JP2010240614A - Separation membrane device and method of manufacturing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a separation membrane in which fine particles having a function of protein adsorption or the like are filled and fixed. <P>SOLUTION: In the separation membrane device, the fine particles of 10 nm-10 μm of liposome or the like are filled in a porous separation membrane and fixed using polymer gel. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a membrane device into which fine particles are introduced, and can be used as an extracorporeal circulation treatment device such as an artificial kidney or a column for adsorption removal of a specific substance from liquid or gas.

A method of adsorbing and removing a specific substance from a liquid to be treated such as blood is widely known. In a membrane that removes β2-microglobulin using polymethyl methacrylate, treatment is performed by optimizing the membrane pore diameter. A method used for this is disclosed (Patent Document 1). However, these methods are limited to the amount of adsorption that the membrane itself can adsorb. In addition, a method for removing a specific substance using fine particles is also known. For example, it is even disclosed that an adsorber filled with an adsorbent obtained by immobilizing a specific compound on a water-insoluble carrier can adsorb cytokines. (Patent Document 2). However, even in this method, there is a problem that if the size of the particles per volume is reduced, the pressure in flowing the liquid to be processed, that is, the pressure resistance, is increased. In addition, in order to reduce this pressure loss, attempts have been made to fill small particles such as liposomes between large particles such as chitosan gel. The amount could not be filled (Non-Patent Document 1). On the other hand, attempts have been made to make use of adsorption characteristics by flowing particles into the space between the hollow fiber membrane and the container through the hollow fiber separation membrane, but a special circuit is required so that the particles do not flow out (Patent Literature). 3).

JP-A 63-109871 Japanese National Patent Publication No. 2003-055545 JP-A-9-248334

Yoshimoto Makoto et al .: Chemical Engineering, 47, 761-765 (2002) Ariel Fernandez et. al Proc. Natl. Acad. Sci. , 100, 6446-6451. (2003)

  An object of the present invention is to provide a device in which a specific function such as adsorption is imparted to a membrane having a separation function by improving the drawbacks of the prior art.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have achieved the following configurations (1) to (7).
1. A separation membrane device, wherein fine particles having an average particle size of 10 nm to 10 μm are introduced into pores of a porous membrane.
2. 2. The separation membrane device according to 1, wherein the separation membrane has pores, and the pore diameter (Dm) and Dp satisfy a relationship of Dp ≧ 2 × Dm.
3. 3. The separation membrane device according to 1 or 2 above, wherein the fine particle is an assembly of molecules composed of a hydrophobic unit and a hydrophilic unit.
4). 4. The separation membrane device according to 3 above, wherein the fine particles are made of a lipid bilayer membrane.
5). 5. The separation membrane device according to any one of 1 to 4 above, wherein the fine particles are introduced into the membrane surface in a state of being encapsulated by a polymer gel.
6). 6. The separation membrane device according to 5 above, wherein the polymer gel comprises a cationic polymer and an anionic polymer.
7). 7. The separation membrane device according to any one of 1 to 6, wherein the separation membrane is a hollow fiber type separation membrane.
8). A method for producing a separation membrane device, wherein fine particles having an average particle diameter of 10 nm to 10 μm are introduced into a membrane and then the fine particles are immobilized on the membrane by enclosing a polymer gel.
9. 9. The method for producing a separation membrane device according to claim 8, wherein the polymer gel is insolubilized by encapsulating the polymer gel inside the membrane and then crosslinking the polymer gel.

According to the present invention, in addition to the separation function based only on the size of the membrane pores, it is possible to combine the functions of particles such as adsorption. Furthermore, products having various performances can be easily created by changing or combining the kinds of particles.

It is a schematic block diagram of the hollow fiber membrane module used for a dextran sieving coefficient measurement. It is a circuit diagram used when fixing microparticles | fine-particles.

