JPS639450A - Body fluid component separating material and body fluid component separator equipped therewith - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (1) Background of the Invention (Technical Field) The present invention relates to a body fluid component separation material that adsorbs and separates specific components from body fluids such as blood, and a body fluid component separation device using the same.

(Prior Art and its Problems) In recent years, plasma exchange therapy has been used as a treatment for diseases in which specific components in body fluids cause serious symptoms. This therapy is particularly effective in cases where dialysis of the pathogenic substance is difficult, myasthenia gravis, rheumatoid arthritis.

It is applied to autoimmune diseases such as lupus erythematosus, immune-related diseases such as glomerulonephritis, bronchial asthma, and polyneuritis, rejection reactions associated with organ transplants, liver failure, hypertension, cancer diseases, and others. . Among these, autoimmune diseases refer to diseases that occur due to humoral or cellular immune responses against antigens possessed by one's own cells and tissues, resulting in the formation of antibodies against oneself.

However, since plasma exchange therapy indiscriminately removes all plasma components, there is a problem in that useful components of plasma are also lost in addition to pathogenic substances. In addition, many problems have been pointed out, such as a shortage of plasma and plasma preparations as replacement fluids, and complications such as serum hepatitis and allergies. Purification therapy is recommended. In this case, it is necessary to sufficiently and selectively remove pathogenic substances from one's own blood to achieve the therapeutic objective and prevent hypoproteinemia. Conventionally, the following adsorbents have been known as purification materials for this purpose. It is being

・Porous resin (for example, Amberlite XAD-74 manufactured by RQhm & Haas, etc.) ・Ion exchanger (for example, carboxymethyl cellulose,
diethylaminoethyl agarose, etc.), inorganic porous materials (e.g. porous glass, ceramics, etc.), affinity adsorbents. However, porous resins and ion exchangers have low adsorption capacity;
Moreover, because the adsorption specificity is low, it also adsorbs albumin in body fluids. As a result, when this is applied as a blood purification material in the above-mentioned therapy, not only the therapeutic effect is insufficient, but also there are safety problems such as osmotic pressure abnormality, which is characteristic of hypoproteinemia, and edema.

In addition, although inorganic porous materials have relatively good adsorption capacity and adsorption properties, they are still insufficient for practical use.

In contrast, affinity adsorbents have excellent adsorption capacity and adsorption specificity, and are considered promising as blood purification materials. This type of adsorbent is classified into biological affinity adsorbent and physicochemical affinity adsorbent based on the difference in their adsorption properties, and their general characteristics and problems are explained as follows.

First, biological affinity adsorbents bind and adsorb pathogenic substances in the blood through biological interactions such as antigen-antibody binding, complement binding, and Fc binding, and have extremely high adsorption specificity. . However, most of them are DNA, anti-LDL
Since physiologically active polymers such as antibodies and protein A are used as ligands (substances that have an affinity for the target pathogenic substance), there is a problem that raw materials are expensive and difficult to secure. Furthermore, due to the poor stability of the ligand, it is difficult to maintain its activity during the manufacture, sterilization, storage, transportation, and storage of adsorbents and columns packed with them. In addition, since the ligand is essentially a physiologically active substance, it must be taken into account that when it comes into contact with blood, it not only exhibits the desired affinity but also exhibits its original physiological action and causes side effects. It won't happen. Moreover, since the ligand is a foreign protein, if it is released and eluted from the adsorbent carrier, side effects will occur due to its antigenicity.

On the other hand, a physicochemical affinity adsorbent binds to a pathogenic substance in blood through physical or chemical interactions such as electrostatic bonding or hydrophobic bonding, and removes it by adsorption and separation. As the ligand in this case, synthetic compounds such as polylysine, methylated albumin, tryptophan, and phenylalanine can be used. Therefore, it has the advantage of being able to be manufactured in large quantities, being relatively inexpensive, and having stable activity. In addition, since many of them are generally excellent in safety when they come into contact with blood, they are most promising as purifying materials for use in extracorporeal circulation body fluid purification therapy for treating the above-mentioned diseases. Furthermore, due to its action and price, it is useful not only as a blood purification material for the above-mentioned therapies, but also for the separation and purification of specific components of body fluids such as immunoglobulins, immune complexes, and immune-related soluble factors, or for the testing of these components. Expected uses. Conventionally known adsorbents belonging to this category are as follows.

■ Porous material having carboxyl group or sulfonic acid group on the surface (JP-A No. 56-147710, No. 57-58038
, 57-75141. 57-170283, 57-197294 > ■Hydrophilic carrier to which hydrophobic amino acids are bound (JP-A-57-122875. 58-
15924. 58-165859, 58-165
881 > ■ Hydrophilic carrier to which modified immunoglobulin (IgG) is bound (Japanese Patent Application Laid-Open No. 57-77624. No. 57-77 [i
25. Same ■ Porous body to which methylated albumin is bound (JP-A No. 55-120875. No. 55-125872)
)■Hydrophilic carrier to which sugar is bound (Japanese Patent Application Laid-Open No. 57-13
4164, 58-133257) ■ Porous body to which purine base, pyrimidine base, or sugar phosphoric acid is bonded (Japanese Patent Application Laid-Open No. 57-192580).

5g-61752, 58-98142) However, these conventional physicochemical affinity adsorbents are still not sufficient for the treatment of autoimmune diseases etc. by extracorporeal circulation body fluid purification therapy. There is a need for a purifying material that can easily remove pathogenic substances and has less negative impact on body fluids.

■ Purpose of the Invention The present invention was made in view of the above circumstances, and its purpose is to adsorb and separate specific components contained in body fluids such as blood, lymph, and ascites with high efficiency and high specificity, and to have stable activity. It is an object of the present invention to provide a body fluid component separation material that is easy to sterilize and store, and a body fluid component separation device using the same.

The body fluid component separating material, which is the first object of the present invention, is an acrylic polymer obtained by polymerizing a monomer mixture containing an unsaturated radically polymerizable monomer having an oxirane group and a crosslinking monomer. is dry weight 1
It is obtained by binding a heterocyclic compound to oxirane-acrylic beads in an amount of 0.1 to 10 mmol per g. At that time, atoms other than the heteroatoms of the heterocyclic compound are covalently bonded to one carbon constituting the oxirane group exposed on the surface of the oxirane-acrylic beads, and the oxirane group is ring-opened, and the oxygen atom of the oxirane group is opened. is covalently bonded to the other carbon atom as a hydroxyl group.The second object of the present invention is a body fluid component separation device in which the above body fluid is placed in a container having a body fluid inlet and a body fluid outlet that communicate with each other. Obtained by filling with component separation material. Add elements such as body fluid circulation pumps as necessary.

The present invention can be particularly suitably used in extracorporeal circulation body fluid purification therapy aimed at treating autoimmune diseases and the like.

■Detailed Description of the Invention The body fluid component separation material of the present invention belongs to the above-mentioned physicochemical affinity adsorbent. The targeted substance to be adsorbed is protein in body fluids, and a more detailed explanation is as follows. That is, normal immunoglobulin (A, D, E,
G, M), various autoantibodies, complexes between immunoglobulins or immunoglobulins and other substances (especially antibodies),
Complement, fibrinogen, soluble fibrin, low-density lipoprotein, cancer cell growth factors, immune-related soluble factors (
IRA; Imtnuno-regulatory
a-globuljn) T cell growth factor (TC
GF: T-cell growth1'acto
r), G S F (Growth 5olable
ractor), SSF (Sppresso
r 5olable ractor), T RF(T
-cell replacement factor) %
K HF (Killercell helper
actor), LSF (Lymphocyt
e-stiLIlulating f'actor)
, CI F (Competence-induci
ng f'actor), T DF (Thymo
cyto-dll'['erentiation ra
ctor), interleukin I, etc. Among these, examples of autoantibodies include cell surface antibodies, gastric parietal cell microsomal antibodies, organ-specific antibodies (group 1) such as adrenal cortex cytoplasmic antibodies, antibodies against acetylcholine receptors, red blood cell antibodies, smooth muscle antibodies, insulin receptor antibodies, etc. Intermediate type (Group Ⅰ), non-organ specific type (Group ①) such as DNA antibodies, coagulation factor antibodies, anti-nuclear antibodies, and anti-1gG antibodies. All of these pathogenic protein substances to be separated in the present invention are contained in the globulin fraction of the body fluid protein fractions.

