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WO2014034787A1 - Dialyseur capable d'éliminer les virus - Google Patents

Dialyseur capable d'éliminer les virus Download PDF

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Publication number
WO2014034787A1
WO2014034787A1 PCT/JP2013/073165 JP2013073165W WO2014034787A1 WO 2014034787 A1 WO2014034787 A1 WO 2014034787A1 JP 2013073165 W JP2013073165 W JP 2013073165W WO 2014034787 A1 WO2014034787 A1 WO 2014034787A1
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WO
WIPO (PCT)
Prior art keywords
virus
heparin
sulfate
group
compound
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PCT/JP2013/073165
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English (en)
Japanese (ja)
Inventor
三浦　博
一郎 横田
典孝 吉川
智昌 松田
重昭 藤枝
綾子 一色
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Dic株式会社
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Publication of WO2014034787A1 publication Critical patent/WO2014034787A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0093—Chemical modification
    • B01D67/00931—Chemical modification by introduction of specific groups after membrane formation, e.g. by grafting
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/08—Hollow fibre membranes

Definitions

  • the present invention relates to a dialysis apparatus capable of removing viruses.
  • Diabetic nephropathy and chronic glomerulonephritis account for over 60% of the primary diseases of patients introduced with hemodialysis, and diabetic nephropathy is the primary disease.
  • the cause of death in dialysis patients is heart failure, cerebrovascular disorder, infection, malignant tumor, etc., and death due to cerebrovascular disorder or heart disease is decreasing, but infection tends to increase.
  • About 15% of patients have a dialysis history of more than 15 years, while less than 5 years account for about 50% (Non-patent Document 1).
  • Dialysis membranes are roughly classified into cellulosic membranes and synthetic polymer membranes. In the former case, a modified cellulose membrane (regenerated cellulose membrane: cellulose diacetate, cellulose triacetate) was developed because it showed transient leukopenia and activation of complement and low biocompatibility.
  • Synthetic polymer membranes used include polysulfone (PS), polymethyl methacrylate (PMMA), ethylene vinyl alcohol (EVAL), polyester polymer alloy (PEPA), polyethersulfone (PES), and polyacrylonitrile (PAN).
  • PS polysulfone
  • PMMA polymethyl methacrylate
  • EVAL ethylene vinyl alcohol
  • PEPA polyester polymer alloy
  • PES polyethersulfone
  • PAN polyacrylonitrile
  • the PS membrane is a synthetic material composed of polyallyl ether and polyvinyl pyrrolidone, and has an asymmetric membrane structure. Therefore, the PS membrane has a capability of removing a wide range of uremic substances from small molecules to large molecules, particularly ⁇ 2 Because of its high removal performance against microglobulin, it contributes to the reduction of joint pain in long-term dialysis patients.
  • HCV antibody positive in hemodialysis patients was 9.8% (2007), and the HCV antibody positive rate (transition from 2006 to 2007) was 1.04% Very high compared to 0.002% of dialysis patients.
  • HCV antibody positive people 75% (about 20,000 people) are positive for HCV-RNA.
  • the rate of treatment with drugs such as interferon is only 2%, and most patients undergo dialysis without treatment.
  • PEG-IFN Pegylated interferon
  • ribavirin antiviral drug
  • SVR blood HCV-RNA negativity
  • Non-Patent Documents 2 and 4 It has been reported that the blood HCV level of hemodialysis patients is relatively lower than that of non-dialysis patients, and the rate of transition to cirrhosis and liver cancer is low. In addition, the blood HCV level decreases temporarily before and after dialysis, and there are differences depending on the type of dialysis membrane (regenerated cellulose, PMMA, PS, etc.) (Non-patent Document 7). There are reports that the amount of HCV (in blood) decreases (Non-Patent Documents 3, 4, and 6). As a factor of the decrease, it is presumed that the virus is destroyed or adsorbed on the dialysis membrane or changes in the immune side of the host.
  • a virus eliminator is incorporated into the dialysis circuit and HCV can be actively removed from the blood, it is thought to lead to the development of a medical device that can contribute to the elimination of HCV in chronic hemodialysis patients.
  • a hemodialysis membrane and a virus remover are connected to perform extracorporeal circulation (blood purification), and dialysis and virus removal are performed simultaneously. If these two operations (actions) can be performed in parallel, the burden on the patient is considered to be greatly reduced.
  • Non-patent Document 8 heparin is immobilized in a substrate in which heparin is immobilized on a polymer support such as a hollow fiber that can pass whole blood without separating blood cells and plasma, or in the pores of a blood cell plasma separation membrane. It is expected that HCV can be removed more easily with such a base material, and an HCV removal module or the like with less burden on the patient can be provided.
  • Examples of the form of the substrate on which heparin is immobilized include porous hollow fibers, nonwoven fabrics, and beads.
  • porous hollow fibers By optimizing the internal or external circulation type using a porous hollow fiber, the shape of the nonwoven fabric, and beads, it is possible to develop a module that suppresses the retention of blood and is less in the formation of thrombus.
  • the type of surface functional group and the immobilization density vary depending on the material of the substrate, and it is necessary to find an optimum method for each substrate.
  • HIV human immunodeficiency virus
  • a polymer substrate having a methylene group in the main chain is contacted with a polymerizable compound having an ethylenically unsaturated bond and a sugar chain, or a polymerizable composition containing the polymerizable compound, After irradiating with ionizing radiation, or after irradiating the polymer substrate with ionizing radiation, it has a sugar chain obtained by contacting the polymerizable compound or a polymerizable composition containing the polymerizable compound.
  • a polymer substrate for HIV adsorption is described.
  • an object of the present invention is an apparatus capable of simultaneously performing dialysis and virus removal on a hepatitis chronic hemodialysis patient and capable of removing viruses in the body (blood) at a high rate. Is to provide.
  • the present inventors conducted a detailed study on a dialysis apparatus capable of removing viruses by combining a dialysis machine and a polymer substrate for virus removal in which saccharides are immobilized. The invention has been completed.
  • the present invention is a dialysis apparatus capable of removing viruses comprising at least a dialysis machine and a virus removal machine using a polymer substrate for virus removal
  • the present invention relates to a virus removing dialysis apparatus, wherein the virus removing polymer substrate is a virus removing polymer substrate composed of a polymer support (A) on which saccharides are immobilized.
  • the apparatus which can perform dialysis and virus removal simultaneously with a hepatitis chronic hemodialysis patient, and can remove the virus in the body (in the blood) at a high rate can be provided. .
  • a dialysis device capable of removing viruses comprising at least a dialysis device and a virus removal device using a polymer substrate for virus removal,
  • a virus removing dialysis apparatus wherein the virus removing polymer substrate is a virus removing polymer substrate comprising a polymer support (A) on which saccharides are immobilized, 2.
  • the polymer substrate for virus removal is bonded to the polymer support (A) surface-treated with a polymer material having a hydroxyl group and the compound (B) having a group capable of reacting with the hydroxyl group to form a covalent bond.
  • the virus-removable dialysis apparatus according to 1 which is a polymer substrate for virus removal in which a saccharide is immobilized via a compound (C) having an amino group, 3.
  • Polymer support (A) surface-treated with a polymer material having a hydroxyl group is a partially saponified product of ethylene-vinyl alcohol copolymer, ethylene-vinyl alcohol-vinyl acetate copolymer, ethylene-vinyl acetate copolymer
  • the virus-removable dialysis apparatus according to 2 which is a hollow fiber surface-treated with a vinyl alcohol-vinyl acetate copolymer, a hydroxymethacrylate copolymer, a partially saponified cellulose acetate, or a glycerin derivative, 4).
  • the dialysis apparatus capable of removing a virus according to any one of 4 to 7, wherein the porous hollow fiber has a thickness of 30 to 100 ⁇ m, 9.
  • Compound (B) having a group capable of reacting with a hydroxyl group to form a covalent bond is epichlorohydrin, carboxylic acid anhydride, dicarboxylic acid compound, dicarboxylic acid chloride, diisocyanate, diepoxy compound, (meth) acrylic acid,
  • the dialysis apparatus capable of removing a virus according to any one of 1 to 9, which is glycidyl (meth) acrylate or (meth) acryloyloxyalkyl isocyanate, 11.
  • the compound (C) having an amino group is polyallylamine, ammonia, 2-aminoethanol, ethylenediamine, butylenediamine, hexamethylenediamine, 1,2-bis (2-aminoethoxy) ethane, 3,3′-diaminodipropyl
  • the dialysis apparatus capable of removing a virus according to any one of 1 to 10, which is an amine, diethylenetriamine, phenylenediamine, or polyethyleneimine, 12
  • the polymerizable compound is a compound having a functional group capable of reacting with any one selected from the group consisting of a compound having a hydroxyl group or an amino group, a compound having at least two epoxy groups, and ammonia; and
  • the saccharide is formed of
  • the saccharide is heparin, a heparin derivative in which the primary or secondary hydroxyl group of heparin is sulfated, a heparin derivative in which an N-acetyl group-elimination product of heparin is N-sulfate, and heparin N-sulfate group.
  • Heparin derivatives obtained by N-acetylation of sulfate group-eliminated compounds low molecular weight heparin, dextran sulfate, dextran sulfate, fucoidan, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, heparin analog, heparan sulfate, rhamnan sulfate, ketalan sulfate, The dialyzer capable of removing a virus according to any one of 1 to 15, which is alginic acid, hyaluronic acid, or carboxymethylcellulose; 17.
  • the dialysis device capable of removing a virus according to any one of 1 to 16, wherein the virus is a hepatitis B or C virus, 18.
  • the saccharide is heparin, a heparin derivative in which the primary or secondary hydroxyl group of heparin is sulfated, a heparin derivative in which an N-acetyl group-elimination product of heparin is N-sulfate, and heparin N-sulfate group.
  • Heparin derivatives obtained by N-acetylation of sulfate group-eliminated compounds low molecular weight heparin, dextran sulfate, dextran sulfate, fucoidan, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, heparin analog, heparan sulfate, rhamnan sulfate, ketalan sulfate,
  • Dialysis device used in the present invention can be a known and commonly used dialysis device without limitation, and a preferable dialysis device is a commonly used hemodialysis therapy that can artificially replace the function of the kidney. Mention may be made of the equipment used. These devices are used to remove blood wastes, maintain charge quality, and maintain water content by external means to prevent patients with renal failure from becoming uremia. Mention may be made of devices used for therapies such as hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration and apheresis.
  • Polymer support (A) As the polymer support (A) used in the present invention, various materials can be used as long as they have high blood compatibility. For example, olefin resins, styrene resins, sulfone resins, acrylic resins, Examples include urethane resins, ester resins, ether resins, and cellulose mixed esters. More specifically, polyethylene terephthalate, polymethyl methacrylate, polysulfone, polyether sulfone, polyacrylonitrile, polyethylene, polypropylene, or poly-4-methyl. The thing comprised with pentene etc. can be mentioned.
  • a polymer support that has been surface-treated with a polymer material having a hydroxyl group can be preferably used, and a resin that has been surface-treated with a polymer material having a hydroxyl group by a known method or a resin that contains a hydroxyl group is known.
  • a resin previously kneaded by the method can be mentioned.
  • the shape of the polymer support (A) is not particularly limited, and the polymer support (A) can be used in various forms such as a hollow fiber, a nonwoven fabric, and beads. When applied to extracorporeal circulation, by optimizing the shape, it is possible to produce a base material or instrument with less thrombus generation in the staying part.