  The fine particles in the present invention are those having an average particle diameter of 10 nm to 10 μm. Various methods are known for its production. For example, scientific condensation methods are known, and a method in which a substance is dissolved in a solvent and then poured into a non-solvent such as water is disclosed. An emulsion polymerization method obtained by polymerizing fine polymer particles in the presence of a surfactant is also a well-known method. Furthermore, adjustment by a gas phase method such as an electric furnace method or a plasma method or a liquid phase method such as a freeze drying method or a spray drying method is also well known. The fine particle component may be a single component, but particles composed of different components such as a hydrophilic unit and a hydrophobic unit have affinity for water in the hydrophilic unit portion, and the hydrophobic unit. This is preferable because a hydrophobic substance can be encapsulated in the portion and a function of easily adsorbing a hydrophobic substance such as a hydrophobic protein can be provided. These fine particles include core-shell type polymer fine particles composed of polymers having different surface (shell) and inside (core), fine particles having a special structure such as a lipid bilayer typified by liposome, etc. Is well known. In particular, liposomes are substances that form the surface of living cells, and are widely used in the field of drugs such as drug delivery systems (DDS). Furthermore, by mixing a plurality of substances, various functions are expressed. It is known. Lipid bilayers have a hydrophilic surface and are easy to adapt to biological components, and can suppress excessive adsorption of cells and proteins, but they can easily incorporate hydrophobic components into the internal hydrophobic components, allowing selective removal. Possible preferred structure. .

  Since the surface area per volume can be increased as the diameter of the fine particles is smaller, the smaller one is preferably 10 μm or less. Furthermore, if it is 1 micrometer or less, since the membrane with a large surface area can be created using the marketed film for the water purifier use etc., it is preferable. However, if it is too small, there is a concern that even if it is filled in the membrane, it will be packed too finely so that substances such as proteins will not flow into the gap, or it will be difficult to immobilize in the polymer gel and will elute. That is necessary. Particles of 30 nm or more are more preferable because they are easy to make.

  Next, the size and distribution of fine particles according to the present invention will be described in detail. The average particle diameter (Dp) here means an average diameter. This Dp is generally performed using a light scattering method, and can be obtained by irradiating the dispersion with an argon or helium-neon laser and measuring the scattered light. At this time, if the particle distribution is a mountain, Dp can be obtained by volume-based calculation. If the distribution has multiple phases having a plurality of peaks or is not uniform, the peaks are appropriately divided to obtain a volume-based particle size.

  Next, the liposome will be described. Liposomes may be formed by any method available to those skilled in the art. Examples of the forming method include Ann. Rev. Biophys. Bioeng. 9, 467 (1980), “Liposomes” (edited by MJ Ostro, MARCELL DEKER, INC.) And the like. Specific examples include sonication, ethanol injection, French press method, ether injection method, cholic acid method, calcium fusion method, freeze-thaw method, reverse phase evaporation method, etc. Absent. The structure of the liposome is not particularly limited, and may be any form such as unilamellar or multilamellar. Moreover, it is also possible to mix | blend the 1 type, or 2 or more types of an appropriate compound inside a liposome.

  Adjustment of the particle size of the liposome can be performed by formulation or process conditions. For example, when the supercritical pressure is increased, the particle size of the formed fine particles is decreased. In order to align the particle size distribution of the fine particles in a narrower range, the produced fine particle suspension may be forcibly permeated through a filtration membrane having a fixed pore size, preferably a polycarbonate membrane. In this case, by passing through a hydrostatic extrusion apparatus equipped with a filter having a pore size of 0.01 to 0.4 μm, preferably 0.05 to 0.2 μm, more preferably 0.05 to 0.2 μm as a filtration membrane, When the fine particles are liposomes, the number of lipid membranes in the liposome multilayer membrane can be reduced, and uniform liposomes having an optimum size of 100 to 300 nm as the center particle size can be efficiently prepared. Specifically, the filter is forced to permeate using various hydrostatic extrusion apparatuses such as “Extruder” (trade name, manufactured by NOF Liposome). As the filter, a polycarbonate type, a cellulose type or the like can be appropriately used. By incorporating such an “extrusion” operation step, there is also an advantage that in addition to the above sizing, exchange of the fine particle dispersion and filtration sterilization are also possible.

In the present invention, these fine particles are used to adsorb substances in the fluid to be treated such as blood to remove specific substances, or to accelerate or suppress reactions such as oxidation and reduction that occur in the fluid to be treated. It is what is used. For example, by using microparticles having affinity for hydrophobic proteins denatured in blood and microparticles having affinity for cytokines such as interleukin-6 generated during diseases such as infectious diseases, high efficiency can be obtained from blood. These substances can be removed and treated. In addition, it can be expected to selectively adsorb and remove proteins such as insulin using the interaction with the protein of the liposome using the liposome, particularly hydrogen bond instability (ρ value) (described in Non-Patent Document 2). ) Is strongly bound to a liposome and it can be expected to selectively remove a protein having a low ρ value. Proteins with low hydrogen bond instability include insulin (ρ value 4.2), amyloid Ig light chain (ρ value 4.8), β ₂ -microglobulin (ρ value 5.2), Ig light chain ( ρ value 5.3) and the like, and those having a ρ value smaller than 5.5 are preferable as the protein to be adsorbed and removed. In addition to this, it is possible to use such a method that a specific substance is encapsulated in the liposome and sustainedly released.

  In the present invention, the state in which the fine particles are introduced into the inside of the membrane is a state in which the fine particles are present inside the porous portion of the porous membrane, and the introduction and fixation of the fine particles are performed during use. Although it is not particularly limited as long as it is introduced into the film chemically or physically and held in the film so as not to be easily detached, several methods can be exemplified. For example, a method of immobilizing a cationic group or an anionic group on the surface of a separation membrane and reacting and immobilizing fine particles having a functional group that reacts therewith, and adding a cationic group or an anionic group to the particle itself, A method of cross-linking and fixing a group of particles using a crosslinkable substance that reacts with a group, a method of covering the particles with a polymer gel and confining the particles can be considered. At this time, it is not necessary to exist only in the inside of the film, and fine particles may be attached or bonded to the inner surface part or the outer surface part of the film. The amount of the fine particles to be introduced depends on the kind of the fine particles and the film, but 5% or more of the pore volume of the porous film is preferable because the effect is exhibited. However, if the amount to be introduced is too large, it may be difficult for the polymer to enter the film in the process of introducing the polymer, or the fine particles introduced into the film may flow out, so that it is less than 60%. Is preferred.

  As a method of covering and confining with the above polymer gel, using a separation membrane having a pore size smaller than fine particles, a suspension containing fine particles is filled into the membrane while filtering from one side, and simultaneously or filled with particles. The polymer gel material can be filled later while being filtered, followed by crosslinking and immobilization. Since the order of filling the particles makes it difficult for the particles to enter later when the polymer gel is introduced first, it is preferable to introduce the polymer gel after introducing the fine particles first. According to the introduction in this order, it is difficult to introduce the polymer gel, but the particles are covered with the polymer gel, so that more stable introduction can be performed. The average particle diameter (Dp) is preferably larger than the pore diameter (Dm) of the separation membrane. When Dp is large, particles are trapped in the film, and the introduction efficiency can be increased. Furthermore, when Dp is 2 times or more of Dm, the capture ratio can be increased, and when it is 5 times or more, it is more preferable because substantially most particles can be captured. Dm represents a diameter, and a sieving coefficient can be obtained using dextran, and the dextran molecular weight corresponding to 50% of the sieving coefficient can be converted into a fine particle diameter. The conversion formula is as described later in the examples.

  As a crosslinking method in the above method, there are a method of crosslinking by irradiating γ rays and a method of crosslinking using a chemical reaction. When crosslinking using γ rays, polypinylpyrrolidone or polyvinyl is used as a polymer gel. A substance that crosslinks with γ rays such as alcohol can be used. On the other hand, in the case of crosslinking using a chemical reaction, a method of preparing a gel by reacting a cationic polymer and an anionic polymer can be used.

  The cationic polymer in the present invention is not particularly limited as long as it has a cationic group in its molecule. The cationic polymer is preferably used so that it has such hydrophilicity that it can be dissolved or swelled in water and that the cationic group has a positive charge in water. Examples of cationic groups include amino groups; monoalkylamino groups such as methylamino groups and ethylamino groups; dialkylamino groups such as dimethylamino groups and diethylamino groups; imino groups; guanidino groups and the like. Is preferably a polymer having two or more amino groups in one molecule. Examples of the cationic polymer include basic polysaccharides such as chitosan, partially deacetylated chitin, and aminated cellulose; homopolymers or copolymers of basic amino acids such as polylysine, polyarginine, and a copolymer of lysine and arginine; Examples thereof include basic vinyl polymers such as polyvinylamine and polyallylamine, and cationic polymers such as salts thereof (hydrochloride, acetate, etc.) and polymers such as polyethyleneimine. Furthermore, a crosslinked polymer obtained by crosslinking these cationic polymers can also be used. Any known method can be used as a method of crosslinking the cationic polymer. When the cationic polymer has an amino group, a method in which the amino group of the cationic polymer is crosslinked by a condensation reaction with a dicarboxylic acid or dicarboxylic anhydride is preferable. The molecular weight of the cationic polymer is not particularly limited, but when the molecular size is smaller than the pore size of the membrane, it is easily retained in the membrane, so the size in water is larger than the membrane pore size. Small is preferable. The size of this molecule can be measured by GPC-MALLS method or the like. In the present invention, two or more kinds of polycationic polymers can also be used.