The body fluid component separation material of the present invention uses oxirane-acrylic beads as an insoluble carrier, and a heterocyclic compound is bonded to the surface of the insoluble carrier. Therefore, the insoluble carrier, the heterocyclic compound, the bonding method thereof, etc. will be explained respectively.

The oxirane-acrylic beads used as insoluble carriers are obtained by copolymerization of glycidyl methacrylate or allyl glycidyl ether, methacrylamide, methylene-bis-methacrylamide. Its manufacturing method is disclosed by R6hm Pharma (UK Patent No. 1.329.062, German Patent Publication No. 2,237.:He, German Patent No. 2,26
3.2H). Among these oxirane-acrylic beads,
Particularly preferably used as an insoluble carrier in the present invention, the proportion of crosslinking monomer is 5% by weight or more, and the proportion of radically polymerizable monomer having an oxirane group is 5 to 8%.
It was obtained from a 0% by weight heptamer mixture. Examples of such particularly preferred oxirane-acrylic beads include "Eupergit C" from Rohm Fufurma.
Examples include products offered under the product name ``. This is imported and sold domestically by Higuchi Shokai.

The shape of the oxirane-acrylic beads is spherical so that they do not damage cells and are difficult to break or chip. The average particle size is set to 0, taking into account the flow rate and circulation pressure of body fluids.
．． (in the range of 15u to 5M, preferably 0.1m to 0.2
A range of u is used.

To determine the average particle size, after classifying each paper using a sieve specified in JIS-Z-8801, the intermediate value between the upper limit particle size and the lower limit particle size is taken as the particle size of the relevant class, and the weight average of these is determined. The overall average particle size is calculated as follows.

The oxirane-acrylic beads are preferably porous bodies with a large surface area in order to adsorb and remove pathogenic substances with high efficiency. Furthermore, if the average pore diameter of the porous body is too small, the amount of the pathogenic substance adsorbed will be small, and if it is too large, the strength and surface area of the porous body will decrease, so either case is not practical.

In this sense, the average pore diameter is preferably in the range of 100 to 5,000 pores, more preferably in the range of 200 to 3,000 pores. The average pore diameter is preferably measured using a mercury intrusion porosimeter. In this method, mercury is injected into a porous body, and the amount of pores is determined from the amount of mercury that has entered, and the pore diameter is determined from the pressure required for injecting.

Oxirane-acrylic beads have oxirane groups on their surface. As described below, this oxirane group has the ability to immobilize a heterocyclic compound on the bead surface. The content of oxirane groups in oxirane-acrylic beads was determined by the thiosulfate method (R, Axen, a
s quoted by L-9undberg an
d J-Porath in J, Chromatgr
aphy, 90 (1974).

89) 800-1000μff1ol
/g-dry range is desirable.

Next, the apocyclic compound bonded to the oxirane-acrylic beads will be explained. What is a heterocyclic compound?
It is a compound containing a heteroatom such as nitrogen, oxygen, or sulfur in addition to a carbon atom in the ring, and the heterocycle is often a 5- or 6-membered ring. Examples are as follows. Namely, furan and its derivatives, thiophene and its derivatives and dithiolane derivatives, pyrrole and its derivatives, azoles, pyridine and its derivatives, quinoline and its related compounds, acridine and its related compounds, pyrimidine and its related compounds, pyrazine and its related compounds. compounds, biran and pyrone and related compounds, phenoxazine, phenothiazine, pterin and alloxazine compounds, purine bases, nucleic acids, hemin, chlorophyll, vitamin B12, phthalocyanine, alkaloids, fused ring heterocyclic compounds, etc. Among these many heterocyclic compounds, sulfonamides (limited to those containing heterocycles) known as sulfa drugs, derivatives thereof, and luminol give favorable results. Furthermore, among the sulfa drugs, sulfathiazole gives particularly favorable results.

The above heterocyclic compound is bonded to the oxirane group present on the surface of the oxirane-acrylic beads. The bond formation position between the two is between an atom other than the heteroatom of the heterocyclic compound and one carbon atom constituting the oxirane group, and the form thereof is a covalent bond. Formation of this bond involves ring opening of oxirane, and the oxygen atom forming the oxirane group bonds only with the other carbon atom (this oxygen atom becomes a hydroxyl group and bonds).

