WO2003033053A1 - Procede permettant d'eliminer de maniere selective des virus et des leucocytes, materiau et appareil a cet effet - Google Patents
Procede permettant d'eliminer de maniere selective des virus et des leucocytes, materiau et appareil a cet effet Download PDFInfo
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- WO2003033053A1 WO2003033053A1 PCT/JP2002/010766 JP0210766W WO03033053A1 WO 2003033053 A1 WO2003033053 A1 WO 2003033053A1 JP 0210766 W JP0210766 W JP 0210766W WO 03033053 A1 WO03033053 A1 WO 03033053A1
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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
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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
-
- 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
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- 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
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- 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
-
- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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 removing viruses and leukocytes in blood simultaneously, and a selective removal material and apparatus therefor.
- the conventional blood treatment system is unnecessary because the plasma component and blood cell component are separated using a plasma separation membrane or centrifuge, and then the plasma component is directly contacted with an immunoadsorbent or low-density lipoprotein adsorbent. It was a system that adsorbs and removes substances (for example, Patent Documents 1 to 3).
- blood cells such as red blood cells, white blood cells, and platelets are separated from plasma components together, so it was difficult to remove unnecessary substances such as viruses and white blood cells at the same time.
- these systems use a charged material that activates platelets, and at the same time as removing unwanted substances and white blood cells, platelets cannot be recovered at a high recovery rate.
- Patent Document 4 describes a method for purifying blood by simultaneously removing leukocytes and immune globulin and other malignant substances from the blood of patients with immune system disease using a leukocyte removing material. Neither removing the virus at the same time nor collecting the platelets at the same time is disclosed.
- Patent Document 5 discloses a blood processing apparatus and method for removing a target substance such as a virus from blood without an anticoagulant by treating the blood with a carrier having a polyamine and an anticoagulant on the surface.
- a carrier having a polyamine and an anticoagulant on the surface due to the large amount of amine on the surface, it was difficult to recover enough platelets, and leukocyte removal was not sufficient.
- Patent Document 6 discloses a material having a cationic compound on its surface, but this publication does not describe any virus removal from blood.
- Patent Document 7 discloses an agent for removing HIV and related substances, which is made of a solid substance whose surface is weakly acidic or weakly basic. The This removal material, the surface - C00H or -.... Having a S0 3 H and the like, a p H 2 5-6 9 or 7 4-1 0 5 a it is characteristic of the surface, the surface It is described that the virus cannot be removed when the existing -C00H or -S0 3 H forms a salt.
- Patent Document 7 when blood is brought into contact with the removal material, the pH of the blood changes, so that the protein component is denatured, which is not a favorable condition for blood. .
- a problem common to these technologies is that there is a risk of blood clotting due to denaturation of blood proteins when the removal material comes into contact with blood.
- An object of the present invention is to solve the above-mentioned problems of the prior art, and in particular, a method capable of simultaneously removing virus and leukocytes from virus-containing blood and achieving a high recovery rate of platelets. It is providing the material and apparatus of this.
- the present inventors contacted a water-insoluble carrier having a surface for removing virus and leukocytes in blood with virus-containing blood, thereby allowing virus and leukocytes from blood.
- a water-insoluble carrier having a surface for removing virus and leukocytes in blood with virus-containing blood, thereby allowing virus and leukocytes from blood.
- platelets The present inventors have found that it can be recovered at a high recovery rate and have reached the present invention.
- the virus can be efficiently removed together with leukocytes when using a material whose activated complement C 3a is 5 times or more the blood concentration before contact.
- the present invention includes a step of contacting a virus-containing blood with a virus and leukocyte selective removing material comprising a water-insoluble carrier having a surface for adsorbing or removing viruses and leukocytes in blood.
- the present invention relates to a method for selectively removing viruses and white blood cells simultaneously from blood.
- the present invention also comprises a water-insoluble carrier having a surface that adsorbs or removes viruses and leukocytes in blood, for selectively removing viruses and white blood cells from blood simultaneously. It also relates to platelet-passing virus and leukocyte selective removal material.
- the virus and leukocyte selective removal material is contained in a container having a blood introduction part and a blood lead-out part of blood, and means for preventing the virus and leukocyte selection removal material from flowing out of the container.
