JPH0653172B2 - β ▲ 2 ▼ -Microglobulin adsorbent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides β ₂ -microglobuli (β ₂ -micro-globuli).
n, β ₂ MG) adsorbent, and more particularly to a β ₂ -microglobulin adsorbent composed of a copolymer of polyvinyl monomers and monovinyl aliphatic monomers or a copolymer of polyvinyl monomers.

[Prior Art] With the progress of technologies such as hemodialysis, blood purification therapy has been established to some extent, which removes toxic or pathogenic substances in blood from low molecular weight substances to high molecular weight substances according to the purpose. As a method for removing the pathogenic substance, hemodialysis, blood passing, or a combination thereof is performed.

Also, an adsorbent capable of adsorbing and purifying a pathogenic substance in blood has been developed. Activated carbon, anion exchange resin, styrene-divinylbenzene copolymer, and other copolymers are known.

However, hemodialysis etc. can remove low molecular weight solutes that pass through the membrane, but proteins with relatively low molecular weight cannot be removed by dialysis alone, and gradually accumulate in the patient's body, changing the patient's condition to one different from that of a healthy person. It goes.

Generally, when removing pathogenic substances in blood using an adsorbent, it is necessary to selectively and surely have an adsorbing ability for these pathogenic substances, which are trace amounts but cannot be completely removed by conventional blood purification methods. is there.

Recent studies have revealed that β ₂ MG is a causative agent of amyloid-cis, which occurs frequently in long-term dialysis cases, and development of a method for removing this substance occupies an important therapeutic position. I am sorry.

However, the effect of removing β ₂ MG is not sufficient by ordinary hemodialysis, hemodialysis, hemodialysis, blood adsorption method using activated carbon and the like.

In addition, no studies have so far been reported to selectively and efficiently adsorb β ₂ MG in blood purification.

[Problems to be solved by the invention]

An object of the present invention, beta ₂ present in the blood - is to provide an adsorbent which selectively and efficiently adsorbing microglobulin (β ₂ MG).

[Means for solving problems]

A copolymer or the like composed of a monovinyl monomer crosslinked with a polyvinyl monomer has a three-dimensional structure, and is therefore stable and therefore has sufficient strength as an adsorbent. However, this copolymer may have different adsorption properties depending on the type and structure of the monomer.

Therefore, the present inventors have conducted research on an adsorbent that specifically adsorbs β ₂ MG, based on a cross-linked copolymer composed of a polyvinyl monomer and a monovinyl monomer,
The present invention has been completed.

That is, the present invention is a polyvinyl aliphatic monomer and /
Alternatively, it is a β ₂ MG adsorbent having a structure composed of a copolymer composed of a polyvinyl aromatic monomer and a monovinyl aliphatic monomer, or a copolymer composed of a polyvinyl aliphatic monomer and a polyvinyl aromatic monomer.

The adsorbent of the present invention selectively adsorbs and removes β ₂ MG, which is not removed during conventional blood purification, but does not adsorb and remove proteins such as albumin. As described above, β ₂ MG cannot be removed by hemodialysis, hemodialysis, hemodialysis and the like.
Further, even adsorbents that have been conventionally known for blood purification and the like cannot be sufficiently removed. The adsorbent of the present invention can release this.

The copolymer as the adsorbent of the present invention will be described.

The polyvinyl aliphatic monomer and / or the copolymer of the polyvinyl aromatic monomer and the monovinyl aliphatic monomer or the copolymer of the polyvinyl aromatic monomer and the polyvinyl aliphatic monomer of the present invention may be an emulsion polymerization method, a bulk polymerization method, or a suspension polymerization method. Although it is produced by a known polymerization method such as a turbid polymerization method, it is preferably produced by a suspension polymerization method. This is because according to this method, a bead-shaped granular material having a uniform particle diameter can be obtained, and further, a material having a desired particle diameter can be obtained by adjusting the stirring speed and the like. The bead-like copolymer is convenient in processing operations such as batch processing and column processing. Although not involved in the composition of the copolymer formed in the polymerization system at the time of polymerization, it is preferable to use a method in which the copolymer is allowed to coexist with a pore-forming agent that imparts physical properties such as porosity. There are various examples of the pore forming agent. For example, acting as a solvent on the monomer mixture,
An organic liquid (precipitating agent) that is substantially insoluble or poorly soluble in water and does not swell the produced copolymer, acts as a solvent on the monomer mixture, and is substantially insoluble or poorly soluble in water, and produces An organic liquid (swelling agent) that swells the copolymer, an organic solvent that allows the swelling agent and the precipitant to coexist, an organic solvent that includes the swelling agent and a monovinyl linear polymer that can form a uniform liquid phase with the swelling agent. Examples include, but are not limited to, an inert polymer that is soluble in a liquid, and further in a monomer mixture, insoluble in a produced copolymer and soluble in water, and is not limited thereto. It is of course possible to use agents and the like. Suspension polymerization may be carried out without adding these pore-forming agents.

Next, the monomer that constitutes the composition of the adsorbent of the present invention will be described.