FIG. 1 shows the surface of "Oibergit C" to which sulfathiazole was bound as described above. The part surrounded by the broken line in the figure shows the ring-opened oxirane group, and in this case, the aniline nitrogen of sulfathiazole is bonded to the oxirane carbon as shown in the figure. The above bond-forming reactions involving ring-opening of oxirane groups are relatively easy. In particular, when the heterocyclic compound contains a hydroxyl group, an amino group, a thiol group, or a carbonyl group, it is possible to react in a wide pH range, and bonds can be formed between these nitrogen or oxygen atoms and the oxirane carbon atom. can be caused. Moreover, the reaction in this case takes place at room temperature (21-2
The reaction is completed in 16 to 72 hours at 5 DEG C.), but the reaction rate can be further accelerated by using a catalyst such as boron trifluoride etherate, sodium phenol, triethylamine, or pyridine.

Next, the body fluid component separating material of the present invention obtained as described above will be explained. One of its characteristics is that the oxirane-acrylic beads used as an insoluble carrier and the heterocyclic compound used as a ligand are firmly bonded via a covalent bond as described above. In addition to covalent bonding, other methods for immobilizing a ligand on the surface of an insoluble carrier include ionic bonding, physical adsorption, embedding, and insolubilization by precipitation on the carrier surface. The ligand is easily detached from body fluids and lacks stability. For this reason, when used, for example, in extracorporeal circulation body fluid purification therapy, serious problems arise such as the ligand getting mixed into the blood and causing side effects. On the other hand, in the body fluid component separating material of the present invention, such a problem does not occur because the ligand is firmly bound to the insoluble carrier and is stable as described above.

The most significant feature of the body fluid component separation material according to the present invention is that it has a highly efficient and highly specific adsorption capacity for the substances to be separated, as shown in the results of the examples described below. At the point. This characteristic was obtained not only by the contribution of the heterocyclic compound used as the ligand but also by the combination of the contribution by the oxirane-acrylic beads used as the carrier.

In general, adsorbents composed only of hydrophobic compounds, that is, adsorbents with strong hydrophobic binding, contain fractions of albumin in body fluids, etc.
Since many useful proteins other than those targeted for removal adhere, it is not suitable for selective removal of pathogenic substances. On the other hand, adsorbents made of hydrophilic compounds with strong hydrogen bonds or compounds with many charged groups with strong electrostatic bonds cannot adsorb pathogenic substances because the amount of protein attached is extremely low. Therefore, in order to separate pathogenic substances in body fluids, an adsorbent that has a suitable combination of various interaction forces is suitable. If the body fluid component separation material of the present invention is examined from this point of view, it will be as follows.

First, the heteroatoms of the heterocyclic compound (the nitrogen atom and sulfur atom of the thiazole ring in the example shown in Figure 1) have a lone pair of electrons in the outermost orbital, which acts as a proton acceptor and acts as a dissociative group. Fewer heterocycles exhibit hydrophobicity. Among the heterocyclic compounds, the sulfonamide moiety of sulfa drugs and the carbonyl group and imino group of luminol have hydrogen bonding properties. On the other hand, acrylic beads bonded with a heterocyclic compound have a methyl group exhibiting hydrophobicity and an acid amide group exhibiting hydrogen bonding properties on the surface of the polymeric carbon chain. Furthermore, the hydroxyl group formed by ring opening of the oxirane group exhibits hydrophilicity. Due to these elements, the separation material of the present invention generates a combination of hydrophobic bonds, electrostatic bonds, and hydrogen bonds with the amino acid residues of the pathogenic substance, and the heterocyclic compound moiety interacts with the amino acid residue of the pathogenic substance. It is interpreted that favorable results were obtained because it fits into the intramolecular gap appropriately.

Next, the body fluid component separation device of the present invention will be explained.

As described above, the separation device of the present invention has the body fluid component separating material filled and held in a container having a body fluid inlet and an outlet. As the material for the container, glass, stainless steel, polyethylene, polypropylene, polycarbonate, polystyrene, polymethyl methacrylate, etc. can be used, but polypropylene, polycarbonate, etc., which can be sterilized in an autoclave and are easy to handle, are particularly preferred.

