JPS63315145A - Adsorbing material and device for removing bilirubin - Google Patents

Abstract

PURPOSE:To constitute an adsorbing material for selectively removing bilirubin from human blood, by fixing an org. synthetic substance having the compatibility with bilirubin to the surface of a porous body composed of a divinyl benzene/ glycidyl methacrylate copolymer. CONSTITUTION:An org. synthetic substance having the compatibility with bilirubin is fixed to the surface of a porous body composed of divinyl benzene/ glycidyl methacrylate copolymer. The monomer compositional ratio of divinyl benzene and glycidyl methacrylate in said copolymer is set to 95:5-85:15 on a wt. basis. The org. synthetic substance having the compatibility with bilirubin is set to a substance selected from a group consisting of a compound having two or more cationic group per 1mol., terpenoid and an anionic surfactant. By this method, a bilirubin removing adsorbing material capable of selectively removing bilirubin from human blood and having high safety can be constituted.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to an adsorbent and an adsorption device for removing bilirubin. More specifically, the present invention relates to an adsorbent and adsorption device for removing pyrirubin that selectively adsorbs and removes bilirubin from human blood.

(Prior Art) Hyperlirubin syndrome (hVperbilirubin syndrome), in which an abnormally large amount of bilirubin or bilirubin is present in blood, is caused by drug-induced, alcohol-induced, Lyssl-induced liver failure or blood type incompatibility in newborns.
rubinemia), which clinically results in jaundice. During the neonatal period, the serum bilirubin level is approximately 5°Qmg/
Although jaundice does not become noticeable unless it exceeds dΩ, in older children and adults, 2. Occurs from On+g/d Ω.

Bilirubin binds to cells and middenture membranes,
Causes cell death in various tissues. This can lead to neurological disorders, cerebral palsy, hearing loss, stroke, and in the worst cases, death.

By the way, the pathophysiology of liver failure has not yet been completely elucidated, but among the various functions of the liver that have declined, harmful substances such as ammonia, free fatty acids, and bilirubin are released into the blood due to impaired metabolism and detoxification and excretion functions. It has been revealed that these harmful substances accumulate in the body, and when these harmful substances increase and become severe, they induce liver disease. The so-called coma factor that causes such hepatic coma has not yet been elucidated, or it may be necessary to eliminate by some means the harmful substances in the blood that increase during liver failure. It is considered to be one of the auxiliary measures for coma treatment.

Up until now, auxiliary methods for the treatment of severe liver failure and hepatic coma have included direct perfusion methods such as exchange transfusion and plasma exchange, and indirect methods that adsorb and remove harmful substances from the blood using adsorbents such as activated carbon. Perfusion methods have been attempted, and light irradiation and exchange transfusion are often used to treat yellow scars in children.

Indirect perfusion is a higher level treatment that does not use precious blood or plasma and is used to remove bilirubin.
Adsorbent columns using activated carbon (Ccho R3-1, manufactured by Sumitomo Bakelite, etc.) and Amberlite X A D -4f Amb, which is a styrene-divinylbenzene copolymer.
erl ite XAD-4 (Roam Ant
Adsorbent column (XR-004, made by Haas)
EXTRA” Poreal Co. [EXtraCOpOrea+
J) is commercially available, and styrene-divinylbenzene copolymer AR-1 is commercially available.Amazaki Z et al.
,, Trans, Am, Soc, Inter
Organs, 25:234, 1981>
, BR601 (Dowex 1X 2, manufactured by Tau Chemical Co., Ltd.)
, Trans, , A, Soc, Intern,
Orc+ans, 29: 693.1983>
, IONEX (tertiary amine anion exchange resin) (Fukuei Kanai et al., Artificial Organs 1984), and strongly acidic anion exchange type ion exchange rim u (QAS) have been used clinically. Also, Plotz et al. (Plotz P, Hl, [3e
rk, P.

0,, et al,, Removing 5ubs
tances from blood by affi
nity chromato qraphy, J.
Cl1n, Invest, Child: 778.1
974) adsorbed and removed bilirubin by contacting plasma from patients with congenital hemolytic yellow scars with an affinity adsorbent in which human serum albumin was bound to agarose beads. Furthermore, adsorbents for removing bilirubin include special proteins such as serum proteins (Japanese Patent Application Laid-Open No. 49-42-189), porous copolymers of crosslinkable monomers and monovinyl monomers (Japanese Patent Application Laid-open No. 49-42-189). 54-69.289), polymers having large amounts of hydroxyl groups, amino groups and 7/or imino groups in the molecule (JP-A-57-64.059), cross-linked polymerizable monomers and cyano-containing monomers Porous copolymer with body
9.134) has been proposed.