Polyvinyl aliphatic monomers include ethylene glycol dimethacrylate, ethylene glycol diacrylate, trimethylolpropane trimethacrylate, diethylene glycol divinyl ether, allyl acrylate, allyl methacrylate, diallyl maleate, diallyl fumarate, diallyl adipate, tetra- and tri-methacrylic acid. Examples thereof include pentaerythritol, neopentyl glycol dimethacrylate, and the like.Polyvinyl aromatic monomers include divinylbenzene, divinyltoluene, trivinylbenzene, divinylchlorobenzene, divinyltoluene, divinylnaphthalene, divinylxylene, divinylethylbenzene, fumaric acid. Examples include diallyl and the like. On the other hand, as monovinyl aliphatic monomers, methyl acrylate, ethyl acrylate, propyl acrylate, isopropyl acrylate, butyl acrylate, ethylhexyl acrylate, hydroxyethyl acrylate, glycidyl acrylate, methyl methacrylate, ethyl methacrylate, propyl methacrylate, propyl methacrylate, isopropyl methacrylate, butyl methacrylate. , Ethylhexyl methacrylate, hydroxyethyl methacrylate, glycidyl methacrylate, acrylonitrile, methacrylonitrile and the like. The ratio of the monomers of these copolymers is arbitrarily selected. Some of these copolymers are commercially available as weakly acidic cation exchange resins or as synthetic adsorbents. Specific examples thereof include Amberlite (registered trademark of Rohm and Haas Company) IRC-50, IRC-
75, IRC-84, Diaion (registered trademark of Mitsubishi Kasei Kogyo Co., Ltd.) WK10, WK11, WK13, WK20, Deuolite (registered trademark of Deuolite Internal Company) C-433, C
-464, CC-3, Levatit (registered trademark of Bayer AG)
CNP80, Dowex (registered trademark of Dow Chemical Company) CC
R-2 and the like are applicable and can naturally be used as the β ₂ MG adsorbent of the present invention.

〔Example〕

Example 1. Amberlite XAD-8, Amberlite IRC-50 and Diaion WK20 were used as the adsorbents of the present invention, and performances were compared using Amberlite XAD-4 and IR-45 as comparative agents.

An adsorbent and a test serum (pool serum of a uremia patient) were added to the plastic tube in a volume of 1: 3, and the mixture was shaken for several seconds until the whole mixture was mixed, and then 0 times, then twice / sec. The mixture was shaken at room temperature at a ratio of 10 to determine the amounts of various components in serum after the indicated time. β ₂ MG was obtained by using β ₂ -microglobulin “Eiken” kit (manufactured and sold by Eiken Chemical Co., Ltd.). The total protein (TP) and albumin (Alb.) Were determined by the visual method and the BCG method, respectively. The results are shown in the table below.

In each of the adsorbents of the present invention, the beads themselves were not cracked or crushed after the lapse of the final time.

Example 2. Soak 2 g of the wet adsorbent in 30 ml of methanol,
This was left to stand on a paper lined on the bottom of a ml syringe, and then washed with 80 ml of pure water. The syringe was equipped with a 22 gauge needle. It can maintain a flow rate of about 1-1.3 ml / min.

After thoroughly washing with pure water, add 20 ml of control serum,
The same serum was treated, and the total protein (TP), albumin (Alb.) And β ₂ MG in the serum were measured for the serum that had flowed out. T. P. Is the view method, Alb. Is BCG
Law, β ₂ MG is β ₂ - using microglobulin "Eiken" Kitsuto (Eiken Chemical Co., Ltd., production and sales).

The following was used as the adsorbent.

1) Copolymer of methyl methacrylate and divinylbenzene (containing 30% divinylbenzene). Suspension polymerization was performed using methylisobutylcarbinol (precipitating agent) and toluene (swelling agent) as pore-forming agents.

2) Copolymer of trimethylolpropane trimethacrylate and divinylbenzene (containing 50% divinylbenzene).
Suspension polymerization was performed using methyl isobutyl carbinol (precipitating agent) as a pore forming agent.

3) Hydrolyzate of methyl methacrylate, trimethylolpropane trimethacrylate and divinylbenzene (70% divinylbenzene content) copolymer. Suspension polymerization was performed using methyl isobutyl carbinol as a pore forming agent.

As a comparison agent, 4) styrene-divinylbenzene (containing 1% divinylbenzene) copolymer and 5) Amberlite XA
D-4 was used.

The results are shown in the table below.

The appearance of the adsorbents of the present invention did not change.

〔The invention's effect〕

The adsorbent of the present invention has a characteristic that it selectively adsorbs β ₂ MG and does not adsorb proteins such as albumin. It can be used in combination with hemodialysis, hemodialysis, blood hyperdialysis, blood adsorption removal method using activated carbon, etc. in blood purification, and can also be used for adsorption tubes such as direct blood perfusion method and plasma perfusion method. is there.

Front Page Continuation (72) Inventor Shuji Tamura 5-2-1 Toshima, Kita-ku, Tokyo Inside Tokyo Organic Chemical Industry Co., Ltd.

Claims (1)

[Claims] 1. A structure comprising a polyvinyl aliphatic monomer and / or a copolymer of a polyvinyl aromatic monomer and a monovinyl aliphatic monomer, or a copolymer of a polyvinyl aliphatic monomer and a polyvinyl aromatic monomer. And a β ₂ -microglobulin adsorbent.