JPS5829134B2 - Adsorption separation agent for blood purification - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel adsorption/separation agent for organic compounds adsorbed to plasma proteins present in blood.

Toxic substances contained in a patient's blood, such as neurotoxic substances that induce hepatic coma in the final stage of liver failure, are organic compounds that exist in a state adsorbed to plasma proteins dissolved in the blood. .

This adsorption state includes hydrophobic bonds, ionic bonds, hydrogen bonds,
Included are all conditions in which strong adsorption occurs due to bonding due to van der Waals forces and the combination of these different bond types.

Here, the term "hydrophobic bond" refers to a phenomenon in which molecules or atomic groups within molecules that are difficult to form bonds with water molecules in an aqueous solution come together due to their affinity.

Since these organic compounds are strongly adsorbed to plasma proteins, they cannot be removed by hemodialysis and must be removed using an adsorbent. There is a strong desire to develop an excellent adsorption/separation agent for blood purification that does not cause any denaturation to proteins.

The inventors of the present invention have been able to conduct extensive research in developing such an adsorbent, but the inventors of the present invention discovered it earlier and published Japanese Patent Application No. 51-128868 and Japanese Patent Application No. 52-52585.
The present inventors have discovered that the cyano-containing porous copolymer disclosed in the patent specification and the like is particularly excellent as an adsorbent for the above-mentioned applications, and has accomplished the present invention.

That is, the present invention comprises 2% to 99% by weight of a cross-linked polymerizable monomer and 1% to 98% by weight of a cyano-containing compound selected from acrylonitrile, metacyclonitrile, α-chloroacrylonitrile, and cinnamitrile. The volume of pores obtained by copolymerizing a monomer mixture containing a monomer and having an average pore diameter d of 60 to 9000 pores and a pore diameter of 0.5 d to less than 2 d is 20 to 20 d of the total pore volume. The present invention relates to an adsorption/separation agent for organic compounds adsorbed to plasma proteins present in blood, which is made of a porous copolymer of 60%.

The present invention will be specifically explained below.

The adsorption/separation agent for organic compounds adsorbed to plasma proteins of the present invention is effective for the adsorption separation of literally all kinds of organic compounds adsorbed from plasma proteins, but these adsorbed organic compounds and 1. Here are some examples:

That is, for serum albumin, unconjugated bilirubin,
Vazoflavin, ascorbic acid, acetylcholine, adenosine, free fatty acids, bile acids, triiodothyronine,
Metabolites such as thyroxine, thyroxine, cortisol, and histamine, physiologically active substances such as chloromycetin, barbituric acid, dicchitonin, neosalpalic acid, aureomycin, penicillin, and salicylic acid, indocyanine green, promsulfofthalene, fromcresol green, and phenol. There are pigments such as red and Congo red.

For serum globulin fraction, vitamin A1, D
, E, etc. are applicable.

In addition, although it is not clear which proteins in the blood are adsorbed to, neurotoxic substances that appear in the blood at the end stage of liver failure and induce hepatic coma, and neurotoxic substances that appear at the end stage of renal failure, etc. do.

Examples of the cyano-containing monomer serving as a structural unit of the porous copolymer which is the adsorbent of the present invention include acrylonitrile, methacrylonitrile, α-chloroacrylonitrile, and cinnamitrile.

The weight fraction of these cyano-containing monomers is 1% to 98%, preferably 5% to 85%.

If the content of the cyano-containing monomer is too high, the content of the cross-linking polymerizable monomer will inevitably decrease, leading to a decrease in strength, and if the content of the cyano-containing monomer is extremely low, the properties of the nitrile group will deteriorate. Not fully demonstrated.

The cyano-containing porous copolymer of the present invention can contain other monomers copolymerizable with the cyanogen-containing monomer.

These monomers include styrene, methylstyrene,
Hydrocarbon compounds such as ethylstyrene, vinylnaphthalene, butadiene, isoprene, hyperylene: chlorstyrene, fromstyrene, N.

Styrene derivatives such as N-dimethylaminostyrene, nitrostyrene, and chloromethylaminostyrene: Vinyl sulfide derivatives such as methyl vinyl sulfite and phenyl vinyl sulfide Niacrylic acid: Acrylic acid esters such as methyl methacrylate and chloromethyl acrylate: Methacrylic acid Methacrylic acid esters such as cyclohexyl acid, dimethylaminoethyl methacrylate, glycidyl methacrylate, tetrahydrofurfuryl methacrylate, and hydroxyethyl methacrylate; Vinyl ketones such as methyl vinyl ketone and ethyl isopropenyl ketone; Vinylidene such as vinylidene chloride and vinylidene bromide. Compound Niacrylamide, N-butoxymethylacrylamide, N
, acrylamide derivatives such as N-dimethylaminoethyl acrylamide; fatty acid vinyl derivatives such as vinyl acetate and vinyl caprate; thiofatty acid derivatives such as methyl thioacrylate and vinyl thioacetate; Vinylpyrrolidone, N-vinylphthalimide, N-vinylcarbazole, vinylfuran, vinylimidazole, methylvinylimidazole, vinylpyrazole, vinyloxazolidone, vinylthiazole,
There are heterocyclic vinyl compounds such as vinylpyridine, methylvinylpyridine, and 2,4-dimethyl-6vinyltriazine.

Examples of cross-linked polymerizable monomers serving as structural units of the porous copolymer of the present invention include divinylbenzene, divinyltoluene,
Divinylquinoline, divinylnaphthalene, divinylethylbenzene, trivinylbenzene, divinyldiphenyl, divinyldibenzyl, divinylphenyl ether, divinyldiphenylamine, divinylsulfone, divinylketone, divinylpyridine, divinylquinoline, diallyl phthalate, diallyl maleate, fumaric acid diallyl,
Diallyl carbonate, diallyl oxalate, diallyl adipate, diallyl tartrate, diallylamine, triallylamine, triallyl phosphate, triallyl tricarballylate, N
, N'-ethylene diacrylamide, N,N'-methylene dimethacrylamide, ethylene glycol dimethacrylate, polyethylene glycol dimethacrylate, trimethylolpropane trimethacrylate, pentaerythritol tetramethacrylate, 1,3-butylene glycol diacrylate, trimethylpropane triacrylate, pentaerythritol tetraacrylate,
These include triallylisocyanurate, 1,3,5-)lyacryloylhexahydro 1,3,5-)lyazine, diarylmelamine, and the like.

The content 1 of these crosslinking polymerizable monomers is 2% to 99% by weight, preferably 5% to 70% by weight, and more preferably 8% to 60% by weight.

If the content of the crosslinking polymerizable monomer is too small, the degree of swelling and shrinkage of the polymer will increase and the mechanical strength will decrease.

Furthermore, if the degree of crosslinking increases too much, it becomes difficult to form micropores that provide a place for adsorption of organic compounds adsorbed on plasma proteins, and the rate of diffusion of liquid into the copolymer decreases.

The porous copolymer of the present invention has an average pore diameter of 60A to 900A.
Although it is a structure with a large number of holes within the range of 0 people,
The average pore diameter is more preferably in the range of 60 to 400A, and even more preferably in the range of 60 to 2,500.

If the average pore size is too small, plasma proteins that have adsorbed organic compounds cannot penetrate into the pores, or the diffusion rate will be significantly reduced, which is disadvantageous. If the pore size is too large, the surface area that contributes to adsorption will be small. This results in disadvantages such as a decrease in mechanical strength and a decrease in mechanical strength.

The pore size distribution is also a very important factor regarding the adsorption ability of the organic compound, and when the average pore size is d, the pore size is 0.5
It is desirable that the volume of pores having a size of d or more and less than 2d is 60% or less, preferably 50% or less of the total pore volume.

There is no particular limit to the lower limit of this value, but since the largest number of pores are around the average pore diameter, it is necessarily 20% or more, but it is generally 30%.

Furthermore, the amount of pores also has an important relationship with the ability to adsorb the organic compound.

That is, when the weight fraction of the crosslinking polymerizable monomer to the total monomer is X%, the total pore amount per 1 g of dry polymer is o, o
5. /Y- or more and 1.5 J'jJme or less, preferably o, 15. /'7- or more 1.3JK-
The following is desirable.

If the amount of pores is too small, it will not be possible to provide a sufficient adsorption surface, and if the amount of pores is too large, it will not only reduce the mechanical strength of the copolymer, but also reduce the amount of adsorption per unit volume of copolymer. lower.

Next, the method for measuring porosity characteristics adopted in the present invention will be described.

The average pore size, pore size distribution, pore volume, and specific surface area were measured using a mercury intrusion porosimeter.

In this method, mercury is injected into a porous material, and the amount of pores is determined from the amount of mercury infiltrated.The pore size is also determined based on the principle that the diameter of a pore is inversely proportional to the pressure required to inject mercury into that pore. It is something to be measured.

Details of this method can be found in the book Fine Particle Measurement (2013).
)ent)Clyde-Orr-Jrand
J, M, Dallavalle) co-author, The-
7 Cumilan Company, New York (TheMa
Cmillan Company, New York
) 1959.

With this method it is possible to measure up to 35-40 holes.

For the purposes of the present invention, pores are defined as pores communicating from the surface with a diameter of 40 Å or more, and the pore volume and surface area are also values derived from the pores.

Further, the average pore diameter is defined as the value of r at which the value of dv/d log r becomes the maximum value.

Here, r is the pore diameter, and ■ is the cumulative amount of pores measured with a porosimeter.

Another value that is an indicator of porosity is bulk specific gravity.

The inventors measured the bulk specific gravity using the following method.

That is, first, a column with a glass filter is filled with resin, water is sufficiently poured, and the volume of the column filled with resin is determined.

Thereafter, the sample was sufficiently dried and weighed, and the bulk specific gravity was calculated from both values.

Next, a method for producing the adsorbent copolymer of the present invention will be described.

Some of the inventors have already discovered a method for making highly porous crosslinked polymers, and this technique can also be used to make the porous copolymers of the present invention.

One method is to use a mixture of copolymerizable monomers,
A mixture of which 2% by weight or more is a cross-linked polymerizable monomer has an affinity for the homopolymer of at least one monomer in the mixture and of at least one other monomer. A copolymer is obtained by copolymerizing in the presence of a single liquid that has no affinity for the homopolymer, dissolves the monomer mixture, and does not react with each monomer, and then the copolymer is The other is a mixture of copolymerizable monomers, of which 2% by weight or more is a crosslinking polymerizable monomer. and a liquid that has an affinity for the homopolymer of at least one monomer in the mixture, dissolves the monomer mixture, and does not react with each monomer, and at least one of the monomers in the mixture. A copolymer is formed by copolymerizing the monomers in the presence of a liquid mixture consisting of a liquid that has no affinity with the homopolymer, dissolves each monomer, and does not react with each monomer. This method is characterized in that the mixed liquid and unreacted monomers are removed from the inside of the copolymer.

To further describe this method in detail for the case where a copolymer is synthesized by copolymerizing two types of monomers A and B, when organic liquids are classified as follows, the following (1) to (4) ) are mixed with the monomer mixture;
A porous structure can be obtained by performing a copolymerization reaction.

That is, (1) at least one type of liquid X (2) a mixture of at least one type of liquid X and at least one type of liquid Y (3) a mixture of at least one type of liquid X and at least one type of liquid Z ( 4) Mixture of at least one type of liquid Y and at least one type of liquid Z Here, the liquids X, Y, and Z each have the following properties.

liquid Liquid Liquid Z: A liquid button that shows no affinity for either Polymer A or Polymer B. Here, a linear polymer of a certain monomer with an average molecular weight of 10,000 or more dissolves at least 1% in the liquid. , the liquid is defined as having an affinity for the polymer.

In the case of a cross-linked polymerizable monomer, a mixture consisting of 5 parts of the monomer, 0.1 part of azobisisobutyronitrile, and 100 parts of a liquid is sealed in a glass tube, and heated at the same temperature as the polymerization reaction to be performed. Heating on a time schedule.

If the product is transparent, the polymer of the monomer is defined as having an affinity for the liquid.

As described above, it is possible to easily synthesize a porous crosslinked copolymer using methods (1) to 4), but in order to obtain the copolymer disclosed in the present invention, in particular ( Methods 2) to 4) are suitable.

In other words, in these methods, a copolymerization reaction is carried out in the coexistence of a mixture of a liquid that has an affinity for the copolymer and a liquid that does not have an affinity for the copolymer, and as a result, a copolymer with a wide pore size distribution is obtained. It is from.

In addition, when two types of liquids having different solubility are used in this way, by changing the mixing ratio, it is possible to continuously change the pore size of the copolymer produced.

For effective porous structure design, it is necessary to increase the amount of organic liquid added as the proportion of crosslinking monomer to total monomer increases.

That is, when the weight percent of the total liquid relative to the total monomer is D, and the weight percent of the crosslinking polymerizable monomer relative to the total monomer is X, the formula
It is preferable to satisfy the formula 101·', /'¥<D<102·2VY, and more preferably to satisfy the formula 101·V or <D<102·1VT.

The amount of pores in a porous copolymer is essentially determined by the relative amount of liquid added.

Next, liquid names used in more specific cases will be listed.

For copolymerization of acrylonitrile-divinylbenzene-ethylstyrene, liquid Y includes dimethylformamide, N-methylacetamide, nitromethane, dimethylsulfoxide, benzonitrile, γ-butyrolactone,
NN-dimethylacetamide, acetophenone, etc., liquid Examples of liquid Z include aliphatic hydrocarbons such as heptane and decalin, aliphatic alcohols such as n-butanol, cyclohexanol, isooctyl alcohol, amyl acetate, dibutyl phthalate, etc.
Examples include dioctyl phthalate.

In the copolymerization of acrylonitrile-ethylene glycol dimethacrylate, the liquid Y may be dimethylformamide, dimethyl sulfoxide, γ-butyrolactone, NN dimethylacetamide, etc.75 The liquid X may be toluene, methyl ethyl ketone dioxane, cyclohexanone,
Methylene chloride, chlorobenzene, etc. are used as liquid Z.
It can be selected from heptane, octane, n-butanol, isopropanol, etc.

Examples of liquids to be used when synthesizing a copolymer from methacrylonitrile-divinylbenzene=ethylvinylbenzene include liquid Y, pyridine, nitromethane, be/sonitrile, cyclohexanone, methyl ethyl ketone, γ-butyrolactone, etc. Examples of the liquid Z include toluene, ethylbenzene, tetralin, butyl acetate, ethyl propionate, etc., and examples of the liquid Z include heptane, butanol, inoctatool, cyclohexanol, dioctyl phthalate, etc.

The above is just an example, and a wide variety of liquids can be used by examining their solubility.

The polymerization method for obtaining the copolymer in the present invention may be either radical polymerization or ionic polymerization, but it is generally recommended to conduct the polymerization by dissolving a radical initiator in a monomer liquid mixture and heating it. be done.

Suitable radical initiators are selected from radical initiators which dissolve in the liquid and monomer mixture and undergo decomposition at the reaction temperature, examples being acyl peroxides such as benzoyl peroxide, lauroyl peroxide, etc. Azonitriles such as azobisisobutyronitrile, 2,2azobis(2,4-dimethylvaleronitrile), ditertiary-butyl peroxide,
There are peroxides such as dicumyl peroxide and methyl ethyl ketone peroxide, and hydroperoxides such as cumene hydroperoxide and tertiary hydroperoxide.

The reaction temperature is 10°C to 200°C, preferably 20°C.
°C to 150 °C1, more preferably 30 °C to 1000 °C, but when a monomer containing acrylonitrile is polymerized in an open system, it is necessary to lower the polymerization temperature because acrylonitrile has a low boiling point.

Therefore, it is desirable to use a low-temperature decomposition type initiator as part or all of the polymerization initiator.

For example, 2,2'-azobis(2,4-dimethylvaleronitrile L2,2'azobis(4-methoxy-2,4-
Dimethylvaleronitrile), tert-butyl pervalerate, diisobutyl peroxocarbonate, etc. are suitable.

One of the preferred polymerization methods for synthesizing the copolymer of the present invention is suspension polymerization in water, and in this case, granular resin can be easily obtained.

Acrylonitrile exhibits some solubility in water, but its solubility in water decreases significantly when water-insoluble liquids or monomers are added.

However, when performing polymerization by adding a water-soluble organic liquid, the suspension polymerization method cannot be used; instead, a method must be used in which a lump is obtained by solution polymerization and then pulverized to an appropriate particle size. It is.

Suspending agents used in the present invention include natural polymeric substances such as starch, gum tragacanth, and gelatin; processed natural polymeric substances such as hydroxyethylcellulose, methylcellulose, and carboxymethylcellulose; polyacrylic acid; polyvinylpyrrolitone, polyvinyl alcohol; Water-soluble synthetic polymer substances such as saponified polyvinyl acetate; inorganic substances such as barium sulfate, talc, hydroxyapatite, bentonite, silicic anhydride, and calcium carbonate are used.

Furthermore, when using acrylonitrile, it is widely recommended to add inorganic salts such as chloride, calcium chloride, etc. to the suspension in order to suppress some of its water solubility.

The above is a typical manufacturing method.

With this production method, a cyano-containing porous copolymer with an arbitrary average pore size and pore size distribution can be produced almost freely, resulting in a large number of small pores with an average pore size of 40 to 9,000. A porous polymer with a wide pore size distribution, which is considered to have branched channels, is obtained.

This porous copolymer is considered to have excellent effects as an adsorbent of the present invention due to its hydrophilic properties due to the cyano groups it contains and its porous structure.
It is stable over a wide range of areas, inert to water, solvents, etc., has excellent mechanical strength, has a long lifespan, does not change its adsorption capacity even after drying, can be made into spherical shapes, and has a simple manufacturing process. It also has the properties that an adsorbent should generally have.

Next, the method of using the adsorbent of the present invention will be described.

One of these is blood containing anticoagulant collected using conventional methods.
By adding 1/10 volume of the porous copolymer disclosed in the present invention and performing a stirring operation, the various organic compounds mentioned above adsorbed to the binding protein albumin or globulin fraction in plasma can be adsorbed. Can be separated.

Further, by filling a column with the porous copolymer shown in the present invention and passing blood containing an anticoagulant through the column, the above-mentioned organic compounds can be adsorbed and separated.

In addition, by incorporating a column filled with the porous copolymer shown in the present invention in the middle of the extracorporeal circulation circuit, organic compounds adsorbed to plasma proteins present in blood circulating in the body can be continuously adsorbed. Can be separated.

Furthermore, in the extracorporeal circulation using the porous copolymer disclosed in the present invention, separation can be achieved by using a plasma separator such as a continuous centrifugal plasma separator or a plasma separator using an artificial membrane. It is also possible to contact only the collected plasma with the porous copolymer disclosed in the present invention, and by using this method, the remaining amount of white blood cells, platelets, etc. can be suppressed.

From the protein aqueous solution of the anoporous copolymer of the present invention,
The details of the adsorption mechanism that adsorbs and separates the organic compounds adsorbed onto the protein have not been elucidated, but the protein that has adsorbed the organic compound diffuses into the porous copolymer.
Adsorbs to the surface of the internal pores.

In some cases, the organic compound may be adsorbed in this state, and in other cases, the interaction with the copolymer is greater than the interaction with the protein, and only the organic compound may be adsorbed.

When the dye indocyanine green is dissolved in plasma, the latter adsorption formation is predominant, and the dye can be efficiently adsorbed and separated from the plasma.

Because of these adsorption properties, by bringing blood into contact with the cyano-containing porous copolymer, organic compounds adsorbed to plasma proteins can be efficiently removed without denaturing plasma proteins.
It has become possible to quickly adsorb and separate it from blood.

Examples are shown below.

Example 1 55 g of freshly distilled acrylonitrile, divinylbenzene (56% purity) were added to a 31-meter three-loaf flask equipped with a reflux condenser, a stainless steel two-blade stirrer, and a thermometer.
, containing 44% vinyl ethylbenzene as impurities,
45 g of 56% divinylbenzene (hereinafter referred to as 56% divinylbenzene), 130 g of acetophenone, 120 g of decalin, 1 g of azobisisobutyronitrile, and 1 g of 2,2'-azobis-(2,4-dimethylvaleronitrile) were added to make a homogeneous solution.

In addition, partially saponified polyvinyl alcohol (viscosity 23 cp)
saponification degree 88%) a 25g, sodium chloride 12.5
Add 1,270 g of distilled water in which
While stirring at a rotational speed of
heated for an hour.

During the reaction, the reaction mixture was sampled at regular intervals and the benzene extract was analyzed by gas chromatography.
When the residual monomer was quantified and the polymerization rate was measured, it was confirmed that the polymerization rate was 98% or more under the above conditions.

Note that since acrylonitrile has a low boiling point, it is necessary to increase the efficiency of the reflux condenser by, for example, circulating cold water inside it.

The produced copolymer has a good spherical shape and a diameter of 60 to 5 mm.
It was in the range of 00μ.

After performing wet classification using a sieve, unreacted monomers, liquid, etc. were removed with methanol.

A portion of it was taken and dried under reduced pressure at 60° C. for 18 hours to prepare a sample for porosimeter.

The remaining copolymer was washed repeatedly with water.

The bulk specific gravity of this product is 0.21, the average pore diameter is 1200,
Pore volume 2.28 rnl/j! , surface area 220 rr
It was measured as r'/g.

In addition, the pore size was 0.871 nl/g between the pore size of 600jSL''7'] and 2,400 people.

Hereinafter, this will be referred to as R1.

In 150 fnl of bovine blood containing an anticoagulant, 0.3 ml of protein-adsorbing dye indocyanine green and 1 m9 of unconjugated vinyl vinyl (manufactured by Sigma, USA) are dissolved to prepare an adsorption mother liquor.

In this mother liquor, the porous copolymer R1 shown in Example 1 (
After adding 2g of particles (particle size 210 to 420μ) and adsorbing them by shaking for 2 hours, indocyanine green remaining in the blood and unconjugated delupine were quantified using a conventional method, and the adsorption rate was calculated using the following formula. .

Adsorption rate (4) Blood concentration before M-adsorption (Blood concentration after M-adsorption) (Blood concentration before adsorption) 100 We also examined the biochemical data of blood before and after adsorption, but found that only a small amount of total protein Other than a slight decrease, almost no changes were observed.

The results are shown in Table 1. Example 2 Hydroxyapatite 10 was added to the flask used in Example 1.
g, 10 g of hydroxymethyl cellulose, 20.9 g of calcium chloride, and 2000 r111 of distilled water, stirred at 70°C to make the solution uniform, and then lowered the liquid temperature to 30°C.

While stirring this aqueous solution at 200 rpm, acrylonitrile 50.9. Ethylene glycol dimethacrylate 10. @, 40 g of styrene, 300 g of chlorobenzene, 0.25 g of tert-butyl pervalerate,
A homogeneous solution of 0.75 g of benzoyl peroxide was added all at once.

30 minutes at 30°C, 1 hour at 40°C, 2 hours at 50°C,
The reaction was carried out at 60°C for 2 hours, at 700°C for 2 hours, and further at 80°C for 2 hours.

The performance of the resin obtained after thorough extraction and water washing was as follows.

Particle size 90-500μ, average pore size 500, pore volume 2.0
The pore volume is 1.03 yd/g based on pores with a diameter of 250 to 1000 yd/7.2 yd/g, and the surface area is 260 ml. This resin is referred to as R2.

Table 1 shows the results of performing the same operation as in Example 1 using this porous copolymer R2 (particle size 210 to 420 μm).

Comparative Example 1 Table 1 shows the results of carrying out the same operation as in Example 1 using 5 g of petroleum pitch-based beaded charcoal (particle size 210 to 420 μ) as an adsorbent.

Example 3 The bovine blood used in Example 1 was separated into blood cells using a centrifuge, and the plasma portion was used as an adsorption mother liquor.

This adsorption mother 11507727! ! and indocyanine green 0.3 ml and unconjugated bilirubin (manufactured by Sigma, USA) 1 mI; dissolve.

Put this adsorption mother liquor into Erlenmeyer flask 1 shown in the attached drawing,
Rotate and stir using magnetic stirrer 2.

In addition, porous copolymer R1 (particle size 2
2 g of 10-420 μ) was packed into column 3 and circulated by pump 4 at a flow rate of 5 rnl/mi.

After 2 hours of circulation, the concentration in the mother liquor was measured using a conventional method, and the adsorption rate was calculated in the same manner as in Example 1.The biochemical data of plasma before and after adsorption was also measured at the same time, and the results are shown in Table 2. Shown below.

Example 4 The porous copolymer R2 shown in Example 2 as an adsorbent (
Table 2 shows the results of carrying out the same operation as in Example 3 using 2 g of particles having a particle size of 210 to 420 μm.

Comparative Example 2 Petroleum pitch-based bead charcoal (particle size 210-42
Table 2 shows the results of performing the same operation as in Example 5 using 0μ)l.

Comparative Example 3 Hydroxy'/7patite 1 was added to the flask used in Example 1.
Add 0 g of hydroxymethyl cellulose, 10 g of calcium chloride, and 2000 g of distilled water, stir at 70°C to make the solution uniform, and then lower the temperature to 30°C.

While stirring this aqueous solution at 20 Orpm, 64 g of acrylonitrile and 36 g of 56% divinylbenzene were added thereto.
, 50 g of methyl isobutyl ketone, and 1 g of 2.2'-azobisisobutyronitrile were added all at once,
30 minutes at ℃, 1 hour at 40℃, 2 hours at 50℃, 60
The reaction was carried out at .degree. C. for 2 hours, at 700.degree. C. for 2 hours, and then at 80.degree. C. for 2 hours.

The performance of the resin obtained after thorough extraction and water washing was as follows.

Particle size 90-500μ, average pore size 525, pore volume 0.7
The porosity was 0.52 dl g (70%) based on 5rd,/g, 260-1050 person diameter pores.

The particles with a particle size of 210 to 420μ were separated using a sieve, and the adsorption rates of indocyanine green and unconjugated bilirubin in the plasma were calculated in the same manner as in Example 3, and the values were 42% and 28%. I got it.

[Brief explanation of drawings]

The drawing shows an example of an adsorption operation device using the adsorbent of the present invention.

Claims (1)

[Claims] 12% to 99% by weight of cross-linked polymerizable monomer and 1% by weight
An average pore size d obtained by copolymerizing a monomer mixture containing ~98% by weight of a cyano monomer selected from acrylonitrile, methacrylonitrile, α-chloroacrylonitrile, and cinnamitrile. ~9000A
Adsorption of organic compounds adsorbed to plasma proteins present in blood, which is made of a porous copolymer with a pore size of 0.5 d or more and less than 2 d, and the volume of pores is 20 to 60% of the total pore volume. Separation agent. 2. An adsorption/separation agent for organic compounds adsorbed to plasma proteins present in blood according to claim 1, wherein the cyano-containing monomer is acrylonitrile. 3. Adsorption and separation of organic compounds adsorbed to plasma proteins present in blood according to claim 1, wherein the weight fraction of the cyano-containing monomer is 5% to 85%. 4. Crosslinked polymer monomer 2. The adsorption/separation agent for organic compounds adsorbed to plasma proteins present in blood according to claim 1, wherein the polymer is divinylbenzene. 5. The adsorption/separation agent for organic compounds adsorbed on proteins according to claim 1, wherein the crosslinking polymerizable monomer is ethylene glycol dimethacrylate or polyethylene glycol dimethacrylate. 6 The weight fraction of the crosslinking polymerizable monomer to the total monomer is
%, the total pore amount per 1 g of dry polymer is o, o
57. The adsorption/separation agent for organic compounds adsorbed to plasma proteins present in blood according to claim 1, wherein tsJ';E- or less.