toxinometer BT-201 (both manufactured by Wako Pure Chemical Industries, Ltd.). When the amount of permeated liquid is 22-, the concentration is 0. O1ng/rn
l, pyrodiene removal rate is 99.99%. Even when raw water with a pyrodiene concentration of 11,000 n/- is used, the concentration is 0.
The concentration can be lower than log/m12.

For comparison, the same P as the starting material used for adsorbent production in Example 1
A similar test is performed using a VA hollow fiber membrane mini module. The pyrodiene concentration in permeated water obtained by conventional membrane separation is 18 ng/d, and the pyrodiene removal rate is 82%.

Example 3. Preparation of histidine-immobilized MFC A 4% suspension of microfibrillated cellulose made from wood bulbs and microfibrillated to a diameter of about 0.4 μm using a high-pressure homogenizer (Daicel Chemical Industry Co., Ltd. > 180 g)
(wet weight) was suspended in 270ml of water, 117rnl of 2N aqueous sodium hydroxide solution and 27ml of epichlorohydrin.
- and stirred at 40°C for 2 hours. After the reaction is completed, the mixture is filtered and the residue is washed with water to obtain epoxidized MFC.

0.625 g of this epoxidized MPC (wet)
% hexamethylene diamine aqueous solution (120 mf') and stirred at 60°C for 2 hours. After the reaction is complete, the mixture is filtered and the residue is washed with water to obtain aminohexylated MP.
(: (C: 41.90%, N: 0.22%, H: 6.
33%, hereinafter abbreviated as AH-NFC). AH-
When NFC is epoxidized again with an aqueous sodium hydroxide solution and epichlorohydrin, epoxidized AH-MFC is obtained.
is obtained. Add this to 1mM histidine (His) solution 6
0-, adjusted to pH 13 with IN sodium hydroxide, and stirred at 60° C. for 2 hours. After the reaction is completed, the mixture is filtered and the residue is washed with 1M saline and water to obtain histidine-immobilized NFC (HisMFC) (C
:42.19%, N:1.99%, H:6.44%)2
Obtain 1 g (wet).

Example 4. Preparation of flat membrane Aromatic polyamide short fibers (diameter 20-24 μm).

3.8 g of sMPc21 (length 3 mm) was mixed with 800 ml of pure water and ground in a mixer, and then the old sMPc21 prepared in Example 3
3% aqueous suspension of microfibrillated aromatic polyamide wi fibers with g and diameter of about 0.4 μm44. Ig (Wet
), thermally crosslinkable polyamide resin binder 12g 1 water 30
Add 〇- and stir. The mixed slurry was sucked through an 80-mesh wire mesh, the resulting sheet was pressed, dried on a hot plate, and filtered through a microfilter (210 mesh) containing old sMFC.
X260 Xo, 2 mm). This is a flat film-like pyrodiene adsorbent (His content: approximately 1%) that is made of cellulose as a base material, has old S bonded to it via a spacer, and is molded together with other m-fibers. The size of the pore is 0
．． As can be seen from the rejection rate of 20% for 5 μm polystyrene standard particles, it is on the order of microns.

Example 5. Pyrodiene Removal Using a Flat Membrane Adsorbent The microfilter containing old sMFC prepared in Example 4 was cut to a diameter of 13 mm and fixed as a flat membrane in a holder. Through this membranous adsorbent, pyrodiene (same as Example 2) 16000
ng/- raw water for 0.12-7 minutes (54R/m”・hour)
Filter under 10 ml of pressure.

The pyrodiene concentration of the obtained permeate is 200 ng/ml.
, the removal rate is 99%. Furthermore, it has been observed that even if approximately the same amount of stock solution is permeated, the pyrodiene concentration of the permeate does not significantly increase. However, the permeation flow rate is approximately 1
At 0x (45 o i 7 m''·hr), it is observed that the pyrodiene concentration in the permeate increases rapidly while passing a similar amount of liquid.

When a similar test was conducted using a product prepared in the same manner as in Example 4 using MFC instead of HisMFC, the pyrodiene concentration of the permeate was 1540hg/! rd! Thea F:) has almost no removal effect.

Claims (1)

[Scope of Claims] 1. Having a membrane structure with a large number of pores through which a liquid can permeate, A nitrogen-containing cyclic compound is bonded to the base material constituting the membrane, and Substances in the permeated liquid A separation membrane characterized by having a function of selectively separating, and having the above-mentioned features. 2. The separation membrane according to claim 1, which has a pyrogen adsorption function.