JPH0229260A - Absorber and absorbing device for treating whole blood - Google Patents

Abstract

PURPOSE:To make it possible to remove detrimental substance from body fluid with a high degree of efficiency and a high selectivity and to enable whole blood to be directly treated by ensuring hollow parts in a hollow fiber-like totally porous body as a blood passage, and by fixing ligand in a large amount with substantial uniformity. CONSTITUTION:Blood introduced through a blood inlet port 1 is fed by a blood transferring means 2 into a whole blood treating absorber 3 is which blood is fed through the inner surface 6 of a hollow fiber-like porous body. Accordingly, a blood plasma component having a size which is less than the diameter of the thin holes in a thin hole part 8 of the hollow fiber-like porous body flows through the inner surface 6 into the thin hole part 8 and merges into a blood corpuscle component having a thick concentration and flowing down along the inner surface 6. The whole blood treating porous body 4 is fixed at its inner surface 6 and outer surface 7 and the thin hole part 8, entirely with ligand 9 which interacts with detrimental substance to be absorbed during the blood plasma passing through the thin hole part 8 so that the substance is absorbed. Further, blood corpuscle component from which the detrimental substance is absorbed, is led out from the blood discharge outlet port 5.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an adsorbent, an adsorber, and an adsorption device for adsorbing malignant substances present in body fluids. The present invention relates to a hollow fiber adsorbent, an adsorbent, and an adsorption device that are not easily clogged even when anticoagulated whole blood is directly applied thereto.

In recent years, advances in medicine, particularly in internal medicine, hematology, immunology, and clinical testing methods, have led to the discovery of malignant substances in the blood that are thought to be closely related to the cause or progression of diseases. For example, autoantibodies and immune complexes for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis, low-density riboproteins and very low-density riboproteins for familial hyperlipidemia, and increases in liver diseases. These are medium- and low-molecular weight substances.

Therefore, by selectively adsorbing and removing the above-mentioned malignant substances from body fluids such as blood and plasma, it is expected that the symptoms of the above-mentioned diseases can be alleviated and furthermore, healing can be accelerated.

(Prior Art) Conventionally known techniques for removing malignant substances from body fluids include (1) attempts to remove malignant substances from whole blood using activated carbon or activated carbon whose surface is coated with a hydrophilic polymer material; (2) Separation of whole blood into blood cells and plasma, and removal of malignant substances contained in the plasma using an adsorbent; (3) Plasma separated in the same manner as (2). Examples include those that attempt to remove high molecular weight malignant substances by passing them through a filter.

However, in methods (2) and (3), since whole blood and plasma are separated and then adsorption or filtration is performed, the circuit for flowing body fluids is complicated and the operations are complicated. Not only that, but the priming volume (volume of blood cell/plasma separator, adsorber or filter, blood circuit, plasma circuit, etc.) becomes large, so a large amount of body fluid is removed from the patient's body, which places a heavy burden on the patient. Ta.

Method (1) has a simple circuit and easy operation because it can process whole blood, but activated carbon has poor adsorption selectivity.
In addition, since the pores are small, large molecular weight malignant substances cannot be adsorbed. In many types of diseases, malignant substances that are closely related to the progression or cause of the disease have become known, and there is a growing need to selectively remove these malignant substances from body fluids. The base adsorbent cannot meet this requirement. In order to solve these problems, attempts have been made to immobilize antibodies, antigens, enzymes, etc. on the inner and outer surfaces of hollow fibers and adsorb and remove the corresponding antigens, antibodies, and other malignant substances. There is no method that utilizes the entire surface of a porous body, including the pores of hollow fibers.
Due to its low adsorption capacity, nothing has been put into practical use yet. Furthermore, these attempts use unstable biological materials such as antigens, antibodies, enzymes, and proteins as ligands, so sterilization may significantly reduce the activity of the ligands or cause them to degrade and lose their antigenicity. There were problems with safety, etc., when the drug developed or came into contact with blood.

(Problems to be Solved by the Invention) In view of the above-mentioned problems, the object of the present invention is to provide an adsorbent and an adsorbent that can remove the malignant substances from body fluids with high efficiency and high selectivity, and can further directly process whole blood. It is an object of the present invention to provide an adsorption device which is less deactivated by sterilization, is safe for living organisms, has a small priming volume, has a simple circuit, and is easy to operate.

(Means for Solving the Problems) As a result of intensive studies in accordance with the above objectives, the present inventors have found that whole blood can be directly processed by securing the hollow part of a hollow fiber-like fully porous body as a blood flow path. Platelet adhesion, aggregation and blood coagulation that tend to occur with particulate adsorbers are difficult to occur, whole blood flows smoothly, and the entire surface of the hollow fiber-like fully porous material is virtually free of ligands that interact with the adsorbed substance. By fixing a large amount uniformly, the adsorption efficiency of malignant substances is surprisingly high.
In addition, the present invention has led to the invention of an adsorption device and an adsorption device for direct processing of whole blood, which have good adsorption selectivity. Furthermore, by adopting a configuration that can directly process whole blood, the blood circuit can be simplified and operations can be made much easier than with conventional adsorbers and devices. The present invention was based on the discovery of a method for reducing the priming volume (priming volume).