As an anionic polymer in this invention, what has an anionic group in the molecule | numerator should just be. Examples of the anionic group include a carboxyl group, a sulfuric acid group, a sulfonic acid group, and a phosphoric acid group. As the anionic polymer, a polymer having a carboxyl group in the molecule is preferable, and an acidic polysaccharide is more preferable. Acidic polysaccharides include alginic acid, hyaluronic acid, chondroitin sulfate, dextran sulfate, pectin, xanthan gum, carboxymethylcellulose, carboxymethyldextran, carboxymethyl starch, carboxymethylchitosan, sulfated cellulose, sulfated dextran, carboxymethylcellulose acetate, carboxymethylcellulose acetate Examples include methyl dextran acetic acid ester, alginic acid ethylene glycol ester, alginic acid propylene glycol ester, hyaluronic acid ethylene glycol ester, hyaluronic acid propylene glycol ester and the like. Among these, branched polymers such as xanthan gum are preferable because they easily swell in water. In addition, when the amount of carboxyl groups is large, the reaction is facilitated, but since the polymer gel contracts, it is preferable that the amount of carboxyl groups per 200 molecular weight is less than one. The molecular weight of the anionic polymer is not particularly limited, but when the molecular size is smaller than the pore size of the membrane, it is easily retained in the membrane, so the size in water is larger than the membrane pore size. Small is preferable. The size of this molecule can be measured by the GPC-MALLS method or the like.
Any known method can be used as a method of crosslinking the anionic polymer. When the anionic polymer has a carboxyl group, a method of crosslinking by reacting the carboxyl group of the anionic polymer with an amine is preferable. As a method for activating a polymer containing a carboxyl group, for example, a method using a water-soluble carbodiimide such as 1- (3-dimethylaminopropyl) -3 ethylcarboimide (EDC) and N-hydroxysuccinimide (NHS). , A method of activating with EDC alone, a method of activating a carboxyl group using any compound of uronium salt, phosphonium salt, or triazine derivative, a nitrogen-containing heteroaromatic having a hydroxyl group activated with a carbodiimide derivative or a salt thereof A method of activating a carboxyl group using any one of a group compound, a phenol derivative having an electron-withdrawing group, or an aromatic compound having a thiol group can be preferably used. Moreover, when making it react using EDC, it is also a good method to add 1-Hydroxy-1H-benzotriazole, monohydrate (HOBt) etc., and to improve reaction efficiency. A crosslinked gel can be prepared by reacting a polymer containing a carboxyl group activated by these techniques with an amino group.

  The operation of filling these fine particles and the operation of introducing a polymer can be performed by immersing the separation membrane in a solution, but each of the operations can be performed by filtering the separation membrane after applying it to a module. Since the substance can be introduced stably, it is preferable.

  Next, the separation membrane used here will be described. The separation membrane used here is not particularly limited, and known ones can be used. In particular, separation membranes using polysulfone are widely used in artificial kidneys, water purifiers and the like.

  Specific examples of polysulfone include Udel (registered trademark) Polysulfone P-1700, P-3500 (manufactured by Teijin Amoco), Ultrason (registered trademark) S3010, S6010 (manufactured by BASF), Victrex (registered trademark) (Sumitomo) Chemistry), Radel (registered trademark) A (manufactured by Teijin Amoco), Ultrason (registered trademark) E (manufactured by BASF) and the like. In addition, the polysulfone used in the present invention is preferably a polymer composed only of the repeating unit represented by the above formula (1) and / or (2). It may be polymerized. The other copolymerization monomer is preferably 10% by weight or less.

  A separation membrane is a porous body having specific pores, and is a membrane capable of sieving substances according to size. Examples of the form of the separation membrane include a hollow fiber membrane and a flat membrane, and are not particularly limited. However, a hollow fiber membrane is preferable because a wide membrane area can be easily provided for the liquid to be treated.

  These separation membranes are housed in a case by a known method, and used after being assembled into a device called a module by providing a nozzle so that a liquid can flow. Artificial kidneys and household water purifiers are typical examples.

  Examples of the method for producing the hollow fiber membrane include solution spinning and melt spinning.

  For example, as a method for producing a porous hollow fiber membrane by solution spinning, the following methods may be mentioned. Polysulfone and polyvinylpyrrolidone (weight ratio 20: 1 to 1: 5 is preferable, 5: 1 to 1: 1 is more preferable) polysulfone good solvent (N, N-dimethylacetamide, dimethylsulfoxide, dimethylformamide, N-methyl) When a film-forming stock solution (concentration is preferably 10 to 50% by weight, more preferably 15 to 40% by weight) dissolved in a mixed solution of pyrrolidone, dioxane and the like is discharged from the double annular die The infusion is poured inside and the dry section is run and then introduced into the coagulation bath.

  At this time, since the humidity of the dry part has an effect, rehydration from the outer surface of the membrane during running of the dry part speeds up the behavior of the phase hollow fiber near the outer surface and reduces the pore diameter of the porous membrane. However, if the relative humidity is too high, solidification of the stock solution on the outer surface becomes dominant and the pore diameter becomes small. This is an example of controlling the pore diameter. The relative humidity is preferably 60 to 90%. Moreover, it is preferable to use what consists of a composition based on the solvent used for the undiluted | stock solution as an injection | pouring liquid composition from process suitability. For example, when dimethylacetamide is used, the injection solution concentration is preferably 80% by weight or less and 70% by weight or less, and more preferably 60% by weight or less.

  The hollow fiber membrane thus obtained has a porous structure. Furthermore, such a porous structure is formed by polysulfone and polyvinyl pyrrolidone being phase-separated and desorbing polyvinyl pyrrolidone to form pores. Therefore, the remaining polyvinyl pyrrolidone has a shape covering the surface of the porous body.

  The pores can be reduced by drying and shrinking the hollow fiber membrane after membrane formation. This is an example of controlling the pore diameter.

  In order to increase the amount of polyvinyl pyrrolidone on the inner surface, it is possible to increase the amount of polyvinyl pyrrolidone in the stock solution or to use a high molecular weight polyvinyl pyrrolidone in the stock solution. Those having a weight average molecular weight of 50,000 or more are preferable. Further, polyvinylpyrrolidone may be added to the injection solution.

  The measurement of the amount of polyvinyl pyrrolidone on the inner surface can be obtained by XPS (X-ray photoelectron spectroscopy). A value measured at 90 ° is used as the measurement angle. Moreover, the average value of three places is used for a measurement place. The amount of polyvinylpyrrolidone can be determined from the ratio of the amount of nitrogen derived from polyvinylpyrrolidone and the amount of sulfur derived from porsulfone.

  When the hydrophilic polymer is a high-energy cross-linked polymer, it is preferable to perform high-energy treatment because the structure is fixed by cross-linking. High molecular energy as used herein refers to heating and radiation irradiation, such as α rays, β rays, γ rays, X rays, ultraviolet rays, electron rays, and the like. An irradiation dose of 5 kGy or more, preferably 15 kGy or more is suitable because crosslinking occurs. On the other hand, if the irradiation dose is too high, the decomposition reaction becomes dominant, so that it is 100 kGy or less, preferably 50 kGy or less.

  The method for modularizing the hollow fiber membrane is not particularly limited, but an example is as follows. First, the hollow fiber membrane is cut into a required length, bundled in a necessary number, and then put into a cylindrical case. Thereafter, a temporary cap is put on both ends, and a potting agent is put on both ends of the hollow fiber membrane. At this time, the method of adding the potting agent while rotating the module with a centrifuge is a preferable method because the potting agent is uniformly filled. After the potting agent is solidified, both ends are cut so that both ends of the hollow fiber membrane are open, and a hollow fiber membrane module is obtained.

  If the hollow fiber membrane is too thin, there will be a problem in durability and the like, and if it is too thick, the heat exchange efficiency will be reduced. Therefore, 5-500 micrometers, Preferably it is 10-100 micrometers, Furthermore, 20-50 micrometers is preferable.

  EXAMPLES The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

EXAMPLES Hereinafter, although an Example and a comparative example are given and this invention is demonstrated, this invention is not limited by these examples.
Measurement method (1) Preparation of liposome POPC (1-Palmitoyyl-2-oleoyl-sn-glycero-3-phosphocholine) Liposomes were prepared by the following method. The phospholipid was solubilized with chloroform / methanol (2: 1), the solvent was distilled off under reduced pressure, and the resulting lipid film was dried in vacuum for at least 3 hours. The lipid film was hydrated with a buffer solution or 100 mM calcein solution to prepare multilamellar vesicles (MLV). Freezing (−80 ° C.)-Thawing (above the phase transition temperature) was repeated 5 times in the MLV solution, and the particle size was adjusted using a 100 nm pore size polycarbonate filter.
The particle size Dp was measured by diluting the prepared liposome sample with a filtered 0.1 M Tris-HCl buffer. The average particle size and particle size distribution of the liposomes were analyzed using an argon laser excited DLS-700 Ar System (manufactured by Otsuka Electronics). In order to verify the polydispersity of the liposomes, the scattering angle was varied from 60 to 120 ° C. All measurements were performed at 25 ° C. After confirming monodispersion with one peak, the volume-based average particle diameter was determined.
(2) Measurement of pore diameter (Dm) of separation membrane using dextran FIG. 1 shows a schematic diagram of an apparatus used for measurement of pore diameter. The pore size was measured by converting the sieving coefficient using dextran into the fine particle size. A dextran solution 2 described later is flowed from the dextran solution containing side (Bi) of the hollow fiber membrane module 1 at a flow rate of 3 × 10 ⁻⁴ m ³ / s, and 1.2 × 10 ⁻⁵ m ³ from the dextran solution filtration side (F). Circulating filtration was performed for 1 hour while taking out the filtrate at / s. One hour later, the concentrated dextran solution flowing out from the dextran solution outlet side (Bo) and the filtrate flowing out from the F side were collected for 15 minutes. Moreover, 5 ml of a stock solution of dextran solution was collected from the Bi side 5 minutes after the start of the sampling.
These dextran solutions were processed using a TSK-GEL (G3000PWXL) column manufactured by Tosoh Corporation GPC (HLC-8220GPC) under the conditions of FLOW RATE 1.0 ml and column temperature 40 ° C., and the results were obtained. The weight average molecular weight of dextran was determined from the differential refractive index.
In addition, the stock solution of a dextran solution is a product made from FULKA, weight average molecular weight-1200 [No. 31394], ~ 6000 [No. 31388], 15000-20000 [No. 31387], to 40000 [No. 31389], ˜60000 [31397], ˜200000 [No. 31398] were prepared to 0.5 mg / ml each. The total solute was 3.0 mg / ml.
The sieve coefficient was determined by the following formula.
Dextran sieve coefficient (%) = (2 × C _F ) × 100 / (C _Bi + C _Bo )
Here, C _F = filtrate concentration, C _Bi = stock solution concentration, and CB _Bo = concentrate concentration.
The pore diameter (Dm) was calculated by calculating the dextran molecular weight having a sieving coefficient of 50% using the following formula.

Dm (nm) = 0.04456 x 2 x (dextran molecular weight) ^0.43821
(3) Water permeability test A plastic tube module having an effective length of 10 cm in which both ends are fixed with an adhesive through a hollow fiber membrane (hereinafter referred to as a mini module), and a water pressure of 1.3 × 104 Pa is applied to the inside of the hollow fiber membrane. The amount of filtration per unit time flowing out was measured. The water permeability was calculated by the following formula.

Water permeability (mL / hr / mmHg / m2) = QW / (T × P × A)
Here, QW is the filtration amount (mL), T is the treatment time (hr), P is the pressure (mmHg), and A is the inner surface area (m ² ) of the hollow fiber membrane.

Example 1
18 parts by weight of polysulfone (Amoco Udel-P3500), 3 parts by weight of polyvinylpyrrolidone (International Special Products Co .; hereinafter referred to as ISP) K30, 6 parts by weight of polyvinylpyrrolidone (ISP K90), 72 parts of dimethylacetamide, 1 part of water Was dissolved by heating to obtain a stock solution.

  This stock solution is sent to a spinneret part at a temperature of 50 ° C., and a solution comprising 63 parts by weight of dimethylacetamide and 37 parts by weight of water as a core liquid from a double slit tube having an outer diameter of 0.35 mm and an inner diameter of 0.25 mm of the annular slit part After discharging and forming a hollow fiber membrane, a coagulation bath having a temperature of 40 ° C. comprising 20% by weight of dimethylacetamide and 80% by weight of water is passed through a dry zone atmosphere having a length of 350 mm having a temperature of 30 ° C. and a dew point of 28 ° C. The hollow fiber membrane was wound into a bundle by passing through and obtaining a water washing step. The inner diameter of the hollow fiber membrane was 200 μm. The molecular weight of the dextran fraction having a sieving coefficient of 50% was 15000, and Dm was 6.2 nm.

  A mini module composed of 100 hollow fiber membranes was produced. A polycarbonate case of 5 mmφ was prepared and filled with 100 hollow fiber membranes. Further, this module was connected to a silicon tube circuit having an inner diameter of 1 mm and a total length of 130 cm. The total volume at this time was 3 ml. An AC-2120 peristaltic pump manufactured by ATTO Corporation was used as the liquid feed pump. The pressure gauge was installed on the filtrate side. Prior to use, the module was washed and used to remove impurities.

  The liposome was immobilized by the following procedure. First, the entire circuit is filled with water. Next, 2 ml of 30 mM POPC liposomes containing calcein is placed in the reservoir 10. In addition, Dp of the liposome used here was 30 nm. Turn on the two pump switches and filter and circulate for about 20 minutes. At this time, control while replenishing water so that the volume of the reservoir is about 1 ml. Add 0.2 ml of xanthan gum aqueous solution and 0.05 ml of water to a 1.5 ml container, and then add 100 mg of EDC (Dojindo Laboratories) and 100 mg of HOBt (Dojindo Laboratories) to the 1.5 ml container and add 1 ml of ethanol. Add 0.05 ml of dissolved EDC / HOBt solution and mix vigorously. This liquid is injected outside the hollow fiber while being sucked up by a pump. Next, the filter is circulated for 20 minutes, and again, the liquid volume in the reservoir is controlled to about 1 ml. Finally, 0.1 ml of an aqueous solution of polyethyleneimine (Wako Pure Chemical Industries, Ltd., molecular weight: 750,000) was sucked from the outside of the hollow fiber and further filtered and circulated for 30 minutes to produce a liposome-immobilized hollow fiber membrane device.

When the produced hollow fiber membrane device was washed with water and measured for water permeability, it was 2000 mL / hr / mmHg / m ² . In order to confirm the effect at the protein level, the adsorption properties were confirmed using insulin and lysozyme. Adsorption rate of lysozyme with high hydrogen bond stability (ρ value) of 6.0 was 40%, but insulin with low ρ value of 4.2 showed 70% adsorption, and more insulin was selected It was confirmed that the adsorption can be removed.

(Comparative Example 1)
A hollow fiber membrane module similar to that in Example 1 was prepared, and a protein adsorption experiment was performed without immobilizing liposomes. The adsorption rate with lysozyme was 40%, but in an insulin with a low ρ value, Only 40% adsorption was shown.

1: Mini module 2: Dextran solution 10 Reservoir 20 Hollow fiber outer pump 30 Hollow fiber inner pump 40 Pressure gauge 50 Disposal line Bi: Dextran solution entry side Bo: Dextran solution outlet side F: Dextran solution filtration side

Claims (9)

A separation membrane device, wherein fine particles having an average particle diameter of 10 nm to 10 μm are introduced into pores of a porous membrane. The separation membrane device according to claim 1, wherein the separation membrane has pores, and the pore diameter (Dm) and Dp satisfy a relationship of Dp ≧ 2 × Dm. The separation membrane device according to claim 1 or 2, wherein the fine particles are an assembly of molecules composed of a hydrophobic unit and a hydrophilic unit. The separation membrane device according to claim 3, wherein the fine particles are made of a lipid bilayer membrane. The separation membrane device according to any one of claims 1 to 4, wherein the fine particles are introduced into the membrane surface in a state of being encapsulated by a polymer gel. The separation membrane device according to claim 5, wherein the polymer gel comprises a cationic polymer and an anionic polymer. The separation membrane device according to claim 1, wherein the separation membrane is a hollow fiber type separation membrane. A method for producing a separation membrane device, wherein fine particles having an average particle diameter of 10 nm to 10 μm are introduced into a membrane and then the fine particles are immobilized on the membrane by enclosing a polymer gel. 9. The method of manufacturing a separation membrane device according to claim 8, wherein the polymer gel is insolubilized by crosslinking after the polymer gel is sealed inside the membrane.

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