Moreover, it is preferable that a filter is provided between the entrance and exit part of the container body and the separation material layer, which has a mesh that allows body fluid to pass through but does not allow the separation material to pass through. The material of the filter is
Any material that is physiologically inert and has high strength may be used, but those made of polyester or polyamide are particularly preferably used.

FIG. 2 is a sectional view showing an embodiment of the body fluid component separation device according to the present invention. The body fluid is introduced through the inlet 4 and adsorbed by the body fluid component separating material 2, and then led out through the outlet 5. The separation material is retained within the column by filters 3°3'.

When applying the device of the present invention to extracorporeal circulation body fluid purification therapy, there are two methods. The first is a method in which blood taken from the body is separated into plasma components and blood cell components, only the plasma component is purified using the separation device, and then returned to the body together with the blood cell components. In this case, a centrifuge or a model or hollow fiber plasma separator is used for blood cell/plasma separation. The second method is to purify blood taken from the body by passing it directly through the device.

Of these, an example applied to the former method is shown in FIG.

In this case, blood is introduced from the blood inlet 6 and pump 7
The blood is supplied to the plasma separator 8 through the plasma separation device 8, where it is separated into blood cells and plasma. The separated plasma is supplied to the body fluid component separation device 1 according to the present invention through a pump 7', subjected to an adsorption treatment, mixed with blood cells in a plasma/blood cell mixing device 9, and then led out from a blood outlet 10. Note that the method for circulating body fluids may be carried out continuously or intermittently depending on clinical needs and equipment conditions.

Hereinafter, more detailed explanation will be given according to examples.

Example 1 First, carbonate buffer (pH 1
0) and dimethylformamide (volume ratio 2:3)
A sulf-7 thiazole solution was dissolved in 100 m/ml at a concentration of 0.1 mol/min. Oxirane-acrylic beads (“Eupergit C” manufactured by Rijhm Pharma) were added to the solution; the ratio of crosslinking monomer was 3.
0% by weight) at 0.1 to 0.2 g/ml! After degassing, tri-n-butylamine and pyridine t,om were added as catalysts. This was heated in a water bath at 80° C. for 1 hour, and then stirred overnight at room temperature using a blood mixer (Model BM-1ot, manufactured by Kayagaki Medical Science Co., Ltd.). Then, in order to remove unreacted oxirane groups, an ethanolamine solution with a concentration of L mol/no (pH 8) was added.
oom was added and stirred overnight.

Thereafter, it was sequentially washed with distilled water, an acetate buffer solution containing 0.5 mol of sodium chloride at a concentration of 0.02 mo+/min (pH 10), and a carbonate buffer solution at a concentration of 0.2 mol/min (pH to). In the thus obtained adsorbent beads, it is presumed that the aniline nitrogen of sulfathiazole was bonded to the oxirane group of "Eupergit C" by ring-opening, as shown in FIG.

3g of the adsorbent beads obtained above were placed in a glass test tube (
It was weighed into a "Larbo" manufactured by Terumo Corporation and subjected to the following adsorption experiment.

In the adsorption experiment, first, a test tube containing the above-mentioned adsorbent was charged with a concentration of 8 ml/lol (p
3 vol of phosphate buffer solution (PBS) of H7,2) was added and degassed using an aspirator (rA-2SJ manufactured by Tokyo Rikakiki). Next, use heparin 61U/mj as an anticoagulant! and ACD-A liquid 50μi/d! The adsorption treatment was carried out by adding bovine plasma 3a2 to which was added and incubating for 90 minutes in a hot air circulation constant temperature bath at 37° C. while stirring using a blood mixer.

Thereafter, the adsorption amounts of albumin (Alb), globulin (Glob), and immunoglobulin G (IgG) were measured by the following method.

That is, PBS was placed in a minicolumn prepared using a disposable syringe manufactured by Terumo Corporation with a capacity of 15 g.
After transferring the contents of the test tube using IrIli, PB
The column was washed with S5M and the effluent was collected. After measuring the volume of the effluent, the amount of Alb and total protein (Prot) contained therein were measured by the bromcresol green (BCG) method and the biuret method, respectively. Also, Glob, fm is prot, ffi and A
It was determined as the difference between Ib and the amount. That is, for convenience, fibrinogen was also included in G job in the calculation. Separately, the same operation as above was performed without using an adsorbent, and the amount of Alb, Gl obtained for the effluent in that case was
The amount of adsorption was calculated by subtracting the amount of ob from each of the above values, and each adsorption rate was calculated by dividing the above values by these values.