  • a porous hollow fiber as such a polymer support (A), as the raw material, for example, olefin resin, styrene resin, sulfone resin, acrylic resin, urethane resin, ester resin
  • examples include ether resins or cellulose mixed esters, and more specifically those composed of polyethylene terephthalate, polymethyl methacrylate, polysulfone, polyether sulfone, polyacrylonitrile, polyethylene, polypropylene, poly-4-methylpentene, or the like.
  • examples thereof include those obtained by subjecting a surface treatment with a polymer material having a hydroxyl group by a known method or a resin obtained by kneading a resin containing a hydroxyl group in advance by a known method.
  • a porous hollow fiber by a well-known and usual method according to the intended purpose.
  • those having various pore diameters and pore diameter distributions can be prepared by subjecting the spun yarn to annealing treatment, cold drawing, hot drawing, and heat setting.
  • the virus can be efficiently removed by passing the virus-containing liquid through the hole of the hollow fiber.
  • a method of separating blood cells and plasma components, allowing only the plasma components to pass through the pores, and removing viruses from the plasma can be mentioned.
  • a liquid that has passed through the holes of the hollow fiber and a liquid that has not passed through the holes are produced. From the examination of the virus removal rate in the liquid containing virus, it is clear that the virus removal rate in the liquid that passed through the hole of the hollow fiber is good, and albumin, which is a useful component in blood, is not removed It became.
  • the virus removal rate in the liquid that did not pass through the hollow fiber holes was lower than the virus removal rate in the liquid that passed through the hollow fiber holes It has been suggested that much of the virus removal is occurring as it passes through the pores of the porous hollow fiber.
  • passing through the hole means a state in which the liquid passes from the inner surface to the outer surface side of the hollow fiber or from the outer surface to the inner surface side.
  • the pore diameter of the porous hollow fiber used is not particularly limited as long as it has a diameter capable of efficiently removing the virus.
  • the mean flow pore size is 500 nm or less so that blood cell components and platelets do not enter the pores.
  • the average flow pore size is preferably 50 nm or more.
  • the optimal pore size varies depending on the size of the virus when virus removal is assumed. Taking hepatitis C virus as an example, the preferred pore size is 80 to 250 nm, more preferably 100 to 180 nm. In the case of a relatively large human immunodeficiency virus, the preferred pore size is 100 to 250 nm, more preferably 120 to 200 nm.
  • the inner diameter of the porous hollow fiber used is not particularly limited as long as it has an inner diameter capable of efficiently removing the virus.
  • the inner diameter of the porous hollow fiber used is not particularly limited as long as it has an inner diameter capable of efficiently removing the virus.
  • the inner diameter is preferably 150 to 500 ⁇ m, more preferably 160 to 400 ⁇ m, and further preferably 170 to 350 ⁇ m.
  • the thickness of the porous hollow fiber used is not particularly limited as long as it has a thickness that can efficiently remove the virus.
  • the virus is efficiently removed from the plasma by extracorporeal circulation, it is preferably 30 to 100 ⁇ m, more preferably 35 to 80 ⁇ m, further considering the plasma separation performance, contact area, mechanical strength of the hollow fiber, etc.
  • the thickness is preferably 40 to 60 ⁇ m.
  • Such other substrate is not particularly limited as long as it has a function of capturing and removing viruses, and examples thereof include a sugar chain-immobilized gel and a sugar chain-immobilized nonwoven fabric.
  • nonwoven fabric When a nonwoven fabric is used as the polymer support (A), various materials can be used as raw materials as long as they have high blood compatibility. Examples thereof include olefin resins, styrene resins, sulfone resins, acrylic resins, urethane resins, ester resins, ether resins, and cellulose mixed esters. More specifically, those composed of polyethylene terephthalate, polystyrene, polymethyl methacrylate, polysulfone, polyether sulfone, polyacrylonitrile, polyvinyl alcohol, polyethylene, maleic anhydride polymer, polypropylene, poly-4-methylpentene, etc. be able to. *
  • These resins may be used alone, or a mixture of several kinds of resins may be used.
  • these resins include those treated with a polymer material having a hydroxyl group by a known and conventional method and those treated by graft polymerization.
  • the resin raw material already has a hydroxyl group, it can be used as it is without being treated.
  • the raw material, processing polymer or polymerizable compound has a functional group other than a hydroxyl group (for example, a carboxyl group or an epoxy group), it is possible to immobilize saccharides using these functional groups. It is.
  • the fiber diameter may be appropriately optimized in the range of 0.01 ⁇ m to 100 ⁇ m.
  • it When passing blood or the like through a non-woven fabric, it must be designed to allow blood cell components to pass through. Therefore, 0.1 um or more is necessary.
  • the fiber diameter is preferably 0.1 ⁇ m to 20 ⁇ m.
  • post-treatment that allows blood cell components to pass through may be performed.
  • blood is not passed through the nonwoven fabric and brought into contact with the nonwoven fabric surface, there is no particular limitation.
  • the basis weight is not particularly limited as long as it is in the range of 1 to 200 g / m 2 . As the weight per unit area increases, the liquid permeability may be deteriorated. Therefore, the liquid permeability may be appropriately optimized according to the purpose.
  • the thickness may be appropriately selected between 10 and 10,000 ⁇ m, and an optimum thickness may be selected depending on the apparatus configuration and liquid permeation performance.
  • a porous gel of a polysaccharide having a hydroxyl group such as cellulose, agarose, hydroxyethyl cellulose, hydroxyethyl agarose, dextran, starch, a (meth) acrylic monomer having a hydroxyl group and a polyfunctional
  • a polysaccharide having a hydroxyl group such as cellulose, agarose, hydroxyethyl cellulose, hydroxyethyl agarose, dextran, starch
  • a (meth) acrylic monomer having a hydroxyl group and a polyfunctional
  • the average particle size of the beads is preferably in the range of 200 ⁇ m to 2000 ⁇ m.
  • polymer material having a hydroxyl group contained in the polymer support (A) examples include an ethylene-vinyl alcohol copolymer, ethylene-vinyl alcohol-vinyl acetate. Copolymer, ethylene-vinyl acetate copolymer partially saponified, vinyl alcohol copolymer such as vinyl alcohol-vinyl acetate copolymer, hydroxy methacrylate copolymer, cellulose acetate part A saponified product or a glycerin derivative can be exemplified. However, in addition to those exemplified, there is no particular limitation as long as the resin has a hydroxyl group.
  • the surface treatment with the polymer material having a hydroxyl group can be carried out by a known and usual method.
  • the porous polyolefin is dipped in a solution in which the polymer material having a hydroxyl group is dissolved, pulled up and then dried.
  • an ethylene-vinyl alcohol copolymer is preferable in that the polyolefin porous hollow fiber can be easily hydrophilized as disclosed in JP-A-61-271003.
  • the compound (B) having a group capable of reacting with a hydroxyl group to form a covalent bond used in the present invention has a group capable of reacting with a hydroxyl group present on the surface of the surface-treated polymer support (A).
  • A a functional group that easily reacts with an amino group after immobilization.
  • compounds such as epichlorohydrin, carboxylic anhydride, dicarboxylic acid, dicarboxylic acid chloride, diisocyanate, diepoxy compound and the like can be mentioned.
  • Examples of the compound that can be graft-polymerized on the substrate include (meth) acrylic acid, glycidyl (meth) acrylate, (meth) acryloyloxyalkyl isocyanate, and maleic anhydride.
  • the compound (B) having a group capable of forming a covalent bond by reacting with a hydroxyl group is reacted with the hydroxyl group present on the surface of the polymer support (A), for example, a known and commonly used hydroxyl group and epoxy are used.
  • the reaction can be performed under the conditions used for the reaction with a group, the reaction between a hydroxyl group and a carboxy group, the reaction between a hydroxyl group and a carboxylic acid anhydride, the reaction between a hydroxyl group and an isocyanate, and the like.
  • the embodiment is used. Accordingly, it can be fixed to either the inner surface or the outer surface of the yarn, or both.
  • the compound (B) having a group capable of forming a covalent bond by reacting with a hydroxyl group may be contacted and immobilized on the inner surface of the hollow fiber.
  • a compound (B) having a group capable of reacting with a hydroxyl group to form a covalent bond may be brought into contact with the outer surface of the hollow fiber.
  • the yarn When it is desired to immobilize on the inner and outer surfaces including inside the pores of the yarn, the yarn may be bundled and immersed in the reaction solution, or the reaction solution may be circulated after assembling as a module.
  • Compound having an amino group (C) The compound (C) having an amino group used in the present invention reacts with the compound (B) having a group capable of reacting with a hydroxyl group to form a covalent bond, and an amino group capable of easily immobilizing a saccharide remains. If it is a thing, there will be no restriction
  • Examples of such compound (C) include polyallylamine, ammonia, 2-aminoethanol, ethylenediamine, butylenediamine, hexamethylenediamine, 1,2-bis (2-aminoethoxy) ethane, and 3,3′-diamino.
  • the amino group of the compound (C) may have a known and commonly used protective group used for the amino group, if necessary.
  • the protecting group used include t-butyl carbamate (Boc group), benzyl carbamate and the like. For deprotection, a known and commonly used method may be used.
  • the reaction between the compound part (C) and the compound (B) having a group capable of reacting with a hydroxyl group to form a covalent bond includes a known and usual reaction between an amino group and an epoxy group, a reaction between an amino group and a carboxy group, It can carry out suitably on the conditions used for reaction of an amino group and carboxylic anhydride, and reaction of an amino group and isocyanate.
  • saccharides used in the present invention are not particularly limited as long as they can efficiently capture the virus by an action such as adsorption and remove the virus from the liquid containing the virus.
  • Such saccharides include, for example, heparin, heparin derivatives obtained by sulfate-forming primary or secondary hydroxyl groups of heparin, heparin derivatives obtained by N-sulfate esterification of heparin N-acetyl group acetyl group-eliminated, heparin Heparin derivatives obtained by N-acetylating a sulfate group-eliminated product of N-sulfate group, low molecular weight heparin, dextran sulfate (preferably having a sulfur content of 3 to 6%), dextran sulfate (having a sulfur content of 15 to 20%) Are preferable), fucoidan, chondroitin sulfate A, chondroitin sulfate C,
  • Heparin As the heparin, a commonly known one can be used without limitation. Heparin is a kind of heparan sulfate that is widely present in the body such as small intestine, muscles, lungs, spleen and mast cells, and is chemically a glycosaminoglycan, ⁇ -D-glucuronic acid or ⁇ -L-iduron. It is a polymer in which an acid and D-glucosamine are polymerized by 1,4-bonds, and has a feature that the degree of sulfation is particularly high compared to heparan sulfate.
  • the average molecular weight of heparin is not particularly limited, but when the average molecular weight is large, the reactivity with the compound (C) is lowered, so that the efficiency of immobilizing heparin is considered to be poor. Accordingly, the molecular weight of heparin is preferably about 500 to 500,000 daltons, more preferably 1,200 to 50,000 daltons, and even more preferably 5,000 to 30,000 daltons.
  • Examples of the heparin derivative used in the present invention include a heparin derivative obtained by sulfate-forming a primary or secondary hydroxyl group of the above-mentioned heparin, a heparin derivative obtained by N-sulfate-esterifying an acetyl group-eliminated product of the N-acetyl group of the above-mentioned heparin, Alternatively, a heparin derivative obtained by N-acetylating a sulfate group elimination product of N-sulfate group of heparin can be preferably used.
  • the heparin amine is treated by passing the alkali salt of heparin through an ion exchange resin (H + ) or the like and treating with an amine. Prepare the salt. Thereafter, it can be treated with a sulfating agent to obtain the desired heparin derivative.
  • a sulfating agent known and commonly used SO 3 • pyridine is preferable.
  • a sulfating agent is used.
  • the target heparin derivative can be obtained by processing.
  • SO 3 .NMe 3 and the like are preferable.
  • N-acetylation When synthesizing a heparin derivative obtained by N-acetylating the N-sulfate group leaving group of heparin, for example, after preparing a pyridinium salt of heparin, only the sulfate group on the nitrogen atom is desulfated, N-acetylation may be performed by a conventional method.
  • low molecular weight heparin dextran sulfate (sulfur content 3-6%), dextran sulfate (sulfur content 15-20%), fucoidan, chondroitin sulfate A, chondroitin sulfate C, dermatan sulfate, heparin analog, heparan sulfate, rhamnan sulfate
  • ketalan sulfate alginic acid, hyaluronic acid, or carboxymethyl cellulose, known and commonly used compounds can be used.
  • the degree of sulfation of dextran sulfate may be either high sulfation degree (sulfur content 15-20%) or low sulfation degree (sulfur content 3-6%), and is obtained by a known and conventional method. If it is a thing, there will be no restriction
  • a heparin-like substance generally refers to a sulfated polysaccharide listed in the Japanese Pharmacopoeia Standards for Pharmaceutical Components. However, as long as it can be obtained by a known and commonly used extraction method or preparation method, it is not limited to those listed in the Japanese Pharmacopoeia Pharmaceutical Component Standards.
  • the saccharide In order for the saccharide to be immobilized via the compound (C) having an amino group, it is necessary that the compound (C) and the saccharide are bound by a covalent bond. Such a bond can be formed by appropriately performing a known and usual reaction.
  • an amidation reaction or a reductive amination reaction can be exemplified.
  • the amidation method is used, for example, in peptide synthesis such as amidation with an active ester, amidation with a condensing agent, combined use, mixed acid anhydride method, azide method, oxidation-reduction method, DPPA method, Woodward method, etc.
  • the known and conventional amidation reaction may be appropriately performed.
  • a known and usual method of reacting the amino group of compound (C) with the reducing end of the saccharide may be used.
  • amidation with an active ester examples include NHS (N-hydroxysuccinimide), nitrophenol, pentafluorophenol, DMAP (4-dimethylaminopyridine), HOBT (1-hydroxybenzotriazole), and HOAT (hydroxyazabenzotriazole). And the like to form an active ester obtained by once condensing a group having a high leaving ability with a carboxy group, and reacting this with an amino group.
  • Amidation with a condensing agent may be used alone or in combination with the active ester.
  • EDC (3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride), HONB (endo-N-hydroxy-5-norbornene-2,3-dicarboxamide), DCC (dicyclohexylcarbodiimide) , BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), HBTU (O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphate) TBTU (O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium tetrafluoroborate), HOBt (1-hydroxybenzotriazole), HOOBt (3,4-dihydro-3- Hydroxy-4-oxo- , 2,3-benzotriazine), di
  • a solvent that can be used in these amidation methods water and an organic solvent used for peptide synthesis can be used.
  • an organic solvent used for peptide synthesis can be used.
  • dimethylformamide (DMF) dimethyl sulfoxide (DMSO), hexaphosphoroamide, dioxane, tetrahydrofuran ( THF), ethyl acetate, and the like, and mixed solvents and aqueous solutions containing these.
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • ethyl acetate ethyl acetate
  • the saccharide can also be immobilized via a compound (B) having a group that can react with a hydroxyl group to form a covalent bond.
  • a compound (B) having a group that can react with a hydroxyl group to form a covalent bond is just to select suitably according to a use purpose, reaction conditions, equipment, etc.
  • the amount of saccharide immobilized is not particularly limited as long as the virus can be efficiently removed. However, since biocompatibility is important during extracorporeal circulation, it is necessary to make adjustments to prevent plasma protein adsorption or complement activation.
  • the amount of immobilization can be adjusted by a method of adjusting the amount of the amino group-containing compound (C) introduced, a method of changing the reaction conditions for immobilizing the saccharide, or the like.
  • it may be 1 to 100 ⁇ g / cm 2 , preferably 2 to 80 ⁇ g / cm 2 , more preferably 3 to 70 ⁇ g / cm 2 .
  • the virus removal apparatus of the present invention can also be produced by graft polymerization reaction of the following polymerizable compounds.
  • the ethylenically unsaturated group of the polymerizable compound is graft-polymerized onto the porous polymer support by radicals generated by irradiating the porous polymer support with ionizing radiation.
  • the ionizing radiation source used in the graft polymerization include known and commonly used ⁇ -rays, ⁇ -rays, ⁇ -rays, accelerated electron beams, X-rays and the like, and practically preferred are ⁇ -rays and accelerated electron beams.
  • the graft polymerization method includes the simultaneous irradiation graft polymerization method in which the porous polymer support and the polymerizable compound are brought into contact with each other and irradiated with ionizing radiation, and the porous polymer support is pre-irradiated and then contacted with the polymerizable compound.
  • Any of the irradiation graft polymerization methods is possible and can be selected according to the purpose.
  • the polymerizable compound can form a graft polymer chain on the surface of the porous polymer support by a graft polymerization reaction.
  • the irradiation dose and the acceleration voltage differ depending on the porous polymer support, so the range cannot be determined unconditionally. It is necessary to adjust the thickness appropriately in consideration of the thickness. For example, when the irradiation amount is large, dielectric breakdown due to charging occurs, and when the irradiation amount is small, the polymerization reaction does not proceed. For this reason, in consideration of the material, form, etc. of the porous polymer support, the irradiation dose that does not cause dielectric breakdown due to charging and the polymerization reaction proceeds sufficiently may be appropriately adjusted.
  • the acceleration voltage is related to the permeability and varies depending on the thickness of the porous polymer support.
  • the acceleration voltage is generally small and may be selected according to the form of the porous polymer support.
  • the porous polymer support is a hollow fiber made of polyethylene and having a thickness of 10 ( ⁇ m) to 100 ( ⁇ m), it is 10 (kGy) or more and 300 (kGy) or less, more preferably 90 ( kGy) or less, and the acceleration voltage can be selected as appropriate.
  • the step of irradiating the porous polymer support with ionizing radiation in this order after contacting the polymerizable compound or the polymerizable composition containing the polymerizable compound in this state may be performed in reverse order.
  • the porous polymer support is first irradiated with ionizing radiation and then the porous polymer support is contacted with the polymerizable compound or the polymerizable composition containing the polymerizable compound in this order. May be.
  • the immobilization is preferably carried out under deoxygenation or in an inert gas. What is necessary is just to remove the unreacted polymerizable compound by methods, such as washing
  • the bonding reaction between the compound having a hydroxyl group or amino group and the polymerizable compound there is no particular limitation on the bonding reaction between the compound having a hydroxyl group or amino group and the polymerizable compound, as long as the compound having a hydroxyl group or amino group and the polymerizable compound can form a covalent bond.
  • a compound having an amino group that is a functional group capable of bonding to a carboxyl group of (meth) acrylic acid is preferred.
  • an amidation reaction between (meth) acrylic acid and a compound having an amino group is performed.
  • Amidation reaction methods include, for example, amidation with an active ester, amidation with a condensing agent, combinations thereof, mixed acid anhydride method, azide method, redox method, DPPA method, Woodward method, etc.
  • the known and commonly used amidation reaction may be appropriately performed.
  • the amidation with an active ester can be performed, for example, by the above method.
  • the method in which the carboxy group of (meth) acrylic acid is once NHS and then reacted with the amino group of compound (C) to be amidated is preferable.
  • a solvent that can be used in these amidation methods water and an organic solvent used for peptide synthesis can be used.
  • an organic solvent used for peptide synthesis can be used.
  • dimethylformamide (DMF) dimethyl sulfoxide (DMSO), hexaphosphoroamide, dioxane, tetrahydrofuran ( THF), ethyl acetate, and the like, and mixed solvents and aqueous solutions containing these.
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • THF tetrahydrofuran
  • ethyl acetate ethyl acetate
  • the proportion of the activated ester residue introduced into the carboxy group depends on the type of activator used and the amount of reagent used. In general, compared to the reaction in solution, the polymer obtained from the polymerizable compound is bonded, and the reactivity is lowered. Therefore, in order to increase the introduction amount, it is necessary to use a considerably excessive amount of the reaction reagent. It is thought that there is. Therefore, the ratio of the activator to the condensing agent reaction reagent with respect to the carboxy group of (meth) acrylic acid polymerized on the porous polymer support cannot be specified, but the active ester group is equivalent to the carboxyl group. In general, it is desirable to use about 1 to 10 in molar ratio. Furthermore, by adjusting the excess amount of the reaction reagent, it is possible to arbitrarily adjust the introduction ratio of the active ester group in the range of 0.01 to 100%.
  • glycidyl (meth) acrylate When glycidyl (meth) acrylate is used as the polymerizable compound, it can be bonded by reacting the hydroxyl group or amino group of the compound having a hydroxyl group or amino group with the glycidyl group of the polymerizable compound.
  • the reaction conditions include a solvent used in the reaction of a normal hydroxyl group or amino group and a glycidyl group, a reaction temperature, and a reaction time.
  • a solvent a solvent that does not dissolve or swell the porous polymer support is used.
  • a solvent that can dissolve the polymer of the polymerizable compound without dissolving and swelling the porous polymer support can be used, and the concentration of the compound having a hydroxyl group or an amino group can be arbitrarily selected, preferably , And can be used by adjusting the concentration to 0.1 to 50% by weight.
  • the reaction temperature can be selected from temperatures at which a compound having a hydroxyl group or an amino group or a solvent does not vaporize, and is preferably 0 to 70 ° C., more preferably 20 to 60 ° C.
  • the reaction time depends on the type, concentration, and reaction temperature of the compound having a hydroxyl group or amino group, and the content of the compound having a hydroxyl group or amino group in the reaction solution can be determined by gas chromatography, liquid chromatography, titration, etc. Monitoring is preferably performed until the compound having a hydroxyl group or an amino group is not consumed. In general, the reaction can be completed in 30 minutes to 12 hours, but is not limited thereto, and reaction conditions can be set by appropriately selecting.
  • (meth) acryloyloxyalkyl isocyanate When (meth) acryloyloxyalkyl isocyanate is used as the polymerizable compound, it can be bonded by reacting the hydroxyl group or amino group of the compound having a hydroxyl group or amino group with the isocyanate group of the polymerizable compound.
  • the reaction conditions include a solvent used in a reaction between a normal hydroxyl group or amino group and an isocyanate group, a reaction temperature, and a reaction time.
  • the solvent can be appropriately selected from solvents that do not dissolve and swell the porous polymer support and do not react with isocyanate, such as ethyl acetate and acetonitrile.
  • the reaction concentration can be arbitrarily selected.
  • the reaction concentration can be selected from 0.5 to 15% by weight.
  • the reaction temperature is preferably 0 to 50 ° C. because the reaction with isocyanate is an exothermic reaction.
  • the reaction time can be 2 to 24 hours, but is not limited thereto, and reaction conditions can be set by appropriately selecting.
  • the sample to be dialyzed with the dialyzer of the present invention is not particularly limited as long as it contains a toxin that causes uremia that is excreted in the blood due to viruses and kidney diseases. More specifically, blood of humans with renal diseases including viruses can be mentioned.
  • the form of the virus removal apparatus using the polymer substrate for virus removal of the present invention is not particularly limited as long as it is a shape applicable to the above-mentioned use.
  • a hollow fiber module, a filtration column, a filter, etc. Is mentioned.
  • the shape and material of the container are not particularly limited, but when applied to extracorporeal circulation of body fluid (blood), a cylindrical container having an internal volume of 10 to 400 mL and an outer diameter of about 2 to 10 cm. It is preferable to use a cylindrical container having an internal volume of 20 to 300 mL and an outer diameter of about 2.5 to 7 cm.
  • the above-mentioned thing can be used regarding a dialysis machine.
  • the dialysis apparatus of the present invention is characterized in that it is composed of at least a virus removal device using a polymer substrate for virus removal from a dialysis device.
  • the dialysis device and the virus removal device are preferably connected in series in order to efficiently remove viruses and toxins in the dialysis device, and the order of connection is not limited.
  • the pore does not necessarily have to penetrate the membrane as a straight tube, and may be bent inside the membrane. Also, some holes may be fused inside the membrane, or conversely, one hole may be branched, or these may be mixed.
  • ⁇ ELISA> The specimen is pretreated with a pretreatment solution (SDS) to release the HCV core antigen and simultaneously deactivate the coexisting HCV antibody to obtain a measurement sample.
  • a measurement sample is added to an HCV core antigen antibody-immobilized plate and incubated. After the reaction for a predetermined time, washing is performed, and whole radish-derived peroxidase-labeled HCV core antigen antibody is added and incubated. After reacting for a predetermined time, washing is performed, and o-phenylenediamine reagent is added and incubated. After the reaction for a predetermined time, a reaction stop solution is added. Measure the color development at a wavelength of 492 nm. The concentration is calculated from the absorbance of the sample.
  • a high density polyethylene (HIZEX 2200J, manufactured by Mitsui Petrochemical Co., Ltd.) having a density of 0.968 g / cm 3 and a melt index of 5.5 has a discharge port diameter of 16 mm, an annular slit width of 2.5 mm, and a discharge cross-sectional area of 1.06 cm 2.
  • the hollow fiber shaping spinneret was used to spin at a spinning temperature of 160 ° C. and wound up with a spinning draft 1427.
  • the dimensions of the obtained unstretched hollow fiber were an inner diameter of 308 ⁇ m and a film thickness of 64 ⁇ m. This unstretched hollow fiber was heat-treated at 115 ° C.
  • the film was stretched 1.8 times at a deformation rate of 21400% / min at room temperature, and then heated in a heating furnace at 100 ° C. until the total stretching ratio was 4.8 times so that the deformation rate was 330% / min.
  • the stretched yarn was further subjected to thermal shrinkage in a heating furnace at 125 ° C. until the total draw ratio was 2.8 times to obtain a drawn yarn.
  • an ethylene-vinyl alcohol copolymer (EVOH) having an ethylene content of 44% was dissolved by heating in a 75% aqueous ethanol solution to obtain a solution having a concentration of 2.5% by weight.
  • EVOH ethylene-vinyl alcohol copolymer
  • the drawn yarn was immersed in the solution kept at 50 ° C. for 100 seconds, kept at 50 ° C. under ethanol saturated steam for 80 seconds, and then the solvent was dried for another 80 seconds.
  • the obtained EVOH hydrophilized porous hollow fiber membrane had an inner diameter of 287 ⁇ m and a film thickness of 52 ⁇ m.
  • the hollow fiber into which an epoxy group was introduced was immersed in a 28% aqueous ammonia solution and reacted at room temperature overnight. After completion of the reaction, it was washed with water to obtain a hollow fiber having a primary amino group introduced. It was found that the amount of amino group introduced was titrated with HCl to introduce about 0.03 ⁇ mol / cm 2 .
  • heparin and 50 mg of sodium cyanoborohydride were put in a test tube, dissolved in 50 mL of PBS, and the hollow fiber into which an amino group was introduced was immersed and reacted at 40 ° C. for 3 days. After completion of the reaction, the reaction mixture was washed with saturated brine and water. In order to acetylate the remaining amino groups, the hollow fiber is placed in 36 mL of an AcONa aqueous solution (0.2 mol / L) containing 50% of methanol and cooled with ice. While cooling with ice, 18 mL of acetic anhydride was added dropwise, and the mixture was allowed to react with ultrasound for 30 minutes.
  • reaction was carried out in a water bath (10 to 25 ° C.) for 30 minutes. After completion of the reaction, washing with water was performed and the same acetylation treatment was performed again. After completion of the reaction, washing with saturated saline, water and PBS was performed to obtain a heparin-immobilized hollow fiber. When the amount immobilized was measured by the amount of methylene blue adsorbed, it was immobilized at 17 ⁇ g / cm 2 (in terms of internal surface area).
  • Production Example 2 Heparin Immobilization of Beads Using cellulose beads having an average particle diameter of 400 ⁇ m, heparin was immobilized on beads instead of hollow fibers in the same manner as in Production Example 1. When the amount immobilized was measured by the amount of methylene blue adsorbed, it was 10 mg / mL immobilized. When the above-mentioned heparin-immobilized beads were immersed in the plasma of an HCV patient, 90% of the HCV was removed.
  • Module 1 Dialysis equipment A polyethersulfone hollow fiber for dialysis equipment is inserted into an acrylic resin housing pipe with an inner diameter of 200 ⁇ m, a film thickness of 40 ⁇ m, and a creatinine clearance capacity of 200 mL / min, and both ends are housing with an epoxy resin adhesive Fixed to the pipe. Further, blood inflow / outflow connectors were attached to both ends to obtain a hollow fiber module having an effective length of 15 cm and an effective filtration area of 285 cm 2 .
  • Module 2 For filtration type hollow fiber
  • the heparin-fixed hollow fiber produced in Production Example 1 was inserted into an acrylic resin housing pipe, and both ends were fixed to the housing pipe with an epoxy resin adhesive. Furthermore, blood inflow / outflow connectors were attached to both ends to produce a hollow fiber module having an effective length of 15 cm and an effective filtration area of 285 cm 2 .
  • the heparin-immobilized hollow fiber produced in Production Example 1 was wound around an acrylic resin pipe having a hole in the side surface for external circulation type hollow fiber, and the outside was sealed with an acrylic resin housing.
  • a blood inflow connector was attached to one side of the pipe, and the other side was filled with an epoxy resin adhesive so that blood did not leak.
  • a hollow hole module having an outer surface area of 285 cm 2 was prepared by making a hole in one side of the housing and attaching a blood outflow connector.
  • Example 1 Blood was collected from a healthy volunteer of filtration type, mixed with a blood preservation solution (CPD solution, citrate phosphate glucose solution) to prepare anticoagulated blood, and HCV patient plasma was added thereto to add virus. Blood for removal ability evaluation was used. Modules 1 and 2 were connected in series to the dialysis circuit. 150 mL of blood containing HCV was placed in a reservoir and heated to 37 ° C., and blood was circulated at a blood flow rate of 5.7 mL / min. At that time, plasma separation was performed by adjusting the plasma filtration flow rate in module 2 to 1.7 mL / min. After 240 minutes, the amount of virus in the reservoir was measured and 90% was removed.
  • CPD solution citrate phosphate glucose solution
  • Example 2 Blood was collected from a healthy volunteer with external circulation, mixed with a blood preservation solution (CPD solution, citrate phosphate glucose solution) to prepare anticoagulated blood, and HCV patient plasma was added thereto. Blood for virus removal ability evaluation was used. Modules 1 and 3 were connected in series to the dialysis circuit. 150 mL of blood containing HCV was placed in a reservoir and heated to 37 ° C., and blood was circulated at a blood flow rate of 5.7 mL / min. After 240 minutes, the amount of virus in the reservoir was measured and found to be 85% removed. During the test, there was no increase in TMP or the like due to clogging, nor was there any significant hemolysis. From this, it was clarified that the virus can be simultaneously removed while performing dialysis by connecting the hollow fiber membrane module on which the ligand is immobilized and the dialysis device in series.
  • CPD solution citrate phosphate glucose solution
  • Example 3 Blood was collected from a healthy volunteer with external circulation, mixed with a blood preservation solution (CPD solution, citrate phosphate glucose solution) to prepare anticoagulated blood, and HCV patient plasma was added thereto. Blood for virus removal ability evaluation was used. Modules 1 and 4 were connected in series to the dialysis circuit. 150 mL of blood containing HCV was placed in a reservoir and heated to 37 ° C., and blood was circulated at a blood flow rate of 5.7 mL / min. After 240 minutes, the amount of virus in the reservoir was measured and found to be 85% removed. During the test, there was no increase in TMP or the like due to clogging, nor was there any significant hemolysis. From this, it was clarified that the virus can be simultaneously removed while performing dialysis by connecting the hollow fiber membrane module on which the ligand is immobilized and the dialysis device in series.
  • CPD solution citrate phosphate glucose solution
  • Example 4 Blood was collected from a healthy volunteer with external circulation, mixed with a blood preservation solution (CPD solution, citrate phosphate glucose solution) to prepare anticoagulated blood, and HCV patient plasma was added thereto. Blood for virus removal ability evaluation was used. Modules 1 and 5 were connected in series to the dialysis circuit. 150 mL of blood containing HCV was placed in a reservoir and heated to 37 ° C., and blood was circulated at a blood flow rate of 5.7 mL / min. After 240 minutes, the amount of virus in the reservoir was measured and 90% was removed. During the test, there was no increase in TMP or the like due to clogging, nor was there any significant hemolysis. From this, it was clarified that the virus can be simultaneously removed while performing dialysis by connecting the bead module on which the ligand is immobilized and a dialysis device in series.
  • CPD solution citrate phosphate glucose solution
  • the polymer substrate of the present invention can be used for a virus removal instrument having a dialysis function.

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Abstract

La présente invention concerne un dialyseur capable d'éliminer les virus, ledit dialyseur étant composé d'au moins une machine de dialyse et une machine d'élimination de virus utilisant un matériau à base de polymère pour une utilisation consistant à éliminer les virus, ledit dialyseur étant caractérisé en ce que le matériau à base de polymère pour l'utilisation consistant à éliminer les virus comprend un support polymère (A) sur lequel un sucre est immobilisé. La présente invention concerne en outre un dialyseur capable d'éliminer les virus tel que mentionné ci-dessus, le matériau à base de polymère pour l'utilisation consistant à éliminer les virus étant produit par liaison d'un support polymère (A) dont une surface est traitée avec un matériau polymère ayant un groupe hydroxy à un composé (B) ayant un groupe capable de réaction avec un groupe hydroxy pour former une liaison covalente, un sucre étant immobilisé sur le matériau à base de polymère par un composé (C) ayant un groupe amino.
PCT/JP2013/073165 2012-08-31 2013-08-29 Dialyseur capable d'éliminer les virus WO2014034787A1 (fr)

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