However, all of these adsorbents have low adsorption selectivity for bilirubin, especially for indirectly reactive (unconjugated) bilirubin, and the amount of adsorption is insufficient for symptoms such as severe yellow scars. Some products have safety issues such as adsorbents leaking into the blood, but this is an adsorbent for bilirubin removal that can remove large amounts of bilirubin more efficiently and has very little negative impact on the blood. and the development of an adsorption device was desired.

(Problems to be Solved by the Invention) Therefore, an object of the present invention is to provide a novel adsorbent and adsorption device for removing bilirubin. Another object of the present invention is to provide a highly safe bilirubin removal adsorbent and adsorption device that can selectively remove bilirubin from human blood. A further object of the present invention is to provide an inexpensive bilirubin removal adsorbent and adsorption device that can efficiently remove large amounts of bilirubin from the blood of hyperpyrirubinemia patients.

(Means for Solving the Problems) The above features are characterized in that an organic compound having an affinity for rilpine is immobilized on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. This is achieved by using an adsorbent for removing bilirubin.

The present invention also provides that the monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 9 by weight.
This shows an adsorbent for removing bilirubin having a ratio of 5:5 to 85:15. The present invention further provides an adsorbent for removing bilirubin in which the average pore diameter of the porous body is 70 to 5,000. The present invention also provides a porous body with an average particle size of 0.0.
This shows an adsorbent for removing bilirubin which is a particulate porous material of 5 to 5 #. The present invention further provides an adsorbent for removing bilirubin, which is selected from the group consisting of an organic compound having an affinity for bilirubin, a compound having two or more cationic groups per molecule, a terpenoid, and an anionic surfactant. It shows.

The present invention further provides adsorption for removing bilirubin, which is a compound having two or more cationic groups per molecule, or a compound having two or more cationic groups per molecule selected from the group consisting of amino groups, imino groups, and ammonium bases. This indicates the material. The present invention also provides an adsorbent for removing bilirubin in which the terpenoid is a diterpene alcohol. The present invention further provides an adsorbent for removing bilirubin which is either a diterpene alcohol or a phytol. The present invention also provides an adsorbent for removing bilirubin in which the anionic surfactant is a sulfosuccinic acid ester. The present invention specifically describes an adsorbent for removing bilirubin, which comprises sulfosuccinate or docusate sodium.

The above-mentioned method is further characterized by having a column filled with an adsorbent made by immobilizing an organic compound having an affinity for bilirubin on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. This is achieved using an adsorption device for bilirubin removal.

The present invention also provides an adsorption device for removing bilirubin that has been subjected to moist heat sterilization. The present invention further includes:
This shows an adsorption device for removing bilirubin in which the column is made of polypropylene or polycarbonate. The present invention also provides an adsorption device for removing bilirubin, which is provided with a filter having a mesh between the inlet and outlet of the column and the adsorbent layer, through which cell components in blood can pass, but through which the adsorbent cannot pass. It is something. The invention further provides an adsorption device for removing bilirubin, in which the filter is made of polyester or polyamide. The present invention also provides an adsorption device for removing bilirubin in which the monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 95:5 to 85:15 by weight. The present invention further provides an adsorption device for removing bilirubin in which the porous body has an average pore diameter of 70 to 5,000. The present invention also provides a porous body with an average particle size of 0.0.
This figure shows an e-adhesion device for removing bilirubin, which is a particulate porous material with a size of 5 to 5 mm. The present invention also provides an adsorption device for removing bilirubin, in which the organic compound having an affinity for bilirubin is selected from the group consisting of compounds having two or more cationic groups per molecule, terpenoids, and anionic surfactants. It shows. The present invention further provides a compound having two or more cationic groups per molecule, or an amine group,
This shows an adsorption device for removing bilirubin, which has two or more cation groups per molecule selected from the group consisting of imino groups and ammonium bases. The present invention also provides an adsorption device for removing bilirubin in which the terpenoid is a diterpene alcohol. The present invention further provides an adsorption device for removing bilirubin, which is diterpene alcohol or phytol. The present invention also provides an adsorption device for bilirubin removal which is an anionic surfactant or a sulfosuccinic acid ester. The present invention generally describes an adsorption device for removing dirirubin, which is sulfosuccinic acid ester or docusate sodium.

(Function) Therefore, the adsorbent for removing bilirubin according to the present invention is characterized in that an organic compound having an affinity for bilirubin is immobilized on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. There are things to do,
It is efficiently produced by utilizing the ring-opening reaction of the epoxy active group of the copolymer of divinylbenzene and glycidyl methacrylate, as it has a large number of organic compounds on its surface that have an affinity for the strongly bonded bilirubin. When it comes into contact with blood or 1 fl. plasma, it exhibits a high affinity for bilirubin due to the action of the organic compound, selectively adsorbs bilirubin in large amounts, and can efficiently remove dilirubin. Moreover, the bilirubin adsorption effect of the adsorbent for removing bilirubin of the present invention is different from that when activated carbon is used as an adsorbent or when immobilized albumin or the like is used as an adsorbent. conjugated) dilirubin and indirect (unconjugated) bilirubin =
14- Does it have a clear affinity for either type?
There are no problems such as peripheral vascular occlusion, decrease in white blood cells or platelets, or activation of blood or plasma components due to the pulverized coal flowing out, and it is possible to adsorb and remove riruhin extremely safely.

Hereinafter, the present invention will be explained in more detail based on embodiments.

In the body, bilirubin is produced from heme, which is a component of red blood cells, and is transferred from the liver to the bile duct, where it undergoes various changes and finally becomes urobilin and stercopyrine, which are excreted in the blood and feces. . However, bilirubin concentration increases in the blood of patients with diseases such as hepatitis, cirrhosis, various hemolytic diseases, Gilbey 1 disease, Crigler-Najjar syndrome, neonatal jaundice, Duhin-Shonson syndrome, and hepatic fluid stasis. Therefore, it becomes necessary to remove these harmful substances from the blood by some means. There are two types of bilirubin: direct reaction type (conjugated) bilirubin, which does not bind or only loosely binds to plasma proteins dissolved in the blood, and indirect reaction type (unconjugated) bilirubin, which binds tightly to plasma proteins. Tightly bound indirectly reactive Ruhin behaves like a human molecule. Therefore, in order to selectively remove total bilirubin including the indirectly reactive bilirubin fraction, it is necessary to have a clear affinity for both low-molecular and high-molecular protein-bound forms of bilirubin, and It must be able to be held by suction.

The adsorbent for removing bilirubin of the present invention is characterized in that an acidic compound having an affinity for bilirubin is immobilized on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate-1. As described in detail below, it has the above characteristics and selectively adsorbs and removes total bilirubin.

In the adsorbent for bilirubin removal of the present invention, a porous 16 monolithic carrier made of a copolymer of divinylbenzene and glycidyl methacrylate is used as a carrier for immobilizing an organic compound having an affinity for bilirubin. The porous body is a porous body obtained by suspension polymerization of divinylbenzene and glycidyl methacrylate in the presence of a pore opening material and a polymerization initiator. The monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 100 by weight:
It can be set to any value in the range of 0 to 5:95.If the proportion of divinylbenzene is high, the surface of the porous material becomes hydrophobic, and conversely, if the proportion of glycidyl methacrylate is high, it becomes hydrophilic. The higher the ratio, the higher the surface density of epoxy active groups capable of binding an acidic compound (however, the amount of binding is limited by steric hindrance of the free compound molecules). From the parameters, the monomer composition ratio of dibylbenzene and glycidyl methacrylate is preferably in the range of 95:5 to 85:15 in weight ratio, more preferably in the range of 90S to 85:15 in weight ratio. The average pore diameter of the pores of the porous body is 70 to 50
00A, more preferably 150-1000A.

That is, if the average pore size is smaller than 7OA, permeation and diffusion of bilirubin-bound proteins, especially albumin, into the pores of the porous body will be inhibited, and good adsorption of bilirubin cannot be expected. This is because if it is larger than 8, the strength of the porous body will decrease and the surface area will become too small.

The shape of such a porous body is not particularly limited, and may take any known shape such as particulate, fibrous, hollow fiber, or membrane, but it may take into account the permeability of white liquor or plasma, the effective surface area,
It is preferable that the material is particulate from the viewpoint of ease of handling during the preparation of absorbent @(A).As for the particulate porous material, the average particle size is in the range of 0.05 to 5 mm, which has an effective surface area and a Preferable from the viewpoint of liquid properties.The average particle size is J15-Z-88.
After classification using a sieve specified in No. 01, the intermediate value between the upper limit particle size and the lower limit particle size of each plate was taken as the particle size of each plate, and the particle size was calculated as the weight average. Further, the particle shape is preferably spherical because it is less likely to damage cells and less likely to cause flaking or chipping.

In the adsorbent for removing bilirubin of the present invention, the organic compound having an affinity for bilirubin, which is immobilized on the surface of the porous body made of a copolymer of divinylbenzene and glycidyl methacrylate, has a molecular weight of 1X102 to
Compounds of 1.times.10.sup.6 Daltons or especially those having more than one cationic group per molecule, terpenoids and anionic surfactants are preferably used.

As the compound having two or more cationic groups per molecule that can be used in the present invention, it is desirable to have an amino group, iminoli, or ammonium base as the cationic group, and the type of cationic group in the molecule is It may also be different. Specific examples of such compounds include polyvalent amines such as hexanediamine and phenylenediamine, diaminomonocarboxylic acids such as alkynine, lysine, and bistidine, and polyethyleneimine. It is not limited to. As mentioned above, when such a compound is immobilized on the surface of a porous material and comes into contact with the vinylyl pin, it exerts an electrostatic interaction force with either the cationic group or the carboxyl group of the bilirubin molecule, and attracts the bilirubin molecule, resulting in a favorable reaction. It is thought that affinity arises.

In addition, the terpenoids used in the present invention include:
Furthermore, diterpene alcohol, more preferably neutol, is desirable from the viewpoint of immobilization on the surface of the porous body. Terpenoids are immobilized on the surface of the porous material as described above, but when they come into contact with lirubin, they exhibit hydrophobic interaction with the methyl group of the terpenoid or the methyl group and heterocycle of the bilirubin molecule, and attract the bilirubin molecule, resulting in a good affinity. This is thought to occur.

Furthermore, as the anionic surfactant used in the present invention, sulfosuccinic acid ester is preferable, more preferably docusate sodium (sulfosuccinic acid 1,4
-bis(2-ethylhexyl)sodium) is preferred. In the case of anionic surfactants, as in the case of terpenoids, when they are immobilized on the surface of the porous material and come into contact with rilpine,
It is thought that the hydrophobic group of the anionic surfactant exhibits hydrophobic interaction with the methyl group and heterocycle of the bilirubin molecule and attracts the pyrubin molecule, resulting in good affinity.

In the adsorbent for removing bilirubin of the present invention, in order to immobilize the organic compound having an affinity for bilirubin as described above on the porous body made of the copolymer of divinylbenzene and glycidyl methacrylate as described above, the porous body This is carried out by covalently bonding the organic compound using a ring-opening reaction of the epoxy active group on the surface, and the elution of the immobilized organic compound is extremely low. Furthermore, if necessary, it is also possible to introduce molecules (spacers) of arbitrary length between the surface of the porous body and the organic compound.

The bilirubin removal adsorbent of the present invention has the above-described action of the organic compound immobilized on its surface.
Although it shows affinity for bilirubin, a porous material made of a copolymer of divinylbenzene and glycidyl methafrylate, which is a carrier, has an affinity for bilirubin even after immobilizing an organic compound on its surface. It is believed that it has the characteristic f) and a hydrophobic surface, and that it adsorbs proteins such as albumin bound to bilirubin through hydrophobic interaction force. Therefore, it is considered that due to these effects, the adsorbent for bilirubin removal of the present invention can selectively adsorb bilirubin present in blood or surface fluids in large amounts.

The adsorption and removal of bilirubin by the adsorbent for removing bilirubin of the present invention is carried out by bringing blood or plasma into sufficient contact with the adsorbent for removing bilirubin of the present invention. From the point of view of ensuring the absolute amount and sufficient adsorption space, an adsorption device for bilirubin removal having a column filled with this bilirubin removal adsorbent A, preferably a particulate adsorbent for bilirubin removal, is used. This is preferably carried out by passing blood or plasma through.

In this adsorption device for removing bilirubin having a column filled with an adsorbent for removing bilirubin, the material constituting the column container includes synthetic resins such as polypropylene, polycarbonate, polystyrene, and polymethyl methacrylate, and metals such as glass and stainless steel. Particularly preferred are polypropylene, polycarbonate, etc., which can be sterilized in an autoclave and are easy to handle.

Furthermore, a filter having a mesh is provided between the inlet/outlet of the column of this adsorption device for removing bilirubin and the adsorbent layer filled with the adsorbent for removing bilirubin, which allows blood components to pass through but does not allow the adsorbent to pass through. It is preferable that the filter be made of a material that is physiologically inert and has high strength, and polyester and polyamide are particularly preferred.

FIG. 1 is a sectional view schematically showing an embodiment of an adsorption device for removing bilirubin according to the present invention. In this embodiment, an adsorption device 1 for removing bilirubin includes a column container 4 having a fluid inlet 2 and a fluid outlet 3 filled with particulate adsorbent 5 for removing bilirubin.
are held in the column container by filters 6a and 6b provided near the fluid inlet 2 and fluid outlet 3. To perform extracorporeal circulation therapy for hyperbilirubinemia using this bilirubin removal adsorption device 1, the bilirubin removal adsorption device 1 is incorporated into a circuit as shown in FIG. 2, for example. Blood from the patient is introduced into the circuit through the blood introduction lower and blood pump 8. It passes through the chamber 9 and is supplied to the laminated plasma separator 10 at a constant flow rate, where it is separated into blood cell components and plasma components. Layered plasma separator 1
The plasma drawn out from the plasma outlet 11 of 0 is transferred to the plasma pump 1.
2. Passing through the chamber 13, the fluid is introduced into the bilirubin removal adsorption device 1 through the fluid inlet 2, and after being adsorbed by the bilirubin removal adsorbent 5 housed in the column container 4, it is led out through the fluid outlet 3. be done. The plasma components processed by the bilirubin removal adsorption device 1 are mixed again in the mixing chamber 14 with the blood cell components drawn out from the blood cell outlet 15 of the laminated plasma separator 10, and passed through the thermostatic chamber 16 through the blood outlet. 17, it is returned to the patient's body.

The bilirubin removal adsorption device of the present invention is subjected to moist heat sterilization by filling purified water, physiological saline, etc. into the device and heating it before use.

(Example) Hereinafter, the present invention will be explained in more detail with reference to Examples.

Reference Example 1 Silica gel (manufactured by Tomiju Dewison Chemical, average pore diameter 324A
, particle size 100-200 mesh) was placed in polyethylene, 7.8 wt % T-glycidoxypropyltrimethoxysilane (GOPTS) aqueous solution, pH 8 was added, degassed, and then a GOPTS aqueous solution was added to the colander for 7J. []
It was set to 300d. Next, after rotating on a rotary table for 30 minutes using Brat Miki'J-- (manufactured by Kayagaki Irika Kogyo, model BM-101), the upper layer liquid was discarded, and the silica gel was transferred to an aluminum booklet at 50'C for a period of 50'C. The reaction was carried out by heating. Divide this into 9 polyethylenes, and add dimethylformamide and 0.2 MrA acid buffer wave buffer Hlo to each.
Octadecylamine at a concentration of 0 and 1M dissolved in a mixture of
Ascorbic acid, cholic acid, anthracene-9-carphonic acid, henzoguanamine, pyridoxine dioctanoate, steering lyserine ether, Dokusei 1-sodium, and p-phenylenecyamine 50/d were added and degassed. The mixture was heated in an aqueous solution at 80°C for 3 hours, and then stirred overnight at room temperature using a brand mixer. Next, after washing the silica gel with distilled water and dimethylformamide, 50 d of a 1M monoethanolamine aqueous solution adjusted to pH 8 with acetic acid was added, and the mixture was stirred overnight at room temperature using a brand mixer to block unreacted epoxy groups. did. The adsorbent thus prepared was mixed with distilled water, 0.5
0.02M acetate buffer containing M 1 helium chloride;
After washing with pH 4 and 0.2M carbonate buffer, pH 10, and finally washing with distilled water and lightly removing water), a glass test tube (manufactured by Terumo Corporation, Ral Small, 15.
5#φX100mm> was weighed in an amount of 1 g and used for the following adsorption experiment. As a comparison, untreated silica gel washed with distilled water was also used in the adsorption experiment.

The adsorption experiment was conducted as follows. That is, 5 d of waste plasma from a patient with hyperbilirubinemia after plasma exchange therapy was added to each test tube containing the above-mentioned adsorbent, and after aeration with IB2 using an aspirator, the tube was capped with a rubber stopper and a Brat mixer was used. The mixture was incubated in a 37°C oven without stirring.

After that, a disposable syringe with a capacity of 5 d (Terumo (
Transfer the contents of these test tubes to a minicolumn prepared using Terumo Syringe (manufactured by Co., Ltd.), collect the effluent, and
The concentration of total bilirubin and direct reaction bilirubin in the effluent was measured using "Bilirubin 811-Test (manufactured by Wako Tsumugi Co., Ltd.) J.
Measured using

Then, by subtracting the above measured values from the total bilirubin and direct bilirubin concentration values of the obtained effluent that was similarly operated without contact with the adsorbent,
The adsorption rate was calculated by calculating the adsorption amount for each adsorbent and removing this adsorption amount using the total bilirubin and direct reaction type hirirubin concentration values of the effluent obtained by the same operation without contact with the adsorbent. was calculated. The results are shown in Table 1.

As is clear from the results shown in Table 1, p-phenylenecyamine, which imparts many amino groups to the surface of the adsorbent, and sodium toxate, an anionic surfactant, act as an organic compound for adsorbing rilubin. I found it to be excellent.

(Left below) Example 1 A copolymer of divinyl pentene and glycidyl methacrylate (manufactured by Fujii Kasei Co., Ltd., MR22OA>409) having a monomer composition ratio of 80':20 by weight was placed in a polyethylene bottle and dimethylformamide was added. and 0.2M carbonated mild solution,
After degassing by adding 0.1 M sodium toxate dissolved in a mixed solution of pH 10, the sodium toxate solution was added to a colander to make 300 ml. and 3 in a water bath at 80'C.
After warming for an hour, it was stirred overnight at room temperature using a Brat mixer. Next, after washing with distilled water and dimethylformamide, 100 ml of a 1M monoethanolamine aqueous solution adjusted to I)H8 with acetic acid was added, and the mixture was stirred overnight at room temperature using a Brat mixer to block unreacted epoxy groups. . The adsorbent thus prepared was washed with distilled water, 0.02M vinegar @ buffer containing 0.5M sodium chloride, 1) H4, 0.2M carbonate buffer, 1) Hlo, and finally distilled. After washing with water and lightly removing water, 13 samples were weighed in a glass test tube (manufactured by Terumo Co., Ltd., Larbo 15°5#φX100) and used for an adsorption experiment. The adsorption experiment was conducted in the same manner as in the reference example.

The results are shown in Table 2.

Comparative Example 1 Silica gel (average pore size: 324) was prepared in the same manner as in the reference example.
After activating 0 g, toxate sodium was immobilized on this silica gel in the same manner as in Example 1. 1 g of the obtained adsorption (A) was weighed in a wet state and subjected to an adsorption experiment in the same manner as in Example 1. The obtained results are shown in Table 2.

(Left below) As is clear from the results shown in Table 2, when docusate sodium was immobilized as an organic compound, it was found to be superior as a carrier to a copolymer of cydonylbenzene and glycidyl methacrylate or silica gel. .

Examples 2 to 4 and Comparative Example 2 A copolymer of divinylbenzene and glycidyl methacrylate with a monomer composition ratio of 80:2'O by weight (
MR22OA (manufactured by B-Kura Kasei Co., Ltd.) was placed in a 31-hard polyethylene bottle, and 0.1M alkynine dissolved in 0.2M carbonate buffer, pH 10 (Example 2) was placed in each bottle.
>, 0.2M carbonate buffer, 1) 4,2 dissolved in Hlo
wt% polyethyleneimine (molecular weight 60,000 to 80,000) (Example 3), or 0 dissolved in dimethylformamide,
After adding 1M phytol (Example 4) and degassing, each solution was further added to make 100 d. Thereafter, an adsorption scavenger was prepared in the same manner as in Example 1, and used for an adsorption experiment.

Untreated copolymer of divinylbenzene and glycidyl methacrylate washed with distilled water for comparison (Comparative Example 2)
was also subjected to adsorption experiments. The results are shown in Table 3.

(Space below) Examples 5 to 8 and Comparative Example 3 Monomer composition 1 of divinylbenzene and glycidyl methacrylate in a weight ratio of 95:5 (MR27OA, Example 5>90:10 (MR180A, Example 6), 8
5:15 (MR29OA, Example 7), 80:2
Divinylbenzene-glycidyl methacrylate copolymer (both manufactured by Genji Kasei Co., Ltd.) which is 0 (MR22OA, Example 8) and divinylbenzene polymer (manufactured by B-Kura Kasei Co., Ltd., MR184A) each of 10 and 4. After adding a solution of 2% by weight polyethyleneimine (molecular weight 60,000 to 80,000) dissolved in 0.2M carbonate buffer, pH 10 and degassing,
Add this polyethyleneimine solution to 100ml
And so. Thereafter, an adsorbent was prepared in the same manner as in Example 1,
It was used for adsorption experiments. The adsorption experiment was carried out in the same manner as in Example 1, except that the amount of blood fallen was 10 m². The results are shown in Table 4.

Comparative Examples 4 to 5 For comparison, the monomer composition ratio of divinylbenzene and glycidyl methacrylate was 9525 (MR27
OA, Comparative Example 4) and 80:20 (MR29OA
, Comparative Example 5), divinylbenzene-glycidyl methacrylate-1 copolymer (all manufactured by Genkasei Co., Ltd.) was washed with distilled water without treatment, and adsorption experiments were conducted in the same manner as in Examples 5-B. Served.

The results are shown in Table 4.

(Margin below) Hede size ■ prisoner ■ Dimensions ('v) "■" C0tncy>to00■ ■　　○　oooo.

H2″
) OO "
Hustle? Example 9 A copolymer of divinylbenzene and glycidyl methacrylate with a monomer composition ratio of 80:20 (manufactured by Genkasei Co., Ltd., MR29OA>107 and 2.1% by weight polyethyleneimine (molecules @ 60,000 ~ 80,000) and 0.1M 1
．． A solution of 6-hexanediamine dissolved in 0.2M charcoal@buffer solution was added and degassed, and then the solution was roughly diluted to 100 HO.

Adsorbents operated in the same manner as in Examples 5 to 8 were prepared and subjected to adsorption experiments. The results obtained are shown in Table 5.

Example 10 Copolymer of didinylbenzene and glycidyl methacrylate with a monomer composition ratio of 90:10 (manufactured by Genkasei Co., Ltd., MR180A) 4.2% by weight in 109
A solution prepared by dissolving polyethyleneimine (molecular weight 60,000 to 80,000) in a 0.2M carbonate buffer was diluted to 100 mol of hydrogen and degassed, and this solution was further added to adjust the temperature to 1°Od. Thereafter, adsorbent materials operated in the same manner as in Examples 5 to 8 were prepared and subjected to adsorption experiments. Results obtained = 39- The results are shown in Table 5.

Comparative Example 6 For comparison, a divinylbenzene-glycidyl methacrylate copolymer (manufactured by Fujishiki Kasei Co., Ltd., MR29OA) in which the monomer composition ratio of divinylbenzene and glycidyl methacrylate was 80:20 by weight was left untreated. It was washed with distilled water and subjected to the same adsorption experiment as in Example 9. The results are shown in Table 5.

Comparative Example 7 For comparison, a polyurethane sheet containing activated carbon powder (■
Manufactured by Nippon Medical Supply, product name: Vesboa UPC-
An adsorption experiment similar to that in Example 9 was conducted using III). The results are shown in Table 5.

(Left below) No. 55 Adsorption I (mg/dΩ) (my/dΩ) (m
g/g, 8/ Immobilized N) IR290 heli 10 polyethyleneimine
0.81 fixed\, 1R180 Comparative example 6 MR290△
0.41n 7 activated carbon powder sheet
0.4 (Pen absorption rate Lupine intake amount Lupine adsorption rate L (%) (mg/s)
(%) 18 77.0 0.465 67.
323 74.8 0.458 66.3
10 40.0 0.281 40.7)
2 36.5 0.286 41.4 (Effects of the Invention) As described above, the present invention has an affinity for bilirubin on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate-1. This is an adsorbent for removing bilirubin that is characterized by immobilizing an organic compound containing bilirubin, so it adsorbs and removes high concentrations of bilirubin present in the blood of patients with diseases such as liver failure, liver cirrhosis, and childhood huangheng. When used in blood or plasma, bilirubin can be selectively and efficiently adsorbed and separated in large quantities by contacting it with blood or plasma. Moreover, it is possible to adsorb and separate bilirubin efficiently and easily without adversely affecting other blood components. Since there are no problems such as leakage of materials into the body, it is possible to provide safe and effective treatment, reducing symptoms and prolonging life without putting a burden on patients.

In addition, in the adsorbent for bilirubin removal of the present invention, the monomer composition ratio of didonylbenzene and glycidyl methacrylate in the copolymer is 95:5 to 85:215 by weight.
The average pore diameter of the porous body is 70 to 5000 A,
The porous body must be a particulate porous body with an average particle size of 0°05 to 5#, and the compounds having an affinity for bilirubin include compounds having two or more cationic groups per molecule, terpenoids, and selected from the group consisting of anionic surfactants, more preferably compounds having two or more amino groups, imino groups or ammonium groups per molecule, diterpene alcohols, especially phytol, and sulfosuccinates, especially doc If it is selected from the group consisting of sodium sate, it can be expected to exhibit higher selective adsorption to either direct reaction type bilirubin or indirect reaction type bilirubin, and more excellent effects can be expected. Become.

The present invention is generally characterized by having a column filled with an adsorbent made by immobilizing an organic compound having an affinity for bilirubin on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. Since this is an adsorption device for removing bilirubin, it is possible to more efficiently contact the absorbent material for removing hirirupin, which has the above-mentioned excellent properties, with blood or plasma. Adsorption removal can be carried out successfully in a short time during extracorporeal circulation therapy, and more effective treatment can be expected. Furthermore, the adsorption device for bilirubin removal of the present invention does not deteriorate its performance even after being subjected to moist heat sterilization and exhibits stable bilirubin adsorption ability, making it possible to perform safer treatment.
The column is made of polypropylene or polycarbonate, and is equipped with a filter between the inlet and outlet of the column and the adsorbent layer, which has a mesh that allows cell components in the blood to pass through but not the adsorbent. Furthermore, if the filter is made of polyester or polyamide, operations such as sterilization are easy, there is less risk of damaging cellular components in the blood passing through it, and bilirubin can be selectively adsorbed more safely and efficiently. It becomes something that can be removed.

Furthermore, in the adsorption device for removing bilirubin of the present invention, the monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 95:5 to 85:1 by weight.
5, the average pore diameter of the porous material is 70 to 5000A, the porous material is a particulate porous material with an average particle diameter of 0.05 to 5#, and an organic compound that has an affinity for bilirubin per molecule. Compounds having 21 or more cationic groups, compounds selected from the group consisting of terpenoids and anionic surfactants, more preferably compounds having 2 or more 7-mino groups, imino groups or ammonium groups per molecule, diterpenes If the alcohol is selected from the group consisting of alcohols, especially phytol, and sulfosuccinates, especially docusate sodium, higher bilirubin adsorption capacity can be obtained and better effects can be expected.

[Brief explanation of drawings]

Figure M1 is a sectional view schematically showing an embodiment of the adsorption device for removing bilirubin of the present invention, and FIG. 2 is a circuit diagram of an extracorporeal circulation therapy incorporating the adsorption device for removing bilirubin of the present invention. DESCRIPTION OF SYMBOLS 1... Adsorption device for bilirubin removal, 2... Fluid inlet, 3... Fluid outlet, 4... Column container, 5... Adsorbent for bilirubin removal, 5a, f
3b... Filter, 9... Laminated plasma separator, 14... Mixing chamber, 46... Constant temperature bath.

Claims (24)

[Claims] (1) An adsorbent for removing bilirubin, characterized in that an organic compound having an affinity for bilirubin is immobilized on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. (2) The monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 95:5 to 95:5 by weight.
The adsorbent for removing bilirubin according to claim 1, which has a ratio of 85:15. (3) The adsorbent for removing bilirubin according to claim 1 or 2, wherein the porous body has an average pore diameter of 70 to 5000 Å. (4) The adsorbent for removing bilirubin according to any one of claims 1 to 3, wherein the porous body is a particulate porous body having an average particle diameter of 0.05 to 5 mm. (5) Claim 1, wherein the organic compound having an affinity for bilirubin is selected from the group consisting of compounds having two or more cationic groups per molecule, terpenoids, and anionic surfactants. The adsorbent for removing bilirubin according to any one of items 1 to 4. (6) Claims in which the compound having two or more cationic groups per molecule has two or more cationic groups per molecule selected from the group consisting of amino groups, imino groups, and ammonium bases. The adsorbent for removing bilirubin according to item 5. (7) The adsorbent for removing bilirubin according to claim 5, wherein the terpenoid is a diterpene alcohol. (8) The adsorbent for removing bilirubin according to claim 7, wherein the diterpene alcohol is phytol. (9) The adsorbent for removing bilirubin according to claim 5, wherein the anionic surfactant is a sulfosuccinic acid ester. (10) The adsorbent for removing bilirubin according to claim 9, wherein the sulfosuccinate is docusate sodium. (11) A method for removing bilirubin characterized by having a column filled with an adsorbent made by immobilizing an organic compound having an affinity for bilirubin on the surface of a porous body made of a copolymer of divinylbenzene and glycidyl methacrylate. Adsorption device. (12) The adsorption device for removing bilirubin according to claim 11, which has been subjected to moist heat sterilization treatment. (13) The adsorption device for removing bilirubin according to claim 11 or 12, wherein the column is made of polypropylene or polycarbonate. (14) A filter is provided between the inlet and outlet of the column and the adsorbent layer, the filter having a mesh that allows cell components in the blood to pass through but does not allow the adsorbent to pass through. 14. The adsorption device for removing bilirubin according to any one of Item 13. (15) The adsorption device for removing bilirubin according to claim 14, wherein the filter is made of polyester or polyamide. (16) The monomer composition ratio of divinylbenzene and glycidyl methacrylate in the copolymer is 95:5 by weight.
The bilirubin removal and adsorption device according to any one of claims 11 to 15, wherein the ratio is 85:15. (17) The adsorption device for removing bilirubin according to any one of claims 11 to 16, wherein the porous body has an average pore diameter of 70 to 5000 Å. (18) The adsorption device for removing bilirubin according to any one of claims 11 to 17, wherein the porous body is a particulate porous body having an average particle diameter of 0.05 to 5 mm. (19) An organic compound having an affinity for bilirubin is
The adsorption agent for removing bilirubin according to any one of claims 11 to 18, which is selected from the group consisting of compounds having two or more cationic groups per molecule, terpenoids, and anionic surfactants. Device. (20) The compound having two or more cationic groups per molecule has two or more cationic groups per molecule selected from the group consisting of amino groups, imino groups, and ammonium bases. The adsorption device for removing bilirubin according to item 19. (21) The adsorption device for removing bilirubin according to claim 19, wherein the terpenoid is a diterpene alcohol. (22) The adsorption device for removing bilirubin according to claim 21, wherein the diterpene alcohol is phytol. (23) The adsorption device for removing bilirubin according to claim 19, wherein the anionic surfactant is a sulfosuccinic acid ester. (24) The adsorption device for removing bilirubin according to claim 23, wherein the sulfosuccinate is docusate sodium.