Further, the amount of IgG in the effluent was measured by single radial immunodiffusion (SRID), and the adsorption amount and adsorption rate of IgG were determined in the same manner as above.

The results of the above adsorption experiment are shown in Table 1.

Example 2 Instead of the sulfathiazole solution used in Example 1, a concentration of 0. An adsorbent was prepared in exactly the same manner as in Example 1 except for using a luminol solution of la+mol/12.

An adsorption experiment similar to that in Example 1 was conducted using the obtained adsorbent. The results are shown in Table 1.

Example 3 Instead of "Oibergit C" used in Example 1 (the proportion of the crosslinking monomer was 30% by weight), a crosslinking monomer (
N,N-methylene-bis-acrylamide) ratio is 5
Oxirane-acrylic beads polymerized from a monomer mixture of 1.5% by weight were used.

An adsorbent was prepared in the same manner as in Example 1 except for this.

Table 1 shows the results of an adsorption experiment similar to that in Example 1 using 1 g of the obtained adsorbent.

Example 4 The same procedure as in Example 3 was carried out except that luminol was used instead of sulfathiazole. Table 1 shows the results of the same adsorption test as in Example 1 using the obtained adsorbent.

Comparative Example 1 An adsorbent was prepared in the same manner as in Example 1 except that a phenylalanine solution with a concentration of 0.1 mrIIol/f' was used instead of the sulfathiazole solution used in Example 1.

An adsorption experiment similar to that in Example 1 was conducted using the obtained adsorbent. The results are shown in Table 1.

Comparative Examples 2 to 4 In these comparative examples, N-hydroxysuccinimide active ester-agarose beads (manufactured by Bjo-Rad Co., Ltd.) were used instead of the oxirane-acrylic beads used in Example 1.
Af'f'1-Ge1-10 J) was used.

In addition, in Comparative Example 2, as in Example 1, the concentration was 0.
．． An adsorbent was prepared in the same manner as in Example 1 except for using a sulf7thiazole solution of 1111[+101/i.

In Comparative Example 3, an adsorbent was prepared in exactly the same manner as in Example 1, except that a luminol solution with a concentration of 0.1 ol/) was used instead of the sulfathiazole solution used in Example 1.

In Comparative Example 4, an adsorbent was prepared in the same manner as in Example 1 except that a phenylalanine solution with a concentration of Q and jmmol/min was used instead of the sulfathiazole solution used in Example 1.

Table 1 shows the results of an adsorption experiment similar to that in Example 1 using each of the adsorbents obtained in Comparative Examples 2 to 4 above.

Comparative Examples 5 to 8 In these comparative examples, oxirane-polystyrene beads ("EX-438"'J manufactured by Mitsubishi Kasei Corporation) were used instead of the oxirane-acrylic beads used in Example 1.

As the heterocyclic compound, sulfathiazole was used in Comparative Example 5, sulfamethizole was used in Comparative Example 6, sulfitumezole was used in Comparative Example 7, and luminol was used in Comparative Example 8.

Other than that, the same procedure as in Example 1 was carried out. Table 1 shows the results of adsorption experiments on the obtained adsorbent.

Comparative Example 9 Polyacrylamide beads produced by copolymerization of acrylamide and N,N'-methylene-bis-acrylamide (r Blo-Ge1 P manufactured by Bio-Rad)
-300j; Particle size when swollen: 100-200 mesh, molecular weight cut-off range: 60,000-400,000, 30m1/g-dry)
was used as an insoluble carrier. The amide group of the side chain of the polyacrylamide beads was converted into a carboxyl group by deamination with a carbonate, and then the following heterocyclic compound was bonded to this carboxyl group by dehydration condensation. At that time, water-soluble carbodiimide l-cyclohexyl-3-(2-morpholinoethyl)carbodiimide I)-
Toluene sulfonate was used as the dehydration condensation agent.

Sulfathiazole (Comparative Example 9) Luminol (Comparative Example 10) Phenylalanine (Comparative Example 11) The same adsorption experiments as in Example 1 were conducted for each of the adsorbents obtained above, and the results shown in Table 1 were obtained. Ta.

■1 Specific Effects of the Invention As is clear from the adsorption experiment results in the above Examples and Comparative Examples, the body fluid component separation material of the present invention is capable of absorbing proteins such as immunoglobulins, immune complexes, and immune-related soluble factors, which are pathogenic substances. can be adsorbed and removed efficiently and with high selectivity. Furthermore, since the ligand is a low-molecular synthetic organic compound, sterilization can be performed easily and reliably. Furthermore, its constituent components, oxirane-acrylic beads and heterocyclic compounds, have low toxicity and are highly safe. That is, LDSo of oxirane-acrylic beads
The value is greater than 15 g/kg for oral administration in rats and the LDS of sulfazole among heterocyclic compounds.
o value is 990 B/kg intravenously in mice.

Due to these characteristics, the body fluid component separation material of the present invention is extremely suitable for adsorbing and removing pathogenic substances in body fluids and purifying body fluids, and is suitable for the treatment of autoimmune diseases, immune-related diseases, etc. by extracorporeal circulation body fluid purification therapy. effective.

Furthermore, it can be effectively used not only for the above-mentioned therapeutic purposes, but also for the separation and purification of proteins such as immunoglobulins, immune complexes, and immune-related soluble factors, or for the testing of these substances.

On the other hand, since the body fluid component separation device of the present invention has a simple structure, it can be used to easily separate and purify pathogenic substances using the body fluid component separation material, or to treat various diseases by purifying body fluids. Can be done.

[Brief explanation of drawings]

FIG. 1 is an explanatory diagram showing a state in which sulfathiazole is bonded to the surface of oxirane-acrylic beads, FIG. 2 is a cross-sectional view showing an embodiment of the body fluid component separation device according to the present invention, and FIG. 1 is a flowchart showing an example of extracorporeal circulation body fluid purification therapy using . 1... Body fluid component separation device, 2... Body fluid component separation material,
3.3'...Filter, 4...Body fluid inlet, 5.
...Body fluid outlet, 6...Blood inlet, 7,7'...
Pump, 8... Plasma separation device, 9... Plasma/blood cell mixing device, 10... Blood outlet. Applicant's agent Patent attorney Takehiko Suzue H Middle 0=S=O Summary 1

Claims (4)

[Claims] (1) Among the acrylic polymers obtained by polymerizing a monomer mixture containing an unsaturated radically polymerizable monomer having an oxirane group and a crosslinking monomer, the oxirane group content is 0.1 to 10 mmol per 1 g of dry weight. A body fluid component separation material in which a heterocyclic compound is bonded to an oxirane-acrylic bead, wherein atoms other than the heteroatom of the heterocyclic compound are one of the carbon atoms constituting the oxirane group exposed on the surface of the oxirane-acrylic bead. A body fluid component separating material characterized in that the oxirane group is ring-opened and its oxygen atom is bonded to the other carbon atom as a hydroxyl group. (2) The content of the unsaturated radically polymerizable monomer having an oxirane group is 5 to 80% by weight, and the content of the crosslinkable monomer is 5% by weight or more.
) Body fluid component separation material described in section 2. (3) The body fluid component according to claim (1) or (2), wherein the heterocyclic compound is selected from the group consisting of sulfa drugs or derivatives thereof, and luminol. Separation material. (4) Among the acrylic polymers obtained by polymerizing a monomer mixture containing an unsaturated radically polymerizable monomer having an oxirane group and a crosslinking monomer, the oxirane group content is 0.1 to 10 mmol per 1 g of dry weight. A body fluid component separation material in which a heterocyclic compound is bonded to an oxirane-acrylic bead, wherein atoms other than the heteroatom of the heterocyclic compound are one of the carbon atoms constituting the oxirane group exposed on the surface of the oxirane-acrylic bead. The body fluid component separating material, in which the oxirane group is ring-opened and its oxygen atom is bonded to the other carbon atom as a hydroxyl group, is housed in a container having a liquid inlet and a liquid outlet. A body fluid component separation device featuring: