JPH0725776A - Filter material for selectively removing leukocyte - Google Patents

Abstract

PURPOSE:To provide the filter material developing leachates little, capable of efficiently removing leukocytes while suppressing thrombocyte loss to the minimum. CONSTITUTION:The filter material is characterized by that a filter material is a porous element having blood-passable pores and the surface of this filter material is coated with a macromer having both hydrophobic portions and polyethylene oxide chains.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a leukocyte selective removal filter material which selectively removes leukocytes and allows platelets to pass through. Specifically, a leukocyte selective removal filter material for selectively removing leukocytes in blood when performing blood transfusion or extracorporeal circulation, or for selectively removing leukocytes mixed in when preparing concentrated platelet plasma from blood. Regarding

[0002]

2. Description of the Related Art In recent years, with advances in immunology and blood transfusion, component blood transfusion, which is a conventional whole blood transfusion, in which only components necessary for treatment of various diseases are transfused has come to be performed. Component transfusion is an excellent transfusion therapy that reduces the burden on the patient due to transfusion and enhances the therapeutic effect, and various blood products used for component transfusion, namely, concentrated red blood cells (CRC), concentrated platelets (PC), Platelet-poor plasma (PPP) and the like are prepared by centrifuging whole blood obtained by donating blood.
However, it has been clarified that many blood cells are contained in the blood product separated by the centrifugation operation, and that the mixed white blood cells cause side effects after blood transfusion. Post-transfusion side effects include relatively minor side effects such as headache, nausea, chills, and non-hemolytic fever reaction.For patients with immunological disorders, transfused leukocytes are found in the recipient's skin and internal organs. Serious side effects such as induction of graft-versus-host reaction (GVH), which has a lethal effect, infection by viruses present in leukocytes such as cytomegalovirus infection, and alloantigen sensitization are known. In order to prevent such post-transfusion side effects, it is effective to remove leukocytes mixed in the blood product. Usually 10 ⁷ / ml in blood products used for blood transfusion such as whole blood and red blood cell products
Contains white blood cells. In order to prevent relatively minor side effects such as headache, nausea, chills, and fever reaction, it is said that it is necessary to keep the number of white blood cells infused to the recipient in a single blood transfusion to about 100 million or less. Therefore, for this purpose, it is necessary to remove the residual rate of leukocytes in the blood product until it becomes 10 ^-1 to 10 ^-2 or less. In order to prevent alloantigen sensitization and virus infection, the leukocyte residual rate is 10 ^-4 to 10 ^-6.
It is expected to be prevented by removing up to the following. As a method for removing leukocytes from a blood product, a centrifugal separation method utilizing a difference in specific gravity of blood and a filter method using a fibrous medium such as a non-woven fabric or a sponge-like structure having three-dimensional mesh-like continuous pores as a filter material are used. It can be roughly classified into two types: good leukocyte removal efficiency and easy operation.
Filtering methods are widely used because of their low cost. However, most of the above-mentioned filter materials adhere to and remove not only leukocytes but also platelets having high adhesiveness. A filter that selectively removes leukocytes and allows platelets to pass through has been earnestly needed for blood transfusion for patients requiring a platelet supply such as aplastic anemia, thrombocytopenic purpura, and leukemia.

In order to selectively remove leukocytes and allow platelets to pass through, it is necessary to consider the physical and chemical factors of the filter material. The physical factor indicates the physical structure of the filter material, and in the case of a fibrous medium such as a non-woven fabric, the fiber diameter, density, thickness, etc. correspond to this, and in the case of a porous body having continuous pores, the pore size, porosity, density. , Thickness, etc. correspond to this. Generally, physical factors of the filter material greatly contribute to the removal of white blood cells, and to enhance the removal ability, use ultrafine fibers with a small fiber diameter, increase packing density, and reduce pore size. It has been known.
On the other hand, when blood is brought into contact with various polymer materials, the presence or absence of thrombus and the presence or absence of cell disruption will differ depending on the material surface selection. Although this difference is not yet understood,
It is believed that it is due to a complex interaction between cells contained in blood and the surface of the material used (“medical polymer material”,
Editorial Committee for Medical Polymer Materials, 1981). When the material surface is classified from the viewpoint of hydrophilicity and hydrophobicity, generally, a polymer material having a hydrophilic surface has a small interfacial energy between the material surface and blood, and the interaction with proteins and blood cells becomes small. It is said that thrombus formation and cell metamorphosis tend to be suppressed (“Biomaterial Science”, Vol. 2, 135, 1982). Therefore, in order for the filter material to have the property of passing platelets, it is effective to make the filter material hydrophilic, and it is known to introduce hydrophilic monomers and multimers into the filter material surface by graft polymerization or coating. Known as the technology of. However, such a filter material having a hydrophilized surface can improve the passage of platelets, but also reduces the leukocyte removal ability, and when a hydrophilic multimer is introduced into the filter material surface by coating. The polymer was eluted.

Japanese Unexamined Patent Publication No. 55-129755 discloses a method for collecting leukocytes and lymphocytes which uses a filter having a non-woven fabric surface coated with an antithrombotic material and in which red blood cells and platelets are less contaminated. However, when blood was flown through this filter, the loss of platelets was small, but the ability to remove leukocytes was also small, and leukocytes could not be selectively removed. WO87 / 05812 discloses a filter material for selective removal of leukocytes, which uses a filter material in which the surface portion of the fiber contains a nonionic hydrophilic group and a basic nitrogen-containing functional group. However, when the surface area of the filter material is controlled so that the leukocyte residual ratio is 10 ^-2 to 10 ^-3 , this filter material can allow platelets to pass through efficiently, but since the side effect after transfusion is more reliably prevented, When the surface area of the filter material is increased so that the leukocyte residual rate is 10 ⁻⁴ or less, there is a problem that the platelet passage rate is reduced. Further, since a multimer having a basic nitrogen-containing functional group and a nonionic functional group is generally easily compatible with water, there is a problem that the polymer is likely to fall off even if it is coated on a hydrophobic filter material, that is, it is easily eluted. It was

Japanese Unexamined Patent Publication No. 1-249063 discloses an apparatus for separating white blood cells from a platelet concentrate using a filter material whose surface is modified with a monomer having a negative charge and a monomer having a hydroxyl group. A method is disclosed. However, as a result of examination by the present inventors, this filter material cannot pass platelets efficiently while maintaining a high leukocyte-removing ability with a leukocyte residual rate of 10 ⁻⁴ or less, as in WO 87/05812. It was a thing. Japanese Unexamined Patent Publication No. 4-187206 discloses a leukocyte separation device and a method for producing a leukocyte separation material in which a polyethylene glycol chain is introduced on the surface of the material. However, this filter material was also not satisfactory in leukocyte removal ability. As described above, up to now, no filter material has been known that reduces platelet loss while maintaining a high leukocyte-removing ability with a leukocyte residual rate of 10 ⁻⁴ or less.

[0006]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a leukocyte selective removal filter material in which platelets hardly adhere even if the surface area of the filter material is increased so that the leukocyte residual rate is 10 ⁻⁴ or less. . Another object of the present invention is to provide a leukocyte selective removal filter material that can be effectively used for platelet transfusion and extracorporeal leukocyte removal treatment of blood and that efficiently removes leukocytes with less platelet adhesion. A further object of the present invention is to provide a filter material free from eluates that can safely carry out blood transfusion and extracorporeal circulation therapy.

[0007]

[Means for Solving the Problems] The above object is to provide a porous element having a pore capable of filtering blood as a filter material, the surface of the filter material having both a hydrophobic portion and a polyethylene oxide chain. This is accomplished by the filter material coating the multimer. That is, a filter material having a multimer having a hydrophobic portion and a polyethylene oxide chain on the surface has a property that platelets hardly adhere while maintaining leukocyte-removing ability, and the multimer does not elute from the filter material, that is, It was revealed that there was no eluate, and the filter material of the present invention was developed.

The multimer having both a hydrophobic portion and a polyethylene oxide chain as referred to in the present invention comprises both a hydrophobic portion having low affinity for water and hardly soluble in water and a polyethylene oxide chain, and constitutes a multimer. It is a multimer in which the number of monomers (degree of polymerization) is 2 or more. For example, a random copolymer or block polymer of a hydrophobic polymerizable monomer having a high reactivity such as a double bond or a triple bond and a polymerizable monomer containing a polyethylene oxide chain, a hydrophobic portion and a polyethylene oxide chain. A polymer composed of a polymerizable monomer containing both, a polymer synthesized by condensation polymerization so as to contain a hydrophobic portion and a polyethylene oxide chain,
Even hydrophilic multimers include, for example, multimers in which a hydrophobic portion and a polyethylene oxide chain are introduced by a chemical reaction.

Even if a polymer having a high solubility in water, that is, a hydrophilic monomer is introduced onto the surface of a hydrophobic material by coating, the physical adhesion to the surface of the material is weak.
When it comes into contact with blood, it easily falls off the material surface. Such a material cannot be used as a material for filtering blood no matter how good the platelet permeability is. The eluate from the surface of the filter material depends on the solubility in water of the monomers constituting the polymer coating the polymer material.
That is, since a polymer material generally has a hydrophobic surface, if a polymer consisting of a monomer whose solubility in water is extremely low is used, the adhesion between the polymer material surface and the polymer is improved, and there is no elution. It can be the surface of the material. However, when a material designed in this way is used and brought into contact with blood, there is a problem that the surface of the material is very hydrophobic and the passage of platelets is reduced.

On the other hand, it is known that a monomer having a polyethylene oxide chain is an excellent blood-compatible material having antithrombogenicity. For example, it is known that when blood is contacted with a polymer material having a polyethylene oxide chain on its surface, plasma proteins such as albumin and globumin do not adhere to the surface of the material, and the reactivity of platelets is low, and thrombus formation is not observed. (Raito Yoshito, Medical Polymer Materials, Kyoritsu Shuppan, 1989). When such a monomer having a polyethylene oxide chain, which is an excellent blood compatible material, is introduced to the surface of the filter material, low cell adhesion and blood compatibility are imparted, and platelets do not adhere to the surface of the filter material. Come to pass. However, since the polyethylene oxide chain is very hydrophilic, leukocytes can pass through at the same time, and it cannot be used as a leukocyte selective removal filter material for this purpose. As described above, it was a general point that if the material surface is made hydrophobic, the platelet permeability is lowered, and conversely, if the material surface is made hydrophilic, the multimer coated on the material surface is likely to be eluted. Against such a problem, the present inventors have diligently studied, and when a filter material surface is coated with a multimer having both a hydrophobic portion and a polyethylene oxide chain, while maintaining high platelet passage property and leukocyte removal ability, It has become possible to use a material having no eluate, and has developed the leukocyte selective removal filter material of the present invention.

The multimer having a hydrophobic moiety and a polyethylene oxide chain of the present invention can be synthesized by various methods as described above. Among them, a polymerizable monomer containing a hydrophobic polymerizable monomer and a polyethylene oxide chain is used. The reason why the monomer multimer or the polymer multimer including both the hydrophobic part and the polyethylene oxide chain is easily available, easy to handle, and easy to synthesize. Is more preferable. In this case, the solubility of the polymerizable monomer having a hydrophobic portion in water (20 to 25 ° C., pH = 6 to 8) is 50 or less, preferably 40 or less, and more preferably 20 to 1. desirable. Similarly, in a multimer composed of a polymerizable monomer containing both a hydrophobic portion and a polyethylene oxide chain, water (2
The solubility in 0 to 25 ° C., pH = 6 to 8) is 60 or less, preferably 50 or less, more preferably 30 to 1. The solubility of the monomer having a hydrophobic portion, the monomer containing both the hydrophobic portion and the polyethylene oxide chain in water exceeds 50, and when it exceeds 60, the adhesion between the filter material and the multimer decreases. ,
It is not preferable because the amount of eluate increases.

When the polymerizable monomer is a solid, the solubility is measured by a fog point method, a thermal analysis method, an electric method for measuring the electromotive force or conductivity of the solution, a gas chromatography analysis method, a tracer method, etc. It can be measured by a known measuring method, and when the polymerizable monomer is a liquid, it can be measured by the same measuring method as in the case of an individual, but further by a known method such as a volume method, a light scattering method, a vapor pressure method or the like. be able to. Further, as a simpler method, water is evaporated from a saturated aqueous solution of the polymerizable monomer,
It can also be determined by a method of measuring the weight of the remaining amount.

The content of the hydrophobic portion contained in the multimer of the present invention is 10% by weight or more, preferably 20% by weight or more. If the content of the hydrophobic portion is less than 10% by weight, the adhesion between the multimer and the filter material is low, and the multimer is eluted when it comes into contact with blood, which is not preferable. The content of polyethylene oxide chain contained in the multimer of the present invention is 2 to 80% by weight, preferably 1
It is desirable that the content is 0 to 80% by weight, more preferably 40 to 80% by weight, and the number of repeating units of the polyethylene oxide chain is 2 to 100, preferably 2 to 60,
It is more preferably 2 to 30, and most preferably 2 to 15. When the content of polyethylene oxide chain in the multimer is less than 2% by weight or the number of repeating units of polyethylene oxide chain is less than 2, platelet permeability is decreased and the content of polyethylene oxide chain exceeds 80% by weight. Alternatively, if the number of repeating units of polyethylene oxide chain exceeds 100, the contact property with the filter material decreases and the amount of eluate increases, which is not preferable.

The molecular weight of the multimer of the present invention is 6000.
As described above, it is desirable that it is 200 million or more. When the molecular weight is less than 6000, the polymer is likely to fall off from the filter material, which is not preferable.

The content of the hydrophobic portion and the content of the polyethylene oxide chain are known, for example, by infrared absorptiometry (ATR-IR) using a multiple total reflection infrared spectrometer, nuclear magnetic resonance spectroscopy (NMR), elemental analysis and the like. It can be measured by the method. The molecular weight of the multimer is, for example, gel permeation chromatography (GPC),
It can be measured by a known method such as a melting point lowering method, a boiling point raising method, a constant temperature distillation method, a membrane osmotic pressure method and the like.

The hydrophobic portion as used in the present invention is a portion having a very low affinity for water, that is, a portion having a carbon-carbon bond of 3 or more, an oxygen atom or a sulfur atom between carbon atoms. Such as a bond portion containing a hetero atom, a halogenated hydrocarbon, and the like. Further, the functional group constituting the hydrophobic part includes an alkyl group, a halogen group, an alkyloxo group, an alkylthio group, an ester bond part, an ether bond part, an aromatic part and the like. Examples of the hydrophobic polymerizable monomer having such a hydrophobic portion include styrene, styrene derivatives such as methylstyrene, methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, and phenyl. (Meth) acrylate,
Acrylic esters such as ethylhexyl (meth) acrylate, hydroxypropyl (meth) acrylate, hydroxybutyl (meth) acrylate and trichloroethyl (meth) acrylate, methacrylic acid ester derivatives, alkenes such as pentene, hexene, heptene and octene However, the polymerizable monomer having a hydrophobic portion is not limited to the above substances.

As the polymerizable monomer containing both the hydrophobic portion and the polyethylene oxide chain, polyethylene glycol / polybutylene glycol (meth) acrylate, polyethylene glycol / polypropylene glycol (meth) acrylate, phenoxy polyethylene glycol (meth) may be used. ) Acrylic acid esters such as acrylate, methacrylic acid ester derivatives and the like can be mentioned, but the polymerizable monomer having both the hydrophobic portion and the polyethylene oxide chain is not limited to the above substances.

Further, as the polymerizable monomer having a polyethylene oxide chain, methoxytriethylene glycol (meth) acrylate, methoxytetraethylene glycol (meth) acrylate, methoxypolyethylene glycol (meth) acrylate, hydroxypolyethylene glycol (meth). Acrylic ester such as acrylate,
Examples thereof include methacrylic acid ester derivatives, but the polymerizable monomer having a polyethylene oxide chain is not limited to the above substances.

The multimer of the present invention has a basic nitrogen-containing functional group in an amount of 0.2 to 4.0% by weight, preferably 0.3 to 3.0.
It is desirable to have wt%, more preferably 0.3-1.5 wt%. It is a general phenomenon that a material having a basic nitrogen-containing functional group becomes positively charged on the surface of the material in a physiological body fluid in which cells are suspended and adheres to negatively charged platelets and leukocytes. Met. However, a filter material coated with a multimer having a basic nitrogen-containing functional group in an amount of 0.2 to 4.0% by weight has a property that white blood cells easily adhere even though platelets do not easily adhere. Therefore, leukocytes can be removed more efficiently. However, when the content of the basic nitrogen-containing functional group is less than 0.2% by weight, the amount of positive charge is insufficient and leukocyte-removing ability is not improved, and when it exceeds 4.0% by weight, platelets are also removed by adhesion. It is not preferable because it will be done. Examples of the basic nitrogen-containing functional group include primary amino groups, secondary amino groups, tertiary amino groups, quaternary ammonium groups, and nitrogen-containing aromatic groups such as pyridyl groups and imidazoyl groups. Specifically, dimethylaminoethyl (meth) acrylate, diethylaminoethyl (meth) acrylate, and the like are available from the viewpoint of easy availability and handling. However, the basic nitrogen-containing functional group that can be used in the multimer of the present invention,
The substance is not limited to the above-mentioned substances, and the polymerizable monomer having a hydrophobic portion or the polymerizable monomer having a polyethylene oxide chain may contain a basic nitrogen-containing functional group.

The multimer of the present invention is a substance containing both a hydrophobic portion and a polyethylene oxide chain. In addition, various functional groups in this polymer, namely, amino group, hydroxyl group, sulfonic acid group, halogen group, nitro group, nitrile group, alkyloxy group, alkyl group, acyl group, thiol group, carboxyl group, carbonyl group. , A formyl group or the like may be included. Furthermore, it is more preferable to introduce a basic nitrogen-containing functional group into the multimer of the present invention.

The filter material of the present invention is not particularly limited as long as it has pores capable of filtering blood, and includes any shape, but specifically, natural fiber,
Examples include fibrous media such as glass fibers, knitted fabrics, non-woven fabrics, and woven fabrics, porous membranes, and sponge-like structures having continuous three-dimensional mesh-like pores. Of these, non-woven fabrics and sponge-like structures are particularly preferable. It is known that the physical structure of the filter material greatly contributes to the removal of leukocytes, and the selection of the filter material is also an important factor in improving the leukocyte removal ability. When using fibrous media such as non-woven fabric as the filter material, the average fiber diameter is 0.3-3.0μ.
m, preferably 0.5 to 2.0 μm, more preferably 0.5 to 1.5 μm. Further, it is desirable that the average pore diameter is 2 to 30 μm, preferably 2 to 20 μm, and more preferably 2 to 10 μm. The filling density when the fibrous medium is filled in a container for removing leukocytes is 0.1 to 0.5 g / cm ³ , preferably 0.1 to 0.3 g / cm ³ , and more preferably 0.15
It is desirable that it is ˜0.25 g / cm ³ . When the average fiber diameter is less than 0.3 μm, the average pore diameter is less than 2 μm, and the packing density is more than 0.5 g / cm ³ , clogging of blood cells and increase in pressure loss are caused, and the average fiber diameter exceeds 3.0 μm. Pore size is over 30μm, packing density is 0.1g
If it is less than / cm ^3, it is not preferable because the ability to remove leukocytes decreases.

When a sponge-like structure having continuous pores is used as a filter material, it is desirable to have an average pore diameter of 2 to 30 μm. If the average pore size is less than 2 μm, blood cells will be clogged and pressure loss will increase, and if the average pore size exceeds 30 μm, leukocyte-removing ability will decrease, which is not preferable.

The average fiber diameter in the present invention means a value obtained by the following method. That is, a portion which is recognized as being substantially uniform is sampled from one or a plurality of fibrous bodies constituting the filter material and photographed by using a scanning electron microscope or the like. When sampling, the effective filtration area of the fibrous body is 0.5 cm on each side.
It divides by the square of, and 6 places are randomly sampled from it. In order to perform random sampling, for example, after designating an address to each of the above parts, a method of using a random number table or the like may be used to select a required place. For each section sampled, three or more locations, preferably five or more locations, are photographed at a magnification of 2500. For each sampled section, take a picture of the central part and its vicinity, and the total number of fibers taken in the picture is 1
Take pictures until the number exceeds 00. Here, the diameter means the width of the fiber in the direction perpendicular to the fiber axis. The value obtained by dividing the sum of the measured diameters of all fibers by the number of fibers is defined as the average fiber diameter. However, when multiple fibers are overlapped and the width cannot be measured due to the shadow of other fibers, or when multiple fibers are melted and become thick fibers, fibers with significantly different diameters In the case of mixed cases, etc., these data are deleted.

The average pore diameter of the filter material in the present invention is a value measured by a mercury porosimeter (Shimadzu Corporation, Poisizer 9320 or an equivalent device),
When the amount of mercury injected into the pores of the filter material is 0% and the amount of mercury contained in all the pores of the filter material is 100%, the amount of mercury injected is 5%.
The point corresponding to 0% is the average pore diameter in the present invention. The mercury porosimeter measures in the pressure range of 1 to 2650 psia.

Further, as the filter material of the present invention,
There is no particular limitation as long as it does not easily damage blood cells, and various types can be used, and examples include organic polymers, inorganic polymers, and metals. Among them, organic polymers are preferable materials because they are excellent in workability such as cutting. As the organic polymer, for example, polyurethane, polyacrylonitrile, polyvinyl alcohol, polyvinyl acetal, polyester, polyamide, polystyrene, polysulfone, cellulose, cellulose acetate, polyethylene, polypropylene, polyvinyl fluoride, polyvinylidene fluoride, polytrifluorochlorovinyl, Vinylidene fluoride-tetrafluoroethylene copolymer, polyether sulfone, poly (meth) acrylate, butadiene-acrylonitrile copolymer, polyether-polyamide block copolymer, ethylene-vinyl alcohol copolymer and the like can be mentioned, but the filter material of the present invention is The present invention is not limited to the above example.

The filter material coated with the multimer of the present invention has a critical wet surface tension (CWST) of 65 to 90 d.
less than yn / cm, preferably 75-90 dyn / cm,
More preferably, it is preferably 75 to 85 dyn / cm. CWST is a physical property value that is related to the surface characteristics of a filter material and is used to define the wetting characteristics of the filter material. That is, it is a surface characteristic value that determines whether wetting of the filter material occurs when the liquid is brought into contact with the surface of the filter material and a slight pressure is applied, and has a CWST value larger than the surface tension of a certain liquid. The filter material will be wetted by the liquid. The present invention relates to a filter material that removes leukocytes mixed in blood products and allows platelets to pass through.In fact, in order to remove leukocytes from blood products, blood is used when blood and filter materials come into contact with each other. Conditions under which the filter material naturally wets are preferable. Therefore, the surface of the filter material used in the present invention preferably has a CWST value equal to or higher than the surface tension of blood to be filtered. The surface tensions of plasma and red blood cells are 73 dyn / cm and 64.5, respectively.
measured as dyn / cm (measurement of surface tension of blood cells and proteins, A. Double Newman et al., New York Academy of Science, 1983, 27)
Therefore, the filter material having a surface of less than 65 dyn / cm cannot filter blood without applying a considerable pressure. Therefore, the CWST value of the filter material should be 65 dyn to reduce the pressure loss.
/ Cm or more is preferable. On the other hand, when the CWST value exceeds 90 dyn / cm, the multimer coating from the filter material is likely to be eluted. Therefore, the CWST value of the filter material is preferably less than 90 dyn / cm. The CWST in the present invention means a value obtained by the following method. Ie 2 to 4d
Aqueous solutions having different concentrations of sodium hydroxide, calcium chloride, sodium nitrate, acetic acid and ethanol are prepared so that the surface tension changes by yn / cm. The surface tension (dyn / cm) of each aqueous solution is 94 to 115 for the sodium hydroxide aqueous solution, 90 to 94 for the calcium chloride aqueous solution, 75 to 87 for the sodium nitrate aqueous solution, and 72.
4, 38-69 with acetic acid aqueous solution, 22 with ethanol aqueous solution
˜35 (“Chemical Handbook Basic Edition II” revised 2nd edition, edited by The Chemical Society of Japan, Maruzen, 164 (1975)).
The surface tension thus obtained is 2 to 4 dyn / cm.
Different aqueous solutions are placed on the filter material in order of decreasing surface tension, 10 drops each, and left for 10 minutes. After standing for 10 minutes, it is defined as a wet state when 9 or more drops out of 10 drops are absorbed by the filter material, and as a non-wet state when absorption is less than 9 drops out of 10 drops. In this way, when a liquid having a small surface tension is sequentially measured on the filter material, a wet state and a non-wet state appear. At this time, the average value of the surface tension values of the liquid observed in the wet state and the surface tension values of the liquid observed in the non-wet state is defined as the CWST value of the filter material. For example, 64dyn /
66 dyn / c, moistened with a liquid having a surface tension of cm
When not wet with a liquid having a surface tension of m, the CWST value of the filter material is 65 dyn / cm.

The white blood cell selective removal filter material of the present invention is a filter material having pores capable of filtering blood coated with the multimer of the present invention. The method of coating the multimeric filter material of the present invention is
There is no particular limitation as long as it can be uniformly coated without significantly blocking the pores of the filter material and without exposing the surface of the filter material, and various methods can be used. For example, a method of impregnating the filter material in a solution in which the multimer is dissolved, a method of spraying the solution in which the multimer is dissolved onto the filter material, a method of directly applying the multimer to the filter material and rinsing off the excess multimer, etc. To be Among them, the method of impregnating a filter material in a solution in which a polymer is dissolved is a preferable method because the coating layer can be made uniform and the cost is low.
As the solvent for dissolving the multimer, various solvents can be used without particular limitation as long as they do not significantly dissolve the filter material. Alcohols such as methanol, ethanol, propanol and butanol, and ketones such as acetone and methyl ethyl ketone. , Esters such as methyl acetate and ethyl acetate, aromatics such as benzene and toluene, hydrocarbons such as hexane and cyclohexane, halogenated hydrocarbons such as chloroform and dichloromethane, sulfur-containing solvents such as dimethyl sulfoxide, dimethylformamide And amides such as dimethylacetamide. Among them, alcohols are preferable solvents because they have low toxicity and excellent handleability. Also,
Drying after coating includes mechanical compression, gravity,
A method of removing excess solution by centrifugation, blowing a gas such as air or nitrogen, and heating at room temperature or in a dry gas or in a vacuum can be used. In addition, before coating, in order to further enhance the adhesion between the multimer of the present invention and the filter material, the surface of the filter material is treated with an acid,
It is also possible to treat with a suitable chemical such as alkali or to irradiate with plasma. Further, after coating the multimer, heat treatment of applying heat of 100 ° C. or higher, and post-processing of irradiating radiation such as γ ray or electron beam of 100 Gy or more to further strengthen the adhesiveness between the filter material and the multimer. You can also The coating may be performed when the filter material is manufactured, or may be performed after the manufacturing. The average thickness of the coating layer thus coated on the surface of the filter material is preferably 1 μm or less, and the coating amount is preferably 200 mg / m ² or less per unit surface area of the filter material. If the average thickness exceeds 1 μm or the coating amount exceeds 200 mg / m ² , the pores of the filter material may be clogged, resulting in high cost, which is not preferable. It is desirable that the average thickness is 40 to 600 angstroms and the coating amount is 0.7 to 10 mg / m ² . The average thickness of the coating layer and the coating amount are measured by Auger electron spectroscopy (AE).
S), secondary ion mass spectrometry (SIMS), electron probe microanalysis (EPMA), X-ray photoelectron spectroscopy (XP)
S), scanning electron microscope (SEM), infrared absorption spectrophotometry (ATR-IR) using a multiple total reflection infrared spectrometer, and the like. If the multimer contains a chargeable functional group such as an amino acid, a carboxyl group, or a sulfonic acid group, the coating amount is adjusted by a dye adsorption method using a dye ionically adsorbed to the charged functional group. It can be easily measured.

[0028]

EXAMPLES The white blood cell selective removal filter material of the present invention will be described in more detail with reference to the following examples.

[0029]

Example 1 Methoxypolyethylene glycol methacrylate (hereinafter, abbreviated as MPGMA-30) having 30 repeating units of ethylene oxide chain as a polymerizable monomer having a polyethylene oxide chain and methyl which is a hydrophobic polymerizable monomer. A copolymer of methacrylate (hereinafter abbreviated as MMA) was synthesized by ordinary solution radical polymerization. The polymerization conditions were such that the molar ratio of MPGMA-30 and MMA was 0.2 and 0.8, and the acetonitrile solution was adjusted to a total amount of 1 mol / 1, and 2.2 'was used as an initiator.
-Azobis (2.4-dimethylvaleronitrile) (V-
65) was added at 1/200 mol / 1 and a polymerization reaction was carried out at 50 ° C. for 8 hours. The polymer was purified by adding the solution after the reaction to a mixed solution of ethanol / hexane and precipitating the polymer. The content of polyethylene oxide chains in the thus obtained multimer was 72.5% by weight.
Met. Average fiber diameter 1.2 μm, average pore diameter 8 μm
24 non-woven fabrics made of polyethylene terephthalate (fiber surface area 2.9 m ² ) for removing the white blood cells of
A non-woven fabric having an average pore diameter of 30 μm or more for removing micro-aggregates contained in the blood product is provided on the blood inlet side of the non-woven fabric with an effective filtration cross-sectional area of 3.0 × 3.0 cm. It was filled in a container having the same. The packing density of the non-woven fabric for removing white blood cells was 0.2 g / cm ³ .

A 1% ethanol solution of the above multimer was put into this container so that air was not introduced, and nitrogen was flown for 4.5 minutes at a flow rate of 1.51 / min to remove an extra multimer solution. Furthermore, the container after coating at 60 ° C. for 16 hours was vacuum dried. CWS of filter material after coating
The T value was 82 dyn / cm. 10 units of concentrated platelets derived from 200 ml blood collection (230 ml, CPD 30 ml
Was added at a constant flow rate of 5 g / min using a blood circuit incorporating the above filter.

The volume of concentrated platelets before filtration (hereinafter, pre-filtration liquid) and the recovered liquid, the number of platelets, and the number of white blood cells were measured, and the platelet recovery rate and the white blood cell residual rate were calculated according to the following equations (1) and (2). . Platelet recovery rate = {collected solution volume x platelet concentration (recovered solution)} / {pre-filter solution volume x blood platelet concentration (pre-filter solution)} (1) Leukocyte residual rate = {white blood cell count (recovered solution)} / { Pre-filtration liquid volume x white blood cell concentration (pre-filtration liquid)} (2) The volume of the pre-filtration liquid and the recovery liquid was the value obtained by dividing the weight of each by the specific gravity of 1.03. The white blood cell count was measured by the following method. Measurement of white blood cell concentration in pre-filtration solution: by Turk's solution, 1
The 0-fold diluted pre-filtration solution was injected into a Birker-Turk type hemocytometer, and white blood cells present in the 8 large sections were counted using an optical microscope, and this value was _designated as n _pre . White blood cell concentration ( _pre -filtration liquid) = n _pre × 1/8 × 10 ⁵ /
ml

Measurement of white blood cell concentration in recovered liquid: recovered liquid 100
ml to EBSS solution (EBSS 10 ml, distilled water 90 m
1, HEPESbuffer2ml, Triton-x
0.87 g) 50 ml was added and mixed for 10 minutes, followed by centrifugation (800 g × 10 minutes). After centrifugation, the supernatant was removed by suction, leaving 0.5 ml of sediment. This precipitate was diluted 1.1 times with acridine orange solution, injected into a Neubauer-type hemocytometer, and the number of leaked leukocytes in 36 sections was counted using a fluorescence microscope, and this value was designated as n _post . White blood cell concentration (recovered solution) = n _post × _1/36 × _11/0 .
7/200 / μl Divided by 0.7 in the above formula because the leukocyte recovery rate at 200-fold concentration is 70%. The platelet concentration was determined by measuring a sample diluted 250,000 times with an automatic blood cell counter. As a result, the platelet recovery rate is 9
2%, white blood cell residual rate was 10 ^−4.3 . The eluate test of the coated non-woven fabric was carried out according to the disposable blood transfusion set and infusion set standards, and the evaporation residue (standard 1.0 mg or less) was measured and found to be 0.1 mg or less.

[0033]

Example 2 As a polymerizable monomer having a polyethylene oxide chain, a copolymer of methoxypolyethylene glycol methacrylate (hereinafter abbreviated as MPGMA-9) having 9 repeating units of ethylene oxide chain and MMA was used as a mole of MPGMA-9 and MMA. Synthesis was performed in the same manner as in Example 1 with the fractions set to 0.7 and 0.3. The content of ethylene oxide chains in the multimer thus obtained was 7
It was 3.5% by weight. Hereinafter, when a filter was prepared, coating, blood filtration, and an eluate test were performed in the same manner as in Example 1, the CWST value of the filter material was 84 dy.
n / cm, the platelet recovery rate was 92.4%, the white blood cell residual rate was 10 ^−4.5 , and the evaporation residue was 0.1 mg or less.

[0034]

Example 3 A copolymer of MPGMA-9 and MMA and diethylaminoethyl methacrylate (hereinafter abbreviated as DM) was used as a copolymer having MPGMA-9, MMA and DM at a molar fraction of 0.
7, 0.2, 0.1, and were synthesized in the same manner as in Example 1. The content of ethylene oxide chains in the thus obtained multimer was 72.4% by weight. Hereinafter, when a filter was prepared, coating, blood filtration, and an eluate test were carried out in the same manner as in Example 1, C of the filter material was found.
WST value is 84 dyn / cm, platelet recovery rate is 91.8.
%, White blood cell residual rate is 10 ^-5.1 , evaporation residue is 0.1 mg
It was below.

[0035]

Example 4 MPGMA-9 and a copolymer of 2-hydroxypropyl methacrylate (hereinafter abbreviated as HPMA) and DM as a polymerizable monomer having a hydrophobic portion are MPG.
The molar fraction of MA-9, HPMA and DM was 0.45,0.
47 and 0.08, and were synthesized by the same method as in Example 1. The content of ethylene oxide chains in the thus obtained multimer was 59.0% by weight. Hereinafter, when a filter was prepared, coating, blood filtration, and an eluate test were performed in the same manner as in Example 1, CW of the filter material was obtained.
ST value is 85 dyn / cm, platelet recovery rate is 94.8.
%, White blood cell residual rate is 10 ^-4.5 , evaporation residue is 0.1 mg
Met.

[0036]

[Comparative Example 1] A filter similar to that of Example 1 was prepared and subjected to blood filtration and eluate test without coating. The CWST value of the filter material was 61 dyn / c.
m, platelet recovery rate is 54.0%, white blood cell residual rate is 10
^-4.0 , the evaporation residue was less than 0.1 mg.

[0037]

[Comparative Example 2] A multimer consisting of MMA alone was synthesized, and a filter was prepared, coating, blood filtration, and an eluate test were conducted in the same manner as in Example 1.
WST value is 59 dyn / cm, platelet recovery rate is 43.2
%, White blood cell residual rate is 10 ^-4.1 , evaporation residue is 0.1 mg
It was below.

[0038]

Comparative Example 3 A multimer consisting of MPGMA-9 alone was synthesized (polyethylene oxide chain content 80%), and Example 1
When the filter production, coating, blood filtration, and eluate test were performed in the same manner as in, the CWS of the filter material
T value is 90 dyn / cm, platelet recovery rate is 96.5%,
The white blood cell residual rate was 10 ^−1.8 , and the evaporation residue was 3.1 mg. Table 1 shows the results of Examples 1 to 4 and Comparative Examples 1 to 3.

[0039]

[Table 1]

[0040]

As shown in Table 1, since the filter material of the present invention has a high platelet recovery rate and a low leukocyte residual rate and a low evaporation residue, it is an effective and safe filter material for use in blood transfusion and extracorporeal circulation therapy. Is.

Claims (1)

[Claims] 1. A filter material is a porous element having pores capable of filtering blood, and a multimer having both a hydrophobic portion and a polyethylene oxide chain is introduced by coating on the surface of the filter material. A white blood cell selective removal filter material characterized by the following.