- the present invention also provides a virus and leukocyte selective removal device characterized by comprising:
- the platelet-passing virus and leukocyte selective removing material has a terminal hydrophilic group, or a terminal hydrophilic group and a polyethylene glycol group, and further a terminal hydrophobic group on the surface of the carrier.
- virus includes not only free viruses in blood but also protein-binding viruses, infected viruses in leukocytes, and the like.
- the substances removed in the present invention are viruses in the blood, protein-binding viruses, etc., and can remove anything such as hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV, etc.
- hepatitis C virus can be removed well. The reason is not clear, but the surface characteristics of the virus and the virus It is estimated that it can be removed as efficiently as leukocytes.
- Hepatitis C virus is activated by hepatitis C virus in blood, hepatitis C virus adsorbed on immunoglobulin, etc., hepatitis C virus adsorbed on plasma protein, etc., and hepatitis C virus.
- White blood cells such as lymphocytes, macrophages present at the site of inflammation, granulocytes, and the like.
- the present invention removes hepatitis C virus, hepatitis C virus adsorbed on plasma proteins, etc., leukocytes infected with hepatitis C virus. And autoreactive T cells activated by hepatitis C virus.
- blood includes blood components such as plasma and serum.
- anticoagulants When processing blood, anticoagulants can be added to the blood for anticoagulation purposes.
- anticoagulants are not particularly limited as long as they are compounds having anticoagulant activity, but preferred examples include heparin, fusan, FO ⁇ , argatroban, quenate, etc., preferably heparin or fuzan. Used for.
- removing viruses and leukocytes means removing them from blood by adsorption and filtration, and the method of contact between the virus and leukocyte removing material and blood for removal is static. Any of a placement method, a shaking method, an adsorption method by diffusion, and a filtration method may be used. Furthermore, in the adsorption and filtration methods, a method of flowing blood using a drop or a pump is useful.
- the virus and leukocyte removal W of the present invention preferably have at least a terminal hydrophilic group on the surface.
- a neutral functional group having no charge is usefully used.
- Illustrative examples include hydroxyl group-containing alkyl groups such as hydroxyl group, hydroxymethyl group, hydroxychetyl group, hydroxypropyl group, hydroxyisopropyl group, hydroxybutyl group, hydroxyisobutyl group, methoxydiethylene glycol, methoxytriethylene glycol group, etc.
- a methoxy polyethylene glycol group or the like is preferably used.
- hydroxyl group, hydroxypropyl group, hydroxyisopropyl And a hydroxyisobutyl group are preferably used.
- methoxydiethylene dallicol and methoxy triethylene glycol group are used.
- hydroxyl group, hydroxypropyl group, hydroxyisopropyl group, hydroxyisopropyl group and methoxydiethylene glycol, methoxytriethylene glycol group It is most preferable to use together.
- the term “end” refers to the end of the main chain or the end of the side chain.
- the terminal group may be directly bonded to the main chain, or may be bonded via an ester bond, an amide bond, a urethane bond, or the like. In the latter case, it refers to the terminal part that does not contain these bonds.
- Preferred terminal hydrophobic groups on the carrier surface of the virus and leukocyte-removing material of the present invention are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, t_butyl group, pentyl group, hexyl group, heptyl.
- an alkyl group having 1 to 30 carbon atoms such as octynyl group, an aromatic ring such as phenyl group, and an aliphatic ring such as cyclopentyl group and cyclohexyl group.
- an alkyl group having 10 to 30 carbon atoms an alkyl group such as a methyl group or an ethyl group, most preferably an alkyl group having 10 to 20 carbon atoms, and methyl. And ethyl group.
- the hydrophilic group is effective for removing Z adsorbed by the hydrophilic protein-adsorbing virus and leukocyte, and is also effective for improving the recovery ability of platelets.
- Hydrophobic groups are effective for improving the adsorptivity of viruses and hydrophobic protein-adsorbing viruses. With the virus and leukocyte-removing material of the present invention, viruses and leukocytes are removed, and platelet permeability is maintained. It is also important to balance the terminal hydrophilic group and the terminal hydrophobic group. Excessive hydrophobicity is detrimental to platelet recovery.
- the abundance ratio of the terminal hydrophilic group is preferably 2% or more and less than 100%.
- the proportion of the terminal hydrophilic group is less than 2%, the hydrophobicity is high, so that leukocytes and viruses can be adsorbed, but the platelet passage rate is extremely lowered, which is not preferable.
- the abundance ratio of the hydrophilic group is 100%, the adsorptivity of the virus decreases, which is not preferable.
- Less than A more preferable range from the above viewpoint is 3% or more and less than 90%, and most preferably 5% or more and less than 80%.
- the abundance ratio of the terminal hydrophobic group is also important, and it is useful when it is 0.1% or more and less than 70%.
- the terminal hydrophobic group is 70% or more, the recovery rate of platelets is not preferable.
- it is less than 0.1%, the hydrophobicity is low, so that the adsorptivity of the virus-adsorbing protein is lowered, which is not preferable. From the above viewpoints, it is more preferably 1% or more and less than 60%, and most preferably 1% or more and less than 55%.
- the abundance ratio of the terminal hydrophilic group and the terminal hydrophobic group is the ratio of the hydrophilic group and the hydrophobic group present on the surface of the virus and leukocyte-removing material, and each functional group in the surface portion where the carrier and blood can contact The molar ratio.
- the abundance ratio of these end groups can be determined by a known solid nuclear magnetic resonance spectrum, infrared absorption spectrum, XPMS, ESCA, or the like.
- the abundance ratio of the coated polymer can be indicated using a molar ratio.
- the surface in the present invention refers to a surface that can be contacted by viruses and the like, and does not include the inside of a material that cannot contact viruses.
- the term “having a surface that captures viruses and leukocytes in blood and allows platelets to pass” only needs to have terminal hydrophilic groups on the surface of the carrier. This includes not only the case where the functional group is applied to the surface by means of, but also the case where a functional group is introduced to the surface of the carrier by radiation graft or covalent bond, or the case where the support material itself has these functional groups on the surface .
- the virus and leukocyte removing material can also have a terminal positive group on the surface of the carrier.
- the terminal positive group is useful particularly in terms of improving the adsorption of viruses having a negative charge on the surface.
- terminal positive group examples include a tertiary amino group formed by bonding a dimethylamino group, a jetylamino group, a dipropylamino group or the like to the end of a polymer main chain or a side chain, an aromatic ring such as a heterocyclic ring, and the like.
- a dimethylamino group, a jetylamino group, and the like are usefully used.
- the terminal is a primary or secondary amino group, it is not preferable because the ion recovery is strong and the platelet recovery rate decreases.
- the abundance ratio of terminal positive groups is preferably less than 15%. 1 Over 5%, excessive The positive group is not preferable because the platelet recovery rate is lowered. A preferred abundance is less than 13%, most preferably less than 11%.
- the selective removal material for viruses and leukocytes of the present invention is found to be able to remove leukocytes and viruses most efficiently at the same time by using a material that activates the activated complement C 3a concentration by 5 times or more before and after contact with blood. It was. Viruses are easily adsorbed by the effect of complex formation with activated complement C 3 a, etc. On the other hand, the virus concentration is relatively lowered due to the excessive increase of activated complement C 3 a concentration. It was found that the adsorptivity decreased. That is, when activated complement C 3 a is less than 5 times the blood concentration before contact, the ability to remove viruses and leukocytes is extremely reduced, which is not preferable.
- the activated complement C 3 a is 5 times or more of the blood concentration before contact, but if the activated complement C 3 a is 1 000 times or more of the blood concentration before contact, It is not practical because it causes lyanaphylaxis. Furthermore, a change in concentration of 500 times or more is not preferable because the change in blood components is remarkable. More preferably, the activated complement C 3 a concentration before and after contact with blood is 7 times or more, and most preferably 10 times or more.
- terminal hydrophilic group-containing monomers include 2-hydroxyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxybutyl methacrylate.
- Hydroxyalkyl methacrylates such as 2-hydroxyisobutyl methacrylate, methoxydiethylene glycol methacrylate, methoxytriethylene glycol methacrylate, methoxytetraethylene glycol methacrylate, etc. Examples include reethylene glycol methacrylate.
- HBMA 2-hydroxyisobutyl methacrylate
- MDG methoxydiethylene glycol methacrylate
- MMA methyl methacrylate
- H BMAZMDGZMMA 5 ⁇ 40: 5 ⁇ 30: 40 ⁇ 60
- HPMA 2-Hydroxyisopropyl methacrylate
- DM dimethylaminoethyl methacrylate Rate
- HBMA 2-hydroxyisobutyl methacrylate
- MD G methoxydiethylene glycol methacrylate
- MMA methyl methacrylate
- a material having a hydrophilic group on the surface is used, and examples of the material include natural polymers such as cellulose and / or its derivatives, polyesters such as polyethylene terephthalate and polybutylene terephthalate, ethylene vinyl alcohol copolymers, and polyurethanes. Polymeric materials are usefully used. From the viewpoint of activation, polyesters such as polyethylene terephthalate and polybutylene terephthalate, ethylene vinyl alcohol copolymer, cellulose and the like are particularly preferable, and polyethylene terephthalate and polybutylene terephthalate are most preferable. Polyesters such as are usefully used.
- Examples of the carrier for the selective removal material for viruses and leukocytes used in the present invention include granular, bead-like, porous material, flat membrane, non-woven fabric, woven fabric and the like. Of these, porous materials and non-woven fabrics are preferably used, and most preferred are non-woven fabrics because leukocytes can be removed simultaneously with viruses and have a high surface area.
- the material of the carrier is not particularly limited as long as it can be surface-treated.
- Natural polymers such as cellulose and Z or derivatives thereof, polyesters such as polyethylene terephthalate and polybutylene terephthalate, Examples thereof include polymer materials such as polyolefins such as polyethylene and polypropylene, polyvinylidene fluoride, polyamides, polyimides, polyurethanes, polysulfones and polyacrylonitrile.
- these non-woven fabrics have affinity for viruses and leukocytes without surface modification, they can be used as they are. In addition, these functions are performed without surface modification. If this is not possible, it is preferable to use it after surface modification such as coating for the purpose of exhibiting its function.
- those whose surfaces have been modified by a treatment such as coating are preferably used.
- the filament When the carrier is a non-woven fabric, the filament may be monofilament or multifilament, and may be a porous filament or an atypical filament.
- the nonwoven fabric a nonwoven fabric having an average fiber diameter of 2.0 m or more and less than 50 jum is preferable. When the fiber diameter is increased, it is difficult to secure the surface area of the base material, and not only the virus adsorption area is decreased, but also the leukocyte removal performance is decreased, which is not preferable.
- a more preferable average fiber diameter is 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 is 0.1 gcm 3 or more and less than 0.45 cm 3 in order to remove leukocytes and increase platelet permeability.
- the bulk density is less than 0.10 gZ cm 3 , leukocyte removal performance is lowered, which is not preferable.
- a bulk density of 0.45 g / cm 3 or more is not preferable because the permeability of platelets is extremely reduced.
- it is preferably 0.15 gZ cm 3 or more and less than 0.45 g / cm 3 , most preferably 0.15 g / cm 3 or more and less than 0.40 gZ cm 3 .
- the virus adsorption in terms of increasing the removal and permeability of platelets in leukocytes, it is also important that the specific surface area of 0. 0 1 0m 2 Zg or 4. less than Om 2 Z g.
- the specific surface area is less than 0.01 m 2 / g, the virus and leukocyte removal performance is lowered, which is not preferable.
- a specific surface area of 4. Om 2 Zg or more is not preferable because the permeability of the platelet plate is extremely reduced.
- a surface-modifying compound that removes viruses and leukocytes and collects platelets at a high rate examples thereof include a polymer compound having at least a terminal hydrophilic group in the side chain, and a polymer compound having a terminal hydrophilic group and a terminal hydrophobic group in the side chain at the same time.
- 2-hydroxyxetyl methacrylate, 2-hydroxypropyl methacrylate, 2-hydroxyisopropyl methacrylate, and 2-hydroxy are used as terminal hydrophilic monomers.
- Hydroxyalkyl methacrylates such as doxybutyl methacrylate, 2-hydroxyisoptyl methacrylate, methoxydiethylene glycol methacrylate, methoxytriethylene glycol methacrylate, methoxytetraethylene
- methoxypolyethylene glycol methacrylate such as dalcoyl methacrylate.
- alkyl methacrylates such as methyl methacrylate, ethyl methacrylate, propyl methacrylate, butyl methacrylate, and octadecyl methacrylate
- aromatic methacrylates such as benzyl methacrylate, and phenyl methacrylate Etc.
- the above-mentioned polymerizable functional group is effectively used even if it is vinyl, acrylate or the like.
- the surface coating material used in the present invention can be obtained effectively by binary or ternary copolymerization of monomers in accordance with the abundance ratio of hydrophilic groups and hydrophobic groups.
- copolymer using these monomers include a copolymer of methoxydiethylene glycol methacrylate, 2-hydroxyisobutyl methacrylate, and methyl methacrylate.
- terminal positive group monomer examples include dialkylamino alkyl methacrylates such as dimethylaminoethyl methacrylate and jetylaminoethyl methacrylate.
- the virus and leukocyte selective removal material of the present invention can be preferably implemented by the blood processing apparatus of the present invention.
- the virus and leukocyte removal device of the present invention is a device for adsorbing and / or removing viruses, protein-binding viruses, and leukocytes from blood.
- the virus and leukocyte selective removal material is used for blood introduction and blood derivation.
- a virus and leukocyte selective removal device provided with a means for preventing the virus and leukocyte selective removal material from flowing out of the container.
- any means that allows all blood components to pass but does not allow the removal material to pass can be used. This can be done by providing a mesh or filter that is finer than the material diameter of the removal material at least on the outlet side of the container.
- the nonwoven fabric is bonded to the upper end or lower end of the container using an adhesive, or sandwiched between gaps between containers. Is possible. Particularly in the case of a cylindrical depth filter, this can be done by closing one end of the cylinder and adhering the outlet end to a nozzle or the like.
- the adhesive used is preferably one that does not weaken the adhesive force due to swelling or the like even when it comes into contact with a liquid such as blood.
- urethane and epoxy adhesives are useful, but are not limited thereto. It is not done.
- the apparatus of the present invention is particularly usefully used in communication with a blood collecting means, an anticoagulant mixing means, a blood returning means and the like through a tube.
- the housing of the apparatus of the present invention is preferably made of a synthetic resin such as polypropylene, polycarbonate, polyethylene, polystyrene, or polymethacrylic acid, or a metal such as glass or stainless steel.
- Random copolymers of 2-hydroxyisobutyl methacrylate (hereinafter abbreviated as HBMA), methoxydiethylene glycol methacrylate (hereinafter abbreviated as MD G) and methyl methacrylate (hereinafter abbreviated as MMA) It was synthesized using a radical initiator.
- the obtained polymerization solution was dropped into 10 L of water while stirring to precipitate a copolymer, and a water-insoluble matter was recovered.
- the composition ratio in the obtained copolymer was the same as the monomer charge ratio. Therefore, the abundance ratio of terminal hydrophilic groups in this copolymer is 50%, and the abundance ratio of terminal hydrophobic groups is 50%.
- a copolymer of 2-hydroxyisopropyl methacrylate (HPMA) and dimethylaminoethyl methacrylate (DM) was prepared in the same manner as in Experimental Example 1.
- the molar ratio HPMA: DM of the copolymer was 97: 3, the abundance ratio of terminal hydrophilic groups was 97%, and the ratio of terminal positive groups was 3%.
- a copolymer of 2-hydroxyschetyl methacrylate (HEMA), dimethylaminoethyl methacrylate (DM), and methyl methacrylate (MMA) was prepared in the same manner as in Experimental Example 1.
- Molar ratio of copolymer HEMA: MMA: DM is 6 2: 30: 8 and the abundance ratio is 6% terminal hydrophilic group, 30% terminal hydrophobic group, 8% terminal positive group .
- Examples of a blood treatment system for hepatitis C are shown below. However, it is not limited to this.
- the resulting non-woven fabric (0.01 g) was cut into strips, collected in a vial, 1 mL of patient blood containing hepatitis C virus was added, and the mixture was shaken at 37 ° C for 2 hours.
- the blood was sampled into a 100 L-pial after treatment, centrifuged at 500,000 rpm for 1 minute, and the amount of hepatitis C virus in the supernatant was measured as HCVRNA.
- an amplicore 1 H C V monitor manufactured by Nippon Roche was used for measurement of the amount of hepatitis C virus.
- the processed blood was subjected to determination of white blood cell count and platelet count using an automatic blood cell counter (manufactured by Sysmex Corporation, SF-300 type).
- the concentration of activated complement C 3a before and after treatment was measured by the nephrometry method, and the increase rate of the post-treatment value relative to the pre-treatment value was determined.
- Example 2 As a control experiment, the same operation as in Example 1 was performed without the removal material of the present invention.
- Hepatitis C virus adsorption rate (%), leukocyte removal rate (%), and platelet recovery rate (%) were calculated by the following formulas.
- Virus adsorption rate (%) [(Vd_ Vc) / Vd] x 1 00
- Vc Virus concentration in control blood
- Vd Virus concentration in adsorption experiment blood
- Leukocyte removal rate (%) [(Wd-Wc) / Wd] X 1 0 0
- Pd Platelet concentration in adsorption experiment blood The results are shown in Table 1. Table 1 also shows the results of a control experiment with no removal material. Even in the control experiment, there is a slight decrease due to leukocytes and platelets adhering to the container.
- Nonwoven fabric made of polypropylene fiber with an average fiber diameter of 2.5 m (weight per unit 60 g / m 2 , thickness 0.35 mm, bulk density 0.12 g / cm 3 , specific surface area 1.76 8 m 2 , g ) was used in exactly the same manner as in Example 1. The results are shown in Table 1. Table 1
- Virus adsorption rate Leukocyte removal rate Platelet passage rate C 3 a concentration
- Example 1 8 5% 80% 90% 1 1.6 times
- Example 2 8 9% 82% 94% 1 8.5 times
- Control experiment example 0% 1% 98% 2.3 times
- Example 2 The same operation as in Example 1 was performed except that a non-woven fabric (weight per unit: 90 gZm 2 , thickness: 0.40 mm) made of polyethylene terephthalate fibers having an average fiber diameter of 2.9 m was used. The results are shown in Table 2.
- Example 2 The same operation as in Example 1 was performed except that a non-woven fabric made of polypropylene fibers having an average fiber diameter of 2.5 jw m (weight per unit: 60 m 2 , thickness: 0.35 mm) was used as it was. The results are shown in Table 2. Table 2
- Virus adsorption rate Leukocyte removal rate Platelet passage rate C 3 a concentration Comparative example 1 58% 84% 2 1% 3.5 times Comparative example 2 63% 80% 1 8% 1.8 times
- Example 3 The removal material of Example 1 was cut into a circular shape with a diameter of 6.8 mm, and 5 pieces were set in a column, and the hepatitis C virus adsorption rate, leukocyte removal rate, and platelet recovery rate were evaluated.
- Example 2 Except for using the removing material of Example 2, the same operation as in Example 3 was performed.
- Virus adsorption rate Leukocyte removal rate Platelet passage rate C 3 a concentration
- Example 3 9 1% 95% 70% 1 2.5 times
- Example 4 94% 97% 7 5% 23.5 times
- Example 3 The same operation as in Example 3 was performed except that the material of Comparative Example 1 was used.
- Example 3 The same operation as in Example 3 was performed except that the material of Comparative Example 2 was used.
- Example 3 Except that the polymer produced in Experimental Example 3 was used for coating, the removal material was obtained by the same non-woven fabric and operation as in Example 1, and blood was processed by exactly the same operation as in Example 1. The virus adsorption rate, leukocyte removal rate, and platelet recovery rate were evaluated.
- Virus adsorption rate Leukocyte removal rate Platelet passage rate C 3 a concentration
- Example 5 7 9% 8 9% 87% 1 9.5 times
- Example 6 9 1% 95% 86% 22.5 times
- Example 2 The same non-woven fabric as in Example 1 was cut into a width of 150 mm and a length of 300 mm and wound around a polyethylene cylindrical mesh having a diameter of 3.4 mm.
- a non-woven fabric (30 gZm with 2 basis weights) made of polyester fibers having an average fiber diameter of 12 mm was used as a first prefilter and wound with a width of 15 Omm.
- a non-woven fabric 50 g / m 2 basis weight
- polyester fiber having an average fiber diameter of 33 m was used as the second prefilter and was spread with a width of 150 mm.
- a polyethylene mesh was wound 150 mm outside. The diameter of this cylinder was 39 mm.
- Both ends of this cylinder are closed with urethane, a cylindrical polycarbonate container with an inner diameter of 41 mm with a blood inlet and outlet at the ceiling and bottom, respectively, and the outer peripheral surface of the cylinder at the blood inlet of the container.
- urethane a cylindrical polycarbonate container with an inner diameter of 41 mm with a blood inlet and outlet at the ceiling and bottom, respectively, and the outer peripheral surface of the cylinder at the blood inlet of the container.
- Bovine fresh blood supplemented with heparin as an anticoagulant (white blood cell count: 4,500 to 6,400 /; UL, platelet count: 150,000 to 3,200,000 L) (heparin concentration Degree: 1 00 0 0 IU / L)
- heparin concentration Degree 1 00 0 0 IU / L
- blood pump The mixture was flushed at room temperature at a constant flow rate of 5 Om and removed leukocytes.
- a virus and leukocyte remover capable of selectively adsorbing and Z or removing viruses and leukocytes present in blood.
- a blood processing device filled with the removal material hepatitis C virus and leukocytes in the liquid to be treated such as blood, plasma, and serum are selectively removed, and platelets are recovered at a high rate. Is possible.
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- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Inorganic Chemistry (AREA)
- Manufacturing & Machinery (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Water Supply & Treatment (AREA)
- Life Sciences & Earth Sciences (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02801582A EP1444996A4 (en) | 2001-10-16 | 2002-10-16 | PROCESS FOR SELECTIVELY REMOVING VIRUSES AND LEUKOCYTES, MATERIAL AND APPARATUS THEREFOR |
CA002464351A CA2464351A1 (en) | 2001-10-16 | 2002-10-16 | Method for selectively removing virus and leukocytes, removing material and removing apparatus |
US10/492,652 US20050014127A1 (en) | 2001-10-16 | 2002-10-16 | Method for selectively removing virus and leukocytes eliminating material and eliminating apparatus |
NO20042076A NO20042076L (no) | 2001-10-16 | 2004-05-19 | Fremgangsmate for a selektivt fjerne virus og leukocytter, fjerningsmateriale samt fjerningsinnretning |
US11/772,448 US7820371B2 (en) | 2001-10-16 | 2007-07-02 | Method for removing viruses and leukocytes from blood using a surface comprising hydroxyl and polyethylene glycol groups |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001-318512 | 2001-10-16 | ||
JP2001318512 | 2001-10-16 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10492652 A-371-Of-International | 2002-10-16 | ||
US11/772,448 Division US7820371B2 (en) | 2001-10-16 | 2007-07-02 | Method for removing viruses and leukocytes from blood using a surface comprising hydroxyl and polyethylene glycol groups |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003033053A1 true WO2003033053A1 (fr) | 2003-04-24 |
Family
ID=19136202
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2002/010766 WO2003033053A1 (fr) | 2001-10-16 | 2002-10-16 | Procede permettant d'eliminer de maniere selective des virus et des leucocytes, materiau et appareil a cet effet |
Country Status (8)
Country | Link |
---|---|
US (2) | US20050014127A1 (ja) |
EP (1) | EP1444996A4 (ja) |
JP (1) | JP4992120B2 (ja) |
KR (1) | KR20050036848A (ja) |
CN (1) | CN100457200C (ja) |
CA (1) | CA2464351A1 (ja) |
NO (1) | NO20042076L (ja) |
WO (1) | WO2003033053A1 (ja) |
Cited By (2)
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WO2003106518A1 (ja) * | 2002-06-17 | 2003-12-24 | 旭メディカル株式会社 | 生体適合性ポリマーおよびそれを用いた白血球選択除去フィルター材 |
EP1635661B1 (en) * | 2003-06-13 | 2010-08-11 | WADSTRÖM, Torkel | Product for absorption purposes |
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CN101151056B (zh) * | 2005-03-31 | 2012-07-04 | 东丽株式会社 | 吸附材料和体外循环柱 |
EP2050457B1 (en) * | 2006-07-12 | 2012-06-27 | Asahi Kasei Medical Co., Ltd. | Method of removing abnormal prion from blood preparation |
WO2010113632A1 (ja) * | 2009-03-30 | 2010-10-07 | テルモ株式会社 | 表面処理剤およびフィルター用濾材ならびに血液処理フィルター |
EP2485983B1 (en) * | 2009-10-08 | 2017-05-03 | Otsuka Pharmaceutical Co., Ltd. | An immunoactivation blood perfusion filter for the treatment of malignant tumors |
US20120219633A1 (en) * | 2011-02-28 | 2012-08-30 | Pall Corporation | Removal of immunoglobulins and leukocytes from biological fluids |
US20120231542A1 (en) * | 2011-03-11 | 2012-09-13 | General Biotechnology, Llc | Biologically Active Human Umbilical Cord Blood Cell Extract Compounds and Methods |
CA2933566C (en) * | 2013-12-13 | 2018-05-22 | Asahi Kasei Medical Co., Ltd. | Leukocyte removal filter material and leukocyte removal method |
US9796166B2 (en) | 2014-03-24 | 2017-10-24 | Fenwal, Inc. | Flexible biological fluid filters |
US9968738B2 (en) | 2014-03-24 | 2018-05-15 | Fenwal, Inc. | Biological fluid filters with molded frame and methods for making such filters |
US10159778B2 (en) | 2014-03-24 | 2018-12-25 | Fenwal, Inc. | Biological fluid filters having flexible walls and methods for making such filters |
US9782707B2 (en) | 2014-03-24 | 2017-10-10 | Fenwal, Inc. | Biological fluid filters having flexible walls and methods for making such filters |
US10376627B2 (en) | 2014-03-24 | 2019-08-13 | Fenwal, Inc. | Flexible biological fluid filters |
JP6400349B2 (ja) * | 2014-06-20 | 2018-10-03 | 旭化成メディカル株式会社 | 放射線が照射された体外循環用顆粒球除去器包装体 |
EP3185926B1 (de) | 2014-08-26 | 2018-11-28 | 3M Innovative Properties Company | System zur entfernung von proinflammatorischen mediatoren sowie von granulozyten und monozyten aus blut |
US10780204B2 (en) * | 2014-10-02 | 2020-09-22 | Asahi Kasei Medical Co., Ltd. | Biological fluid-treating filter and filter device |
DE102016208024A1 (de) * | 2016-05-10 | 2017-11-16 | B. Braun Avitum Ag | Adsorbermaterial zur Prävention oder Behandlung von schweren Verläufen von Infektionskrankheiten |
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2002
- 2002-10-16 WO PCT/JP2002/010766 patent/WO2003033053A1/ja not_active Application Discontinuation
- 2002-10-16 US US10/492,652 patent/US20050014127A1/en not_active Abandoned
- 2002-10-16 CA CA002464351A patent/CA2464351A1/en not_active Abandoned
- 2002-10-16 CN CNB02822714XA patent/CN100457200C/zh not_active Expired - Fee Related
- 2002-10-16 EP EP02801582A patent/EP1444996A4/en not_active Withdrawn
- 2002-10-16 KR KR1020047005468A patent/KR20050036848A/ko not_active Application Discontinuation
-
2004
- 2004-05-19 NO NO20042076A patent/NO20042076L/no not_active Application Discontinuation
-
2007
- 2007-07-02 US US11/772,448 patent/US7820371B2/en not_active Expired - Fee Related
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2008
- 2008-08-21 JP JP2008212496A patent/JP4992120B2/ja not_active Expired - Fee Related
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JP2001161807A (ja) * | 1999-12-10 | 2001-06-19 | Kuraray Co Ltd | 輸血用血液のイオン濃度調節材 |
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EP1635661B1 (en) * | 2003-06-13 | 2010-08-11 | WADSTRÖM, Torkel | Product for absorption purposes |
Also Published As
Publication number | Publication date |
---|---|
US20050014127A1 (en) | 2005-01-20 |
NO20042076L (no) | 2004-06-10 |
CN1589163A (zh) | 2005-03-02 |
CA2464351A1 (en) | 2003-04-24 |
CN100457200C (zh) | 2009-02-04 |
US7820371B2 (en) | 2010-10-26 |
JP4992120B2 (ja) | 2012-08-08 |
EP1444996A4 (en) | 2005-11-16 |
EP1444996A1 (en) | 2004-08-11 |
KR20050036848A (ko) | 2005-04-20 |
US20070248942A1 (en) | 2007-10-25 |
JP2009018177A (ja) | 2009-01-29 |
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