That is, in the present invention, a large number of hollow fiber-like fully porous bodies are bundled almost in parallel, both ends of which are adhesively fixed with the hollow portions open, and blood entrances and exits are fluid-tightly fixed to each of the ends. 1. An adsorbent for whole blood processing, wherein a ligand that interacts with an adsorbed substance is substantially uniformly immobilized on the entire surface of the fully porous body, the ligand By mainly using a substance with low antigenicity and fixing it to a hollow fiber-like fully porous body through covalent bonds, a safer adsorbent for whole blood processing can be obtained. In addition, when a hydrophobic compound is used as a ligand, it is possible to selectively adsorb autoantibodies, immune complexes, etc., and when a polyanion is used as a ligand, low density lipoproteins, very low density lipoproteins, etc. can be adsorbed selectively. It can selectively adsorb proteins, anaphylatoxins, etc.

The hollow fiber-like fully porous material referred to in the present invention is a porous structure that has a hollow fiber-like appearance, and the microstructure of the hollow fiber structure portion (hereinafter referred to as pore portion) communicates from the inner surface to the outer surface of the membrane. refers to something that has virtually all of it. The entire surface of the hollow fiber-like fully porous body refers to the entire surface including the inner surface, outer surface, and pore inner surface of the hollow fiber-like fully porous body.

The pore size of the membrane can be freely selected depending on the size and shape of the adsorbed substance, but the pore size must be such that the adsorbed substance can freely pass through.
In addition, it is desirable that there be a sufficient surface area with which the adsorbed substance can come into contact. When the average pore diameter is defined as the pore diameter indicating the local pore volume of the total pore volume on the pore diameter-pore volume integral curve determined by a mercury porosimeter, the average pore diameter of the hollow fiber-like total porous body used in the present invention It is preferable to set the average pore size in the range of 0.005 to 3 μm in order to particularly increase the passage rate of plasma proteins, and the more preferable average pore size is in the range of 0.0 to 2 μm.
m, preferably in the range of 0.02 to 1 μm. Furthermore, when the pore surface area of the porous structure of the membrane is defined as the value determined from the nitrogen adsorption amount using a BET type surface area measuring device, the pore surface area of the hollow fiber-like fully porous body used in the present invention is 5rn.
It is preferable that the amount is 7 g or more because it increases the adsorption efficiency of isomer substances, more preferably 15m2 or more, and desirably 7 g or more.

Furthermore, the difference between the average effective length (L) and the average inner diameter (D) of the hollow fiber-like fully porous body incorporated in the adsorber is L/D ''≧20.
A configuration that satisfies the relational expression 00 mm-' is preferable because it allows plasma components to flow very effectively into the hollow fiber-like fully porous body and the voids in the outer cylindrical container.

The average effective length of the hollow fiber fully porous body is the length of the hollow fiber porous body between the adhesive parts where both ends are adhesively fixed to the outer cylindrical container,
It refers to the average length of the part of a hollow fiber-like fully porous body that is not covered with an adhesive or the like.

By setting L/D to 222,000 mm-', a large amount of plasma can come into contact with the surface on which the ligand is immobilized, including the inside of the pores of the hollow fiber-like fully porous material, which greatly improves the adsorption efficiency of malignant substances from plasma components. I can do it. In addition, by having the ability to effectively flow plasma components out of the hollow fiber-like all-porous body in this way, blood cell components are absorbed from the upstream to the midstream side of the blood-fi and Tfl passages in the hollow part of the hollow fiber-like all-porous body in the adsorber. The ratio of blood to whole blood (hematocrit) gradually increases, and the viscous resistance of blood increases. This resistance provides an appropriate filtration pressure and acts as a driving force to effectively extract plasma components from the hollow fiber-like fully porous body. The amount of components that come into contact with the glue gunt increases, increasing adsorption efficiency. Further, downstream of the blood flow path in the hollow part of the hollow fiber-like all-porous body in the adsorber, plasma components carried out from the upstream to the midstream into the voids outside the hollow fiber-like all-porous body and inside the outer cylindrical container flow into the upper and middle streams. Due to plasma pressure generated by blood flow viscous resistance in the hollow part of the hollow fiber-like fully porous body, plasma flows into the hollow part of the hollow fiber-like fully porous body, mixes with blood of increased hematocrit, and is carried out to the blood outlet of the absorber. Ru.

At this time, when the plasma flows out of the hollow fiber-like fully porous body, a considerable amount of malignant substances have been adsorbed and removed, and when it flows into the hollow part of the hollow fiber fully porous body, it comes into contact with the ligand again and completely removes the malignant substances. It can be removed.

Furthermore, by providing at least one opening in the outer cylindrical container, plasma from which malignant substances have been adsorbed and removed can be taken out of the adsorber and returned to the blood flow path downstream of the adsorber.

The inner diameter of the hollow fiber-like fully porous material is preferably small in order to reduce the priming volume and improve plasma separation efficiency, and it is sufficient that the inner diameter is large enough to allow whole blood to pass through, from 100 μm to 1 μm.
000 μm is preferable, and the range is from 150 μm to 400 μm.
μm is more preferable. The thickness of the hollow fiber-like fully porous body is preferably as large as possible to increase the pore internal surface area without practically impairing plasma separation efficiency, and is preferably 10 μm or more.
The thickness is more preferably from 50 μm to 500 μm, and preferably from 50 μm to 200 μm.

As the material for the hollow fiber-like fully porous body, any of hydrophilic materials such as cellulose, cellulose derivatives, polyvinyl alcohol, and ethylene-vinyl alcohol copolymers, and hydrophobic materials such as polyethylene, polypropylene, polysulfone, and polytetrafluoroethylene can be used. However, in the case of hydrophobic materials, it is difficult to filter aqueous liquids, so it is preferable to perform hydrophilic treatment by coating with a hydrophilic material, making the surface hydrophilic by chemical treatment, making the surface hydrophilic by plasma treatment, etc. In addition, in order to immobilize a ligand that interacts with the adsorbed substance, it is necessary to have functional groups such as hydroxyl groups, amino groups, carboxyl groups, thiol groups, etc. that can easily immobilize the ligand on the surface of the hollow fiber-like fully porous material. is preferable, but it may be omitted since the ligand can be immobilized by methods such as plasma treatment and ligand embedding coating.

The method for producing the hollow fiber-like fully porous material is not limited to the conventional methods such as wet spinning, dry spinning, and melt spinning. From the viewpoint of ease of use, mechanical strength of the hollow fiber porous material when increasing the inner surface area of the pores, etc., the stretching method after forming hollow fibers by melt spinning of a crystalline polymer is preferable, and the stretching method of polyolefins is more preferable. It is preferable from the viewpoint of chemical resistance during the ligand immobilization reaction.

All known methods such as covalent bonding, ionic bonding, physical adsorption, embedding, and precipitation insolubilization on the membrane surface can be used to immobilize the ligand on the surface of the hollow fiber-like fully porous material. It is preferable to immobilize and insolubilize by covalent bonding. For example, immobilized enzymes, known carrier activation methods used in affinity chromatography, and immobilization methods can be used. Examples of activation methods include cyanogen halide method, periodic acid method, crosslinking reagent method, and epoxide method. The activation method modifies the surface of the hollow fiber-like fully porous material to make it highly reactive.
It is sufficient that it can undergo a substitution and/or addition reaction with a nucleophilic reactive group having active hydrogen such as an amino group, a hydroxyl group, a carboxyl group, a thiol group, etc. of the ligand, and is not limited to the above-mentioned examples.

The ligand referred to in the present invention is an adsorbed substance, that is, a substance contained in blood that selectively interacts with the substance to be adsorbed by an adsorbent, attracts the adsorbed substance to the surface of the hollow fiber-like fully porous body, and adsorbs the substance. Amino acids, peptides, proteins, antigens, antibodies, complements, blood coagulation proteins, enzymes, monosaccharides, oligosaccharides, polysaccharides, glycoproteins, lipids, nucleic acids, non-protein organic compounds, inorganic substances, etc. I can give an example, but
Even if it elutes into the blood, it is preferable that the substance has low antigenicity and toxicity, and when it comes into contact with blood cells, it will hemolyze red blood cells, sensitize white blood cells, and react with platelets to cause adhesion and/or Alternatively, it is preferable to use one that does not cause aggregation. Taking these things into consideration, preferred ligands include amino acids, peptides, proteins, and glycoproteins with a molecular weight of 104 or less, more preferably amino acids, peptides, monosaccharides, oligosaccharides, polysaccharides, and nucleic acids with a molecular weight of 103 or less. ,
Non-protein organic compounds, inorganic substances, etc.

More specific examples of ligands will be given below.

For the treatment of systemic lupus erythematosus, homopolymers or copolymers of mono-, di-, and trinucleotides such as adenine, guanine, cytosine, uracil, and thymine, and naturally occurring D
Nucleic acids such as NA and RNA can be used. Furthermore, a basic compound such as actinomycin D can be used to adsorb and remove DNA, RNA, and ENA present in blood. Hydrophobic compounds can be used to adsorb and remove immune complexes for the treatment of a group of diseases called immune complex diseases such as rheumatoid arthritis, malignant tumors, and systemic lupus erythematosus. For the treatment of a group of diseases called autoimmune diseases such as myasthenia gravis, multiple sclerosis, and rheumatoid arthritis.
Hydrophobic compounds can be used for adsorption and removal of autoantibodies. For the treatment of hyperlipidemia, polyanions such as heparin, acidic polysaccharides such as dextran sulfate, and synthetic polyanions such as polyvinyl sulfate and polyacrylic acid are used to adsorb and remove low-density lipoproteins and very low-density lipoproteins. Can be used.

The ligands that can be used in the present invention are not limited to the above examples, and two or more types of ligands may be immobilized, or two or more types of hollow fiber-like fully porous bodies with immobilized ligands may be used. The above may be used.

Among the above-mentioned ligands, hydrophobic compounds and polyanions will be described in more detail.

The hydrophobic compound referred to in the present invention has a solubility in physiological saline of 1
00 mmol/di or less (at 25°C), more preferably 30 mmol/di or less. A compound having a solubility in physiological saline of more than 100 mmol/d2 becomes too hydrophilic and has a reduced affinity for autoantibodies and immune complexes, resulting in an extremely low adsorption capacity. Also,
A more prophylactic affinity for albumin arises, and albumin is also non-specifically adsorbed, which is undesirable.

Among the hydrophobic compounds, compounds having at least one aromatic ring give particularly favorable results. The term "aromatic ring" refers to a cyclic compound having aromatic properties, and any of them can be usefully used, but benzene-based aromatic rings such as benzene, naphthalene, and phenanthrene, pyridine, quinoline, acridine, isoquinoline, phenanthrene, etc. Nitrogen-containing 6-membered rings, indole, carbazole, isoindole, indolizine, porphyrin, nitrogen-containing 5-membered rings such as 2', 3'-pyrrolovirol, pyridazine, pyrimidine, sym-) lyazine, sym-tetrazine, Polyvalent nitrogen-containing 6-membered rings such as quinazoline, 1,5-naphthyridine, pteridine, phenazine, pyrazole, imidazole, 1
．． 2.4-triazole, 1.2.3-triazole,
Polyvalent nitrogen-containing five-membered rings such as tetrazole, penziminazole, imidazole, purine, norharman ring, perimidine ring, oxygen-containing aromatic rings such as benzofuran, isobenzofuran, dibendofuran, pendothiophene, chenothiophene, thiepin, etc. Sulfur aromatic ring, oxazole, isoxazole, 1.2.5-oxadiazole, oxygen-containing heteroaromatic ring such as benzoxazole, thiazole, isothiazole, 1.3.4-thiadiazole,
Hydrophobic low-molecular-weight organic compounds having at least one aromatic ring such as a sulfur-containing heteroaromatic ring such as benzothiazole and its derivative give preferable results. Among these, compounds containing an indole ring such as tryptamine give particularly favorable results.

This can be interpreted as a result of the hydrophobicity and molecular rigidity of the compound acting effectively in binding the autoantibody or immune complex to the compound.

In addition, as a result of intensive research in search of inexpensive hydrophobic compounds that can be used more safely and practically, the present inventors have discovered that hydrophobic amino acids and their derivatives are highly and specifically capable of producing autoantibodies and immune complexes. It was discovered that it adsorbs and removes the body.

Hydrophobic amino acids and their derivatives are defined by Tanford
, Nozaki (J, Am, Chem.

Soc, 184 4240 (1962),
J.

Biol, Chem, 246 221 1 (
1971) [Tanford, Nozaki (Journal of the American Chemical Society, Vol. 14.42)
40 (1962), Journal of Biological Chemistry 246.2211 (1971)]
Based on the hydrophobicity scale defined by
Amino acids and derivatives thereof having mo1 or more, and a compound having a solubility in physiological saline of 100 mmol/dJZ or less. Examples include lysine, valine, leucine, tyrosine, phenylalanine, isoleucine, tryptophan and derivatives thereof. Among these hydrophobic amino acids and their derivatives, tryptophan and its derivatives,
Phenylalanine and its derivatives give particularly good results. Furthermore, the amino acid can be used without any particular limitation on the 2,d conformation.

The hydrophobic compound of the present invention preferably has a molecular weight of 10,000 or less, more preferably 311,000 or less. This makes it easier to handle during immobilization and to store after immobilization compared to natural polymers such as Protein S (molecular weight 42,000). Furthermore, even when the substance is eluted from the hollow fiber-like fully porous material, hydrophobic compounds with molecules of 111,000 or less are safe and have negligible antigenicity to living organisms, and can be easily sterilized.

The polyanion referred to in the present invention has a weight average molecular weight of 60
0 or more, and refers to a polymer that has a functional group such as a sulfonic acid group, a carboxyl group, or a phosphoric acid group in its molecule that exhibits a negative charge in body fluids. The form of the polymer is preferably a chain polymer.

Further, the molecular weight is preferably from 600 to 107, more preferably from 1000 to 5X10', and desirably from 2000 to 106.

Examples of polyanions include vinyl-based synthetic polyanions such as polyacrylic acid, polymethacrylic acid, polyvinyl sulfonic acid, polyvinyl sulfate, polymaleic acid, polyfumaric acid, and derivatives thereof, and styrene-based synthetic anions such as polystyrene sulfonic acid and polystyrene phosphoric acid. Examples of polyanions include polyglutamic acid, polyaspartic acid, etc.; examples of nucleic acid polyanions include Pol U, polyA, etc.; examples of synthetic polyanions include polyphosphoric acid ester, polyα-methylstyrene sulfonic acid, Examples include styrene-methacrylic acid copolymer, and polysaccharide polyanions include heparin, dextran sulfate, chondroitin sulfate, alginic acid, pectin, hyaluronic acid, and derivatives thereof. The polyanion referred to in the present invention is not limited to the above-mentioned examples.

Since the adsorbed substances, low-density riboproteins and very low-density lipoproteins, are large molecules with a diameter of 200 to 80 OA, it is necessary to use a polyanion with the above-mentioned molecular weight as a ligand. Low molecular weight anions may not have sufficient adsorption capacity for low-density lipoproteins and very low-density riboproteins. The polyanion preferably has at least one functional group exhibiting a negative charge per molecular weight of 300, more preferably one functional group per molecular weight of 200, and one functional group per molecular weight of 50 to 150. is desirable. The molecular weight referred to herein also includes the molecular weight of functional groups exhibiting negative charges.

It is sufficient that the above-mentioned gant, which interacts with the adsorbed substance, is fixed substantially uniformly on the entire surface of the hollow fiber-like fully porous body, and there may be some uneven fixation. Further, even if there are some parts that are not fixed, it does not matter as long as it has almost no effect on the whole.

Further, more favorable results can be obtained by applying a treatment for inhibiting platelet adhesion and blood coagulation to the inner surface of the hollow fiber-like fully porous body in the adsorption device for whole blood processing of the present invention.

As a method for incorporating the hollow fiber fully porous body into a container, known methods such as hollow fiber artificial kidneys can be used, and cast molding methods, centrifugal molding methods, etc. can be used.

The adsorption device for whole blood processing of the present invention includes a blood inlet, a blood outlet, a blood circuit connecting the blood inlet and the blood outlet,
A whole blood processing adsorbent and a blood inlet installed between a blood processing inlet and a blood outlet so that a blood circuit communicates with the inner surface of a hollow fiber-like fully porous body in the whole blood processing adsorber. It can be used as an adsorption device for whole blood processing characterized by having a blood transport means installed between the adsorption device for whole blood processing.

In addition, a blood inlet, a blood outlet, a blood circuit connecting the blood inlet and the blood outlet, and a blood circuit installed between the blood treatment inlet and the blood outlet are installed inside the whole blood processing adsorption device. An adsorption device for whole blood processing that communicates with the inner surface of a hollow fiber-like fully porous body, and an adsorption device for whole blood processing that has an outer surface of the hollow fiber-like fully porous body within the whole blood processing adsorption device of the whole blood processing adsorption device. Whole blood processing characterized in that main parts include a plasma circuit connected to a blood circuit connecting a blood outlet and a blood outlet, a blood transport means installed in the blood circuit, and a plasma transport means installed in the plasma circuit. It can also be used as an adsorption device.

That is, the patient's blood is introduced into the inner surface of the hollow fiber-like all-porous material in the whole blood processing adsorption device, and is introduced into the pores from the inner surface of the hollow fiber-like all-porous material in the whole blood processing adsorption device. The transferred substance to be adsorbed interacts with the ligand fixed on the membrane, and the adsorbed plasma components flow from the outer surface of the hollow fiber-like all-porous body downstream of the adsorber to the inner surface of the hollow-fiber-like all-porous body. It is used as an adsorption device that is suitable for use in that it is mixed with the concentrated blood cell component fluid flowing through the hollow part of the body and then led out of the container. In addition, an opening is provided in the outer cylindrical container to take out the plasma components that have adsorbed and removed the adsorbed substances (malignant substances) that flowed from the inner surface of the hollow fiber-like fully porous body to the outer surface, and to discharge them from the blood outlet of the adsorber. It is used as an adsorption device for mixing with concentrated blood cell components.

The present invention will be described below with reference to the drawings.

FIG. 1 is a schematic diagram showing one example of the adsorption device for whole blood processing of the present invention, FIG. 2 is a schematic diagram showing another example, and FIG. 3 is a schematic diagram showing an example of the adsorption device for whole blood processing of the present invention. FIG. 2 is a schematic cross-sectional view showing one hollow fiber-like fully porous body.

In FIG. 1, blood is introduced from a blood inlet 1 and sent by a blood transport means 2 to an adsorption device 3 for whole blood processing. In the adsorption device 3 for whole blood processing, blood is sent to the inner surface of the hollow fiber-like all-porous material in the whole blood processing adsorption device, and plasma components smaller than the pore diameter flow out from the inner surface into the pores of the hollow fiber-like all-porous material. and is stored in the voids on the outer surface of the hollow fiber-like fully porous body and inside the outer cylinder,
Thereafter, the plasma flows into the inner surface of the hollow fiber fully porous body from the outer surface of the hollow fiber fully porous body downstream of the adsorber, and joins with the concentrated blood cell components that have flowed down the inner surface of the hollow fiber fully porous body.

In this process, the adsorbed substance (malignant substance) is adsorbed to the ligand fixed to the hollow fiber fully porous material of the adsorbent for whole blood processing, and the blood with the adsorbed substance adsorbed is led out from the blood outlet 5. . FIG. 3 schematically shows the hollow fiber fully porous body in the adsorption device for whole blood processing. A ligand 9 is immobilized throughout the pore 8, and while plasma passes through the pore 8, the adsorbed substance (malignant substance) interacts with the ligand 9, and the adsorbed substance is adsorbed.

FIG. 2 is a schematic cross-sectional view showing another example of the adsorption device for whole blood processing of the present invention, in which blood is introduced from the blood introduction port 1,
The blood is sent by the blood transport means 2 to the adsorption device 3 for whole blood processing.

In the adsorber 3 for whole blood processing, blood is sent to the inner surface of the hollow fiber fully porous material 4 of the adsorber for whole blood processing, and plasma components are sent from the inner surface through the membrane to the outer surface of the hollow fiber fully porous material of the adsorber for whole blood processing. It will be done.

In this process, the adsorbed substance (malignant substance) interacts with the ligand in the membrane and is adsorbed. The plasma from which adsorbed substances have been adsorbed and removed is sent in the direction of the blood outlet 5 by the plasma transport means 10, and is led out from the blood outlet 5 after being combined with the whole blood.

The whole blood processing adsorption device and adsorption device of the present invention have been described above, and the present invention will be explained in more detail below with reference to Examples.

(Example) (Example 1) High density polyethylene (density 0.968 g/cm', Ml
value 5.5, product name HIZEX 2208J), outer diameter 3
It was spun into hollow fibers using a circular double spinneret with a diameter of 5 mm and an inner diameter of 27 mm. Polymer extrusion was carried out at a rate of 11 log/min, a spinning winding speed of 200 m/min, and a spinneret temperature of 150°C. After annealing the obtained hollow fibers at 115°C for 2 hours, the rotation speed of the feed roll was adjusted, and the stretching section was 200 mm.
, cold-stretched to 1.33 times at room temperature, and further hot-stretched in three stages: first stage at 78°C, 3 times, second stage at 95°C, 1.28 times, third stage.
The step was carried out at a temperature of 98°C, a temperature of 1.14 times, and a drawing ratio such that the total amount of drawing was 480% with respect to the undrawn yarn.

0.9% by weight of polyethylene vinyl alcohol (Soarnol 2 manufactured by Nippon Gosei Kagaku) in a 70% ethanol aqueous solution
The obtained polyethylene hollow fibers were immersed in the solution of
After being left at 50°C for 5 minutes, it was taken out and dried at 55°C for 1.5 hours. The obtained polyethylene hollow fiber-like fully porous body has an inner diameter of 3
40μm, outer diameter 440μm5 film thickness 50μm, average pore diameter 0
．． It had a diameter of 3 μm and a surface area of 21 m 2 /g. Hollow fiber-like fully porous body 200 with a length of 25 cm manufactured in this way
0 bottles of acetone 500mj! , epichlorohydrin 39
It was immersed in a mixed solution of 0 mM, 40% by weight NaONaOH9O, and reacted at 30° C. for 5 hours while applying ultrasonic waves. Thereafter, it was washed with acetone and distilled water to obtain an epoxy-activated polyethylene hollow fiber-like fully porous body.

The epoxy-activated polyethylene hollow fiber-like fully porous body was immersed in 1000 ml of 0.1M sodium carbonate buffer (pH 9,8) containing 10.20 g of tryptophan.

The immobilization reaction was carried out at 50° C. for 24 hours while applying ultrasound. Thereafter, it was thoroughly washed with water to obtain an adsorbent for whole blood processing.

The amount of tryptophan immobilized as a ligand is 36
It was 0 μmof/g (dry weight). After drying the adsorbent for whole blood processing obtained as above, both ends were centrifugally molded and fixed with urethane adhesive in a polycarbonate container, and both ends were cut to form a nozzle, as shown in Figure 4. We have manufactured various adsorption devices for whole blood processing. The effective length of the hollow fiber-like fully porous body of the adsorber for whole blood processing is 255 mm, and L/D2=2
It was 206 mm-'.

Using this whole blood processing adsorption device, an adsorption device for whole blood processing shown in FIG. 2 was assembled.

Heparinized whole blood derived from a patient with chronic rheumatoid arthritis was introduced through the blood inlet 1, and was sent by the pump 2 to the whole blood processing absorber 3 at a rate of 50 ml/min. The plasma is filtered by the hollow fiber-like fully porous body 4 of the adsorbent for whole blood processing, and the plasma is sent toward the blood outlet by the pump 10, where it is combined with the blood rich in blood cell components drawn out from the adsorbent for whole blood processing 3. , taken out from the blood outlet 5. The flow rate of pump IO was designated as the flow rate of pump 2.

No blood coagulation or hemolysis was observed during circulation, and stable circulation was achieved.

Rheumatoid factor and immune complexes were measured in the blood (plasma) before treatment and in the plasma filtered with an absorber for whole blood treatment (after 30 minutes of circulation). The rheumatoid factor was measured by the passive sensitized hemagglutination test (RAHA test, manufactured by Fuji Organ Pharmaceutical Co., Ltd.), and the immune complex was measured by the Raji Ce11 method.

As a result, the rheumatoid factor was 1280 before treatment, while it was 320 after filtration, and the immune complex was 1280 before treatment.
0μg/m 11 and 28gg/m
It was down to J2.

In addition, when comparing the platelet concentration in whole blood before treatment and the platelet concentration in whole blood obtained from the blood outlet, it was 347,000 m3 before treatment, and 300,000 m3 after treatment. /
m m 3, which did not decrease much.

That is, when whole blood was processed, malignant substances (rheumatoid factor, immune complexes) could be selectively adsorbed and removed with little loss of platelets.

(Example 2) Using an epoxy-activated polyethylene hollow fiber-like fully porous body obtained in the same manner as in Example 1, it was reacted with a 30% by weight aqueous dextran sulfuric acid solution at pH=13.50°C for 24 hours.

After immobilizing the ligand, it was thoroughly washed with water to obtain an adsorption device for whole blood processing. Using the adsorption device for whole blood processing, an adsorption device for whole blood processing shown in FIG. 1 was assembled, and the following experiment was conducted.

Heparinized whole blood (hematocrit Ht = 35%) derived from a patient with familial hypercholesterolemia was introduced through the blood inlet 1, and was sent to the adsorption device 3 for whole blood processing by the pump 2 at 50 mff1/min. Ten minutes after the whole blood began to be fed, the spaces between the outside of the hollow fiber-like fully porous body and the inside of the outer cylindrical container were almost completely replaced with pale yellow plasma. Further retransmission continues, 3
Total cholesterol at the blood outlet after 0 minutes was measured by an enzymatic method. In the case of familial hypercholesterolemia patient blood,
Cholesterol is derived mostly from low-density lipoproteins.

As a result, the total cholesterol before treatment was 540mg
/dl, whereas after filtration it was 110mg
/dl was down.

In addition, the platelet concentration of whole blood before treatment and whole blood after treatment was 270,000/mm3. After treatment, it did not decrease much at 250,000/mm3.

That is, when whole blood was processed, malignant substances (cholesterol, low-density riboprotein) could be selectively adsorbed and removed with little loss of platelets.

(Examples 3 to 4, Comparative Example 1) High density polyethylene (density 0.968 g/cm3.Ml
value 5.5, trade name HIZEX 2208J) were spun into hollow fibers using various circular double spinners with different inner diameters.

Polymer extrusion rate 1 log/min, spinning speed 200-600
m/min, and the spinneret temperature was 150°C. After annealing the various hollow fibers obtained at 115°C for 2 hours,
The rotation speed of the feed roll was adjusted, and the stretching section was 200 mm, and cold stretching was carried out at room temperature by a factor of 1.33, followed by three stages of hot stretching.
The temperature was 78°C in the stage, 95°C in the second stage, and 98°C in the third stage so that the total amount of stretching was 480% of the undrawn yarn. The drawn hollow fibers were heat-set at 115° C. for 2 minutes to obtain a polyethylene hollow fiber-like fully porous body.

Polyvinyl alcohol coating, epoxy activation, and ligand immobilization were performed in the same manner as in Example 1 to obtain a whole blood adsorption device, which was incorporated into the apparatus shown in FIG. However, pump 1
The plasma circuit containing 0 was removed, and the amount of plasma discharged from the plasma outlet and the rheumatoid factor were measured. The results are summarized in Table 1.

As shown in Table 1, although the total surface area of the hollow fiber-like porous body in the adsorbers of Examples 3 to 4 and Comparative Example 1 is almost the same, the rheumatoid factor concentration is inversely proportional to L/D2, and the discharge Since the plasma volume is directly proportional to L/D 2, Examples 3 and 4 with high plasma separation efficiency and L/D 2≧2000 mm-' were very effective compared to the comparative example.

(Effects of the Invention) As described above, by using the whole blood processing adsorption device and adsorption device of the present invention, platelet adhesion and blood coagulation are unlikely to occur even when whole blood is directly poured into the adsorption device. It has become possible to adsorb and remove malignant substances (substances to be adsorbed) from the blood with simple operations using a simple blood circuit. Furthermore, since the priming volume can be reduced, the amount of blood taken out of the patient's body can be reduced, making it a safe treatment method. Furthermore, the adsorption selectivity can be improved by selecting the ligand and the pore size and pore distribution of the hollow fiber-like fully porous material, so that non-selective adsorption of substances useful to living organisms can be reduced. INDUSTRIAL APPLICABILITY The present invention is useful for adsorption of malignant substances in the blood and for treating diseases in which malignant substances remain in the blood.

Although the present invention is useful for processing whole blood, it goes without saying that it can also be used for plasma processing.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing an example of the adsorption device for whole blood processing of the present invention. FIG. 2 is a schematic diagram showing another example of the adsorption device for whole blood processing of the present invention. FIG. 3 is a schematic cross-sectional view showing the structure of the hollow fiber-like fully porous body in the adsorption device for whole blood processing of the present invention. FIG. 4 is a schematic diagram showing one example of the adsorption device for whole blood processing of the present invention. 1. Blood introduction port 2, blood transport means (pump) 3. Whole blood processing adsorption device 4, hollow fiber-like fully porous body in the whole blood processing adsorption device 5, blood outlet port 6, hollow fiber-like fully porous body inner surface 7 , hollow fiber-like fully porous body outer surface 8, pore portion 9, ligand 21 Figure 2 Plasma transport means (pump) Blood inlet side nozzle Blood outlet side nozzle Plasma outlet nozzle

Claims (11)

[Claims] (1) A large number of hollow fiber-like fully porous bodies are bundled almost in parallel,
An adsorbent for whole blood processing, which is adhesively fixed at both ends with a hollow part open, and further equipped with a blood inlet/outlet fixed liquid-tightly at each end, and which is made of a fully porous body. An adsorbent for whole blood processing in which a ligand that interacts with the adsorbed substance is substantially uniformly immobilized on the entire surface. (2) The adsorption device for whole blood processing according to claim 1, wherein the ligand is a substance with low antigenicity. (3) The adsorption device for whole blood processing according to claim 1 or 2, wherein the ligand is fixed to the hollow fiber-like fully porous body by a covalent bond. (4) The adsorption device for whole blood processing according to any one of claims 1 to 3, wherein the ligand is a hydrophobic compound. (5) The adsorption device for whole blood processing according to any one of claims 1 to 3, wherein the ligand is a polyanion. (6) The adsorption device for whole blood processing according to any one of claims 1 to 5, wherein the hollow fiber-like fully porous body has an average pore diameter of 0.005 μm or more and 3 μm or less. (7) The adsorption device for whole blood processing according to any one of claims 1 to 5, wherein the hollow fiber-like fully porous body has an average pore diameter of 0.01 μm or more and 2 μm or less. (8) Any one of claims 1 to 7, wherein the relational expression L/D^2≧2000mm^-^1 is established between the average effective length (L) and the average inner diameter (D) of the hollow fiber-like fully porous body. Adsorption device for whole blood processing described in . (9) The adsorption device for whole blood processing according to any one of claims 1 to 8, wherein the outer cylindrical container has at least one opening. (10) A blood inlet, a blood outlet, a blood circuit connecting the blood inlet and the blood outlet, a blood circuit installed between the blood inlet and the blood outlet, and the blood circuit connected to an adsorbent for whole blood processing. The whole blood processing adsorption device is configured to communicate with the inner surface of the hollow fiber fully porous body inside the blood treatment device, and a blood transport means is installed between the blood inlet and the whole blood processing adsorption device. Adsorption device for whole blood processing. (11) A blood inlet, a blood outlet, a blood circuit connecting the blood inlet and the blood outlet, a blood circuit installed between the blood inlet and the blood outlet, and the blood circuit connected to an adsorbent for whole blood processing. A whole blood processing adsorption device that communicates with the inner surface of the hollow fiber fully porous body inside the whole blood processing adsorption device; 1. An adsorption device for whole blood processing, comprising: a plasma circuit connected to a blood circuit connecting a blood circuit; a blood transport means installed in the blood circuit; and a plasma transport means installed in the plasma circuit.