JPH0526507B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field of the Invention) The present invention relates to a blood treatment agent that specifically adsorbs harmful components in blood that cause brain damage, liver necrosis, etc. when liver function is impaired, and lipids such as cholesterol in blood. (Prior art) When liver function deteriorates significantly due to viruses, drugs, or cancer, a large amount of toxic substances that should be detoxified by the liver leak into the blood, which reaches the brain and causes serious brain damage. It is known. Furthermore, cholesterol in the blood accelerates arteriosclerosis, leading to strokes and myocardial infarctions.
It is extremely difficult to selectively remove these toxic components in the blood and lipids such as cholesterol in the blood without using expensive immunological techniques. (Problems to be Solved by the Invention) The present inventors provide an adsorbent that selectively removes harmful components and cholesterol from blood, which can be used for clinical analysis and treatment. (Means for Solving the Problems) A blood treatment agent made of a vinyl polymer having an aromatic nucleus into which a functional group represented by the following general formula (1) is introduced as a side chain. [In the above formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and R ₃ represents an alkylene group having a methylene chain length of 2 or more. In addition, R ₅ is an alkyl group, an alkenyl group, an acyl group,

【formula】

[Formula] is shown. Moreover, R ₆ and R ₇ represent an alkenyl group or an alkyl group. R ₄ represents R ₅ or a hydrogen atom or a lower alkyl group. ] (Description of means) The vinyl polymer having an aromatic nucleus as used in the present invention is a homopolymer of a vinyl monomer having an aromatic nucleus such as styrene, α-methylstyrene, vinyltoluene, etc., or a vinyl polymer having these as a main component. It is more preferable that these polymers are crosslinked. Further, it is more preferable that the polymer is reinforced with polyα-olefin, such as crystalline polypropylene or polyethylene, since mechanical properties will be improved. Examples include copolymers with polyvinyl compounds such as divinylbenzene or methylenebisacrylamide, as well as monovinyl compound polymer molded products crosslinked with formaldehyde, chlorosulfonic acid, etc. Crosslinked polymers have no fluidity and are difficult to mold, so when the polymer molded product is a fiber, membrane, etc., a method of crosslinking after molding is preferably employed. If the surface area of the blood treatment agent of the present invention is too small, the immobilization density will be low, but if it is too large, the liquid permeability of the column packed therein will be poor, so the surface area of the treatment agent should be 0.01 or more. It is preferably 50 m ² /g or less, more preferably 0.05 or more and 10 m ² /g or less. Specifically, those in the form of fibers are particularly preferred. In the present invention, the side chain introduced into the vinyