Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
  • A61M1/3496—Plasmapheresis; Leucopheresis; Lymphopheresis
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
• • 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
  • B01D67/0088—Physical treatment with compounds, e.g. swelling, coating or impregnation
• • 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
  • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
  • B01D71/06—Organic material
  • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
  • B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
  • B01D71/4011—Polymethylmethacrylate
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3206—Organic carriers, supports or substrates
  • B01J20/3208—Polymeric carriers, supports or substrates
  • B01J20/321—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions involving only carbon to carbon unsaturated bonds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
  • B01J20/3206—Organic carriers, supports or substrates
  • B01J20/3208—Polymeric carriers, supports or substrates
  • B01J20/3212—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3244—Non-macromolecular compounds
  • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
  • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
  • B01J20/30—Processes for preparing, regenerating, or reactivating
  • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
  • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
  • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
  • B01J20/3268—Macromolecular compounds
  • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
  • A61M1/3621—Extra-corporeal blood circuits
  • A61M1/3627—Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
  • A61M1/3633—Blood component filters, e.g. leukocyte filters
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D2323/00—Details relating to membrane preparation
  • B01D2323/38—Graft polymerization
  • B01D2323/385—Graft polymerization involving radiation

Definitions

• the present invention relates to a method for selectively and simultaneously removing viruses and leukocytes in blood and to a material and an apparatus for the selective removal method.
• Patent Document 4 describes a method for purifying blood of a patient with an immunologic disease by simultaneously removing leukocytes and malignant substances such as immunoglobulin from the blood using a material for removing leukocyte.
• the specification describes neither simultaneous removal of leukocytes and viruses nor recovery of platelets to be performed simultaneously with the removal of leukocytes and viruses.
• Patent Document 5 describes an apparatus and a method for processing blood, comprising removing a target substance such as a virus from the blood without using an anticoagulant by treating blood with a carrier having a polyamine and an anticoagulant on the surface.
• a target substance such as a virus
• Patent Document 5 describes an apparatus and a method for processing blood, comprising removing a target substance such as a virus from the blood without using an anticoagulant by treating blood with a carrier having a polyamine and an anticoagulant on the surface.
• a carrier having a polyamine and an anticoagulant on the surface.
• Patent Document 6 describes a material having a cationic compound on the surface.
• Patent Document 7 describes a material for removing HIV and its related substances, the material having the surface of a weak acidic or weak basic solid substance. This removing material is characterized by having —COOH, —SO 3 H, or the like on the surface and a surface pH of 2.5-6.9 or 7.4-10.5. The specification describes that a virus cannot be removed when —COOH, —SO 3 H, or the like on the surface forms a salt.
• An object of the present invention is to solve the above problems in the prior arts.
• an object of the present invention is to provide a method that can simultaneously remove viruses and leukocytes from virus-containing blood and can achieve a high platelet recovery rate, and to provide a material and an apparatus for the method.
• the present inventors have found that viruses and leukocytes can be simultaneously removed from blood and platelets can be recovered at a high recovery rate by bringing virus-containing blood into contact with a water-insoluble carrier of which the surface can remove viruses and leukocytes in blood. This finding has led to the present invention. Further, the present inventors have found that leukocytes and viruses can be simultaneously removed effectively by using a material that can increase the concentration of an activated complement C3a by five times or more when blood is brought into contact with the material. This has led to the completion of the present invention.
• the present invention relates to a method for selectively removing viruses and leukocytes simultaneously from blood, comprising a step of bringing virus-containing blood into contact with a material for selectively removing viruses and leukocytes which comprises a water-insoluble carrier having a surface for adsorbing or removing viruses and leukocytes in blood.
• the present invention also relates to a platelet-permeable material for selectively and simultaneously removing viruses and leukocytes from blood, comprising a water-insoluble carrier having a surface for adsorbing or removing viruses and leukocytes in blood.
• the present invention further provides an apparatus for selectively removing viruses and leukocytes, comprising a container having a blood inlet section and a blood outlet section in which the material for selectively removing viruses and leukocytes is placed, and means for preventing the material from escaping from the container.
• the method, the removing material, and the apparatus are particularly useful when the blood contains hepatitis C virus.
• the platelet-permeable material for selectively removing viruses and leukocytes has a terminal hydrophilic group or a combination of a terminal hydrophilic group and a polyethylene glycol group and, in addition, a further terminal hydrophobic group on the surface of the carrier.
• a virus includes a free virus in blood, a protein-bound virus, avirus in infected leukocytes, and the like.
• substances to be removed in the present invention include viruses, protein-bound viruses, and the like in blood. Any viruses such as hepatitis A virus, hepatitis B virus, hepatitis C virus, and HIV can be removed. Of these, the hepatitis C virus can be removed at a particularly high efficiency. It may be assumed, although not definitively proven, that the hepatitis C virus can be removed at the same high efficiency as leukocytes, due to surface properties and the size of the virus.
• the hepatitis C virus examples include hepatitis C virus in blood, hepatitis C virus adsorbed in immunoglobulin or the like, hepatitis C virus adsorbed in plasma protein, and leukocytes such as lymphocytes activated by hepatitis C virus, macrophage in an inflamed part, and granulocytes.
• the viruses that can be previously removed using the method of the present invention are hepatitis C virus, hepatitis C virus adsorbed on a plasma protein, leukocytes infected by hepatitis C virus, and autoreactive T cells activated by hepatitis C virus.
• leukocytes it is more advantageous to remove lymphocytes, since the lymphocyte is infected with the hepatitis C virus.
• blood includes blood components such as plasma and serum.
• the anticoagulant is not specifically limited inasmuch as the anticoagulant is a compound having anticoagulant activity.
• the anticoagulant heparin, Futhan, FOY, Argatroban, citric acid and the like can be given. Of these, heparin and Futhan are particularly preferably used.
• removal of viruses or leukocytes means to be removed from blood by adsorbing and/or filtering the viruses or leukocytes. Any methods such as a standing method, shaking method, adsorption method using diffusion, and filtration method may be employed for bringing blood into contact with a material for removing viruses and leukocytes. For adsorption and filtration, a method of causing blood to flow by a head drop, using a pump, or the like is advantageously used.
• the material for removing viruses and leukocytes of the present invention preferably has at least a terminal hydrophilic group on the surface.
• a uncharged neutral functional group is preferably used as the terminal hydrophilic group on the surface of the carrier of the material for removing viruses and leukocytes.
• a preferable functional group include a hydroxyl group., hydroxyl group-containing alkyl groups such as a hydroxymethyl group, hydroxyethyl group, hydroxypropyl group, hydroxyisopropyl group, hydroxybutyl group, and hydroxyisobutyl group, and methoxypolyethylene glycol groups such as a methoxydiethylene glycol group and methoxytriethylene glycol group.
• a hydroxyl group, hydroxypropyl group, hydroxyisopropyl group, and hydroxyisobutyl group are particularly preferably used.
• a methoxydiethylene glycol group or methoxytriethylene glycol group is preferably used.
• a hydroxyl group, hydroxypropyl group, hydroxyisopropyl group, or hydroxyisobutyl group in combination with a methoxydiethylene glycol group or methoxytriethylene glycol group.
• a terminal means a terminal of a main chain or a terminal of a side chain.
• the terminal group may be bonded directly to the main chain or via an ester bond, amide bond, urethane bond, or the like. In the latter case, the terminal refers to a terminal part which does not include the bond.
• alkyl groups having 1 to less than 30 carbon atoms such as a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, heptyl group, and octynyl group, aromatic groups such as a phenyl group, aliphatic groups such as a cyclopentyl group and cyclohexyl group, and the like can be given.
• alkyl groups having 10 to less than 30 carbon atoms i.e. alkyl group such as a methyl group, and an ethyl group are more preferable.
• Alkyl groups having 10 to less than 20 carbon atoms, a methyl group, and an ethyl group are most preferable.
• the hydrophilic group is effectively used for adsorbing/removing hydrophilic protein-adsorbed viruses and leukocytes and for improving recovery capability for platelets.
• the hydrophobic group is effectively used for improving adsorption of viruses or hydrophobic protein-adsorbed viruses.
• the material for removing viruses and leukocytes of the present invention to remove viruses and leukocytes and maintain permeability of platelets, it is important to ensure a well-balanced proportion of the terminal hydrophilic groups and the terminal hydrophobic groups. Excessive hydrophobicity is disadvantageous for recovery of platelets.
• the percentage of the terminal hydrophilic groups is preferably 2% or more, and less than 100%.
• hydrophobicity is high. In this case, leukocytes and viruses can be adsorbed, whereas permeability of platelets unpreferably decreases extremely.
• the percentage of the hydrophilic groups is 100%, adsorption of viruses unpreferably decreases. From the above standpoint, the percentage is more preferably 3% or more, and less than 90%, and most preferably 5% or more, and less than 80%.
• the percentage of the terminal hydrophobic groups is also important. When the percentage is 0.1% or more, and less than 70%, the material is advantageously used. When the percentage of the terminal hydrophobic groups is 70% or more, the platelet recovery rate is unpreferably reduced. If the percentage is less than 0.1%, adsorption of a virus-adsorbing protein unpreferably decreases due to the low hydrophobicity. For these reasons, the percentage is more preferably 1% or more, and less than 60%, and most preferably 1% or more, and less than 55%.
• the percentages of the terminal hydrophilic groups and the terminal hydrophobic groups refer to the percentages of the hydrophilic groups and the hydrophobic groups on the surface of the material for removing viruses and leukocytes, specifically, the molar ratios of the funtional groups of the carrier coming in contact with blood.
• the percentages of these terminal groups can be determined by solid state nuclear magnetic resonance spectroscopy, infrared absorption spectroscopy, XPMS, ESCA, or the like known in the art.
• the percentages of the terminal groups in the coating polymer can be indicated in molar ratios.
• the surface refers to the surface of the material with which viruses or the like can come in contact and excludes the inside of the material with which viruses cannot come in contact.
• the surface of the carrier can have a function of capturing viruses and leukocytes in blood and allowing platelets to permeate therethrough insofar as the surface of the carrier is provided with the terminal hydrophilic groups.
• the terminal hydrophilic groups may be provided by coating the surface with a material containing the terminal hydrophilic groups, or by introducing the funtional groups into the surface of the carrier by radiation graft polymerization, covalent bonding, or the like. It is also possible to use a material having the functional groups on the surface as a carrier.
• the material for removing viruses and leukocytes having the terminal hydrophilic groups can have terminal cationic groups on the surface of the carrier.
• the terminal cationic group is particularly advantageously used for improving adsorption of a virus having negative charges on the surface.
• terminal cationic group examples include tertiary amino groups formed by bonding of a dimethylamino group, diethylamino group, dipropylamino group, or the like to the terminal of the main chain or side chain of a polymer, and aromatic groups such as heterocyclic groups. Of these, a dimethylamino group, diethylamino group, and the like are advantageously used. If the terminal cationic group is a primary or secondary amino group, ionicity is strong, unpreferably resulting in a reduction in the platelet recovery rate.
• the percentage of the terminal cationic groups is preferably less than 15%. If the percentage exceeds 15%, the platelet recovery rate is reduced due to the excessive amount of the cationic groups.
• the percentage is more preferably less than 13%, and most preferably less than 11%.
• the material for removing viruses and leukocytes of the present invention is a material that can increase the concentration of an activated complement C3a by five times or more after bringing blood into contact with the material. It has also been found that viruses can be easily adsorbed under the influence of forming a complex with the activated complement C3a, whereas an excessive increase in the concentration of the activated complement C3a relatively reduces the concentration of the viruses, resulting in a decrease in adsorption of the viruses. When the increase in the concentration of the activated complement C3a is less than five times after blood has been brought into contact with the material, removing capability of viruses and leukocytes unpreferably decreases extremely.
• the concentration of the activated complement C3a increases by five times or more after bringing blood into contact with the material, effectiveness of the material is ensured.
• the concentration of the activated complement C3a increases by 1,000 times or more after bringing blood into contact with the material, the material cannot be used in practice due to anaphylaxis or the like caused by the complement.
• the concentration of the activated complement C3a increases by 500 times or more, the component composition of blood significantly unpreferably changes.
• the concentration of the activated complement C3a increases by more preferably seven times or more, and most preferably by ten times or more, after bringing blood into contact with the material.
• the material for increasing the concentration of the activated complement C3a by five times or more after bringing blood into contact with the material a material having 5 mol % or more of the above-described terminal hydrophilic groups on the surface is used.
• the terminal hydrophilic group-containing monomer include, as terminal hydrophilic group monomers, hydroxyalkyl methacrylates such as 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 2-hydroxybutyl methacrylate, and 2-hydroxyisobutyl methacrylate, and methoxypolyethylene glycol methacrylates such as methoxydiethylene glycol methacrylate, methoxytriethylene glycol methacrylate, and methoxytetraethylene glycol methacrylate.
• a polymer obtained by copolymerizing or terpolymerizing these monomers is effectively used for activation.
• HBMA 2-hydroxyisobutyl methacrylate
• MDG
• HBMA 2-hydroxyisobutyl methacrylate
• MDG methoxydiethylene glycol methacrylate
• MMA methyl methacrylate
• a material with inherent characteristics that can increase the concentration of the activated complement C3a by five times or more after bringing blood into contact with the material is also effectively used.
• Such a material has the hydrophilic groups on the surface.
• the material advantageously used include natural polymers such as cellulose and/or its derivatives, and polymeric materials such as polyesters including polyethylene terephthalate and polybutylene terephthalate, an ethylene-vinyl alcohol copolymer and polyurethane.
• polyesters such as polyethylene terephthalate and polybutylene terephthalate, an ethylene-vinyl alcohol copolymer, cellulose, and the like can be given, most preferably, polyesters such as polyethylene terephthalate and polybuthylene terephthalate are advantageously used.
• particles, beads, a porous material, a flat membrane, a nonwoven fabric, a woven fabric, or the like can be given, for example.
• a porous material and a nonwoven fabric are preferably used, since these carriers can remove viruses and leukocytes simultaneously and have a large surface area.
• a nonwoven fabric is most preferable.
• the constituent of the carrier is not specifically limited insofar as the carrier can be subjected to surface treatment.
• the constituent include natural polymers such as cellulose and/or its derivatives, and polymeric materials such as polyesters including polyethylene terephthalate and polybutylene terephthalate, polyolefins including polyethylene and polypropylene, polyvinylidene fluoride, polyamide, polyimide, polyurethane, polysulfone, and polyacrylonitrile.
• the nonwoven fabric can be employed as is, when the nonwoven fabric has affinity with viruses and leukocytes without surface modification.
• the nonwoven fabric is preferably subjected to surface modification such as coating to provide affinity.
• a nonwoven fabric of which the surface is modified by a treatment such as coating is preferably used.
• the filament may be either a monofilament or a multifilament, or either a porous filament or an irregular filament.
• the average fiber diameter of the nonwoven fabric is preferably 2.0 ⁇ m or more, and less than 50 ⁇ m. If the fiber diameter is too large, it is difficult to secure the surface area of the base material. This unpreferably results in a reduction in the area for adsorbing viruses and a decrease in leukocyte removing capability.
• the average fiber diameter is more preferably 2.0 ⁇ m or more, and less than 30 ⁇ m, and most preferably 2.3 ⁇ m or more, and less than 20 ⁇ m.
• the bulk density of the nonwoven fabric be 0.10 g/cm 3 or more, and less than 0.45 g/cm 3 . If the bulk density is less than 0.10 g/cm 3 , the removing capability of leukocytes decreases. If the bulk density is 0.45 g/cm 3 or more, permeability of platelets decreases extremely. For these reasons, the bulk density is preferably 0.15 g/cm 3 or more, and less than 0.45 g/cm 3 , and most preferably 0.15 g/cm 3 or more, and less than 0.40 g/cm 3 .
• the specific surface area of the nonwoven fabric be 0.010 m 2 /g or more, and less than 4.0 m 2 /g. If the specific surface area is less than 0.01 m 2 /g, the removal capability of viruses and leukocytes decreases. If the specific surface area is 4.0 m 2 /g or more, permeability of platelets decreases extremely. For these reasons, the specific surface area is preferably 0.02 m 2 /g or more, and less than 3.0 m 2 /g, and most preferably 0.04 m 2 /g or more, and less than 2.5 m 2 /g.
• a polymer compound having a terminal hydrophilic group on the side chain and a polymer compound having a terminal hydrophilic group and a terminal hydrophobic group on the side chain at the same time can be given.
• Examples of the monomer forming those polymer compounds include, as terminal hydrophilic group monomers, hydroxyalkyl methacrylates such as 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 2-hydroxybutyl methacrylate, and 2-hydroxyisobutyl methacrylate, and methoxypolyethylene glycol methacrylates such as methoxydiethylene glycol methacrylate, methoxytriethylene glycol methacrylate, and methoxytetraethylene glycol methacrylate.
• hydroxyalkyl methacrylates such as 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, 2-hydroxybutyl methacrylate, and 2-hydroxyisobutyl methacrylate
• methoxypolyethylene glycol methacrylates such as methoxydiethylene glycol methacrylate, methoxytriethylene glycol methacrylate, and
• alkyl methacrylates such as methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, and octadecyl methacrylate
• aromatic methacrylates such as benzyl methacrylate and phenyl methacrylate
• the surface coating material used in the present invention can be effectively obtained by copolymerizing two kinds of monomers or terpolymerizing three kinds of monomers according to the percentages of the hydrophilic groups and the hydrophobic groups.
• copolymer using the monomers include a copolymer of methoxydiethylene glycol methacrylate, 2-hydroxyisobutyl methacrylate, and methyl methacrylate.
• Examples of the terminal cationic group monomer when the terminal cationic group is introduced include dialkylaminoalkyl methacrylates such as dimethylaminoethyl methacrylate and diethylaminoethyl methacrylate.
• These exemplified polymer compounds can be effectively used directly as a base material or used by coating on the surface of a base material.
• these monomers may be effectively used as is or may be effectively used after polymerizing or copolymerizing monomers such as glycidyl methacrylate and then appropriately introducing a necessary terminal group into the polymer.
• Various conventional methods can be used as the method for providing the surface of the carrier with a hydroxyl group, a polyethylene glycol group, a hydrophobic group, and a neutral group.
• To provide the surface of the carrier with such groups means that the groups must be caused to be present on the surface so as not to be eluted into water or blood.
• Examples of the method include graft polymerization, coating, and a method comprising introducing a functional group such as an epoxy group, amino group, formyl group, carboxyl group, hydroxyl group, acid halide group, or cyanogen halide group into the surface of the carrier and bonding the functional group to the compound which should possess the target functional group directly or via a coupling agent or a spacer.
• the material for removing viruses and leukocytes of the present invention can be more suitably used in the blood processing apparatus of the present invention.
• the apparatus for removing viruses and leukocytes of the present invention is an apparatus for adsorbing and/or removing a virus, a protein-bound virus, and leukocytes from blood, comprising a container having a blood inlet section and a blood outlet section in which the material for selectively removing viruses and leukocytes is included, and a means for preventing the material for removing viruses and leukocytes from escaping from the container.
• any means through which all blood components can pass but through which the removing material cannot pass can be used.
• the means can be a mesh, filter, or the like, having a mesh size smaller than the diameter of the removing material, installed in at least the outlet port of the container.
• the means which the nonwoven fabric may be bonded to the upper end or lower end of the container using an adhesive, or inserted in a clearance between the containers can be adopted, in addition to providing the above-described mesh.
• a cylindrical depth filter is used, one end of the cylinder is blocked and the other end on the outlet port side is connected to a nozzle or the like.
• an adhesive of which bonding strength is not weakened by swelling or the like when the adhesive comes in contact with a liquid such as blood is preferable.
• a urethane-based adhesive and an epoxy-based adhesive are advantageously used.
• the adhesive used is not limited to these.
• the apparatus of the present invention can be particularly advantageously used if connected with a blood collection means, an anticoagulant mixing means, a retransfusion means, and the like via a tube.
• the housing of the apparatus of the present invention is preferably formed from a synthetic resin such as polypropylene, polycarbonate, polyethylene, polystyrene, or polymethacrylic acid, glass, or a metal such as stainless steel.
• a synthetic resin such as polypropylene, polycarbonate, polyethylene, polystyrene, or polymethacrylic acid, glass, or a metal such as stainless steel.
• a random copolymer of 2-hydroxyisobutyl methacrylate (HBMA), methoxydiethylene glycol methacrylate (MDG), and methyl methacrylate (MMA) was synthesized using a conventional radical polymerization initiator.
• the obtained polymer solution was added dropwise to 101 of water while stirring.
• the copolymer was precipitated and the water-insoluble components were collected.
• the composition ratio of the obtained copolymer was the same as the mixing ratio of the monomers. Accordingly, the percentages of the terminal hydrophilic groups and the terminal hydrophobic groups in the copolymer were respectively 50% and 50%.
• a copolymer of 2-hydroxyisopropyl methacrylate (HPMA) and dimethylaminoethyl methacrylate (DM) was produced in the same manner as in Experimental Example 1.
• the molar ratio HPMA:DM of the copolymer was of 97:3.
• the percentages of the terminal hydrophilic groups and the terminal cationic groups in the copolymer were respectively 97% and 3%.
• a copolymer of 2-hydroxyethyl methacrylate (HEMA), dimethylaminoethyl methacrylate (DM), and methyl methacrylate (MMA) was produced in the same manner as in Experimental Example 1.
• the molar ratio HEMA:MMA:DM of the copolymer was 62:30:8.
• the percentages of the terminal hydrophilic groups, the terminal hydrophobic groups, and the terminal cationic groups in the copolymer were respectively 62%, 30%, and 8%.
• 1 g of the copolymer obtained in Example 1 was dissolved in 99 g of 70% aqueous solution of ethanol to obtain a 1% coating solution.
• 1 g of a nonwoven fabric (the weight of the substrate per unit area (Metsuke): 90 g/m 2 , thickness: 0.40 mm, bulk density: 0.24 g/cm 3 , specific surface area: 0.966 m 2 /g) comprising a polyethylene terephthalate fiber with an average fiber diameter of 2.9 ⁇ m was immersed in 10 ml of the 1% coating solution, followed by drying the mixture at 25° C. for 12 hours.
• 0.01 g of the obtained nonwoven fabric was cut into strips and collected in a vial. 1 ml of blood of a patient containing hepatitis C virus was added to the vial. The vial was shaken at 37° C. for two hours.
• HCVRNA The amount of hepatitis C virus was determined using Amplicor HCV Monitor manufactured by Nippon Roche K.K.
• the number of leukocytes and the number of platelets in the treated blood were determined using an automatic blood cell counter (SF-3000, manufactured by Sysmex Corporation).
• the concentrations of the activated complement C3a before and after treatment were measured by nephelometric analysis to determine the rate of increase in the concentration for the value after treatment as compared with the value before treatment.
• Example 2 As a control experiment, the same operation as in Example 1 was carried out without using the removing material of the present invention.
• Virus adsorption rate(%) [( Vd ⁇ Vc )/ Vd] ⁇ 100
• Example 1 The same operation as in Example 1 was carried out except for using a nonwoven fabric (the weight per unit area (Metsuke): 60 g/m 2 , thickness: 0.35 mm, bulk density: 0.12 g/cm 3 , specific surface area: 1.768 m 2 /g) comprising a polypropylene fiber with an average fiber diameter of 2.5 ⁇ m.
• a nonwoven fabric the weight per unit area (Metsuke): 60 g/m 2 , thickness: 0.35 mm, bulk density: 0.12 g/cm 3 , specific surface area: 1.768 m 2 /g
• Example 2 The same operation as in Example 1 was carried out except for using a nonwoven fabric (the weight per unit area: 90 g/m 2 , thickness: 0.40 mm) comprising a polyethylene terephthalate fiber with an average fiber diameter of 2.9 ⁇ m as is. The results are shown in Table 2.
• Example 2 The same operation as in Example 1 was carried out except for using a nonwoven fabric (the weight per unit area: 60 g/m 2 , thickness: 0.35 mm) comprising a polypropylene fiber with an average fiber diameter of 2.5 ⁇ m as is.
• a nonwoven fabric the weight per unit area: 60 g/m 2 , thickness: 0.35 mm
• the results are shown in Table 2.
• TABLE 2 Virus adsorption Leukocyte Platelet C3a rate removal rate recovery rate concentration Comparative 58% 84% 21% 3.5 times
• Example 1 Comparative 63% 80% 18% 1.8 times
• Example 2 TABLE 2 Virus adsorption Leukocyte Platelet C3a rate removal rate recovery rate concentration Comparative 58% 84% 21% 3.5 times
• Example 1 Comparative 63% 80% 18% 1.8 times
• Example 1 The removing material of Example 1 was cut into disks, each with a diameter of 6.8 mm. Five sheets of the disks were respectively placed in a column. The hepatitis C virus adsorption rate, the leukocyte removal rate, and the platelet recovery rate were evaluated.
• Example 3 The same operation as in Example 3 was carried out, except for using the removing material of Example 2. The results are shown in Table 3. TABLE 3 Virus Leukocyte Platelet C3a adsorption rate removal rate recovery rate concentration Example 3 91% 95% 70% 12.5 times Example 4 94% 97% 75% 23.5 times
• Example 4 The same operation as in Example 3 was carried out, except for using the material of Comparative Example 1. The results are shown in Table 4.
• Example 4 The same operation as in Example 3 was carried out, except for using the material of Comparative Example 2. The results are shown in Table 4. TABLE 4 Virus adsorption Leukocyte Platelet C3a rate removal rate recovery rate concentration Comparative 60% 98% 8% 4.8 times Example 3 Comparative 75% 97% 6% 2.3 times Example 4
• Example 2 The same operation as in Example 1 was carried out using the same nonwoven fabric as in Example 1 to obtain a removing material, except for using the polymer produced in Experimental Example 2 for coating. Blood was treated in the same manner as in Example 1 and the hepatitis C virus adsorption rate, the leukocyte removal rate, and the platelet recovery rate were evaluated.
• Example 2 The same operation as in Example 1 was carried out using the same nonwoven fabric as in Example 1 to obtain a removing material, except for using the polymer produced in Experimental Example 3 for coating. Blood was treated in the same operation as in Example 1 and the hepatitis C virus adsorption rate, the leukocyte removal rate, and the platelet recovery rate were evaluated.
• Example 2 The same nonwoven fabric as in Example 1 was cut into a sheet (width: 150 mm, length: 300 mm) and the sheet was wound around a cylindrical mesh with a diameter of 3.4 mm made from polyethylene.
• a nonwoven fabric (the weight per unit area: 30 g/m 2 ) comprising a polyester fiber with an average fiber diameter of 12 ⁇ m was provided as the first prefilter.
• the first prefilter with a width of 150 mm was wound around the above nonwoven fabric.
• a nonwoven fabric (the weight per unit area: 50 g/m 2 ) comprising a polyester fiber with an average fiber diameter of 33 ⁇ m was provided as the second prefilter.
• the second prefilter with a width of 150 mm was wound around the first prefilter.
• a mesh with a width of 150 mm made from polyethylene was wound around the second prefilter.
• the cylinder thus formed had a diameter of 39 mm. Both ends of the cylinder were blocked by urethane.
• the cylinder was placed in a cylindrical polycarbonate container with an internal diameter of 41 mm of which the top and the bottom were respectively provided with a blood inlet port and a blood outlet port, so that the outer circumference of the cylinder was connected to the blood inlet port of the container and the inner circumference of the cylinder was connected to the blood outlet port of the container. An apparatus for removing leukocytes was thus produced.
• 50 ml of plasma containing hepatitis C virus was added to 2,000 ml of fresh bovine blood (number of leukocytes: 4,500-6,400 ⁇ L, number of platelets: 150,000-320,000 ⁇ L) to which heparin was added as a anticoagulant (heparin concentration: 1,000 IU/L) (amount of virus: 2,500,000/l).
• the mixture was fed into the apparatus using a blood pump at a constant flow rate of 50 ml/min at room temperature to remove leukocytes.
• the present invention can provide a material for removing viruses and leukocytes that can selectively adsorb and/or remove viruses and leukocytes in blood.
• a blood processing apparatus comprising the removing material
• hepatitis C viruses and leukocytes in a liquid to be processed such as blood, plasma, or serum can be selectively removed and platelets can be recovered at a high recovery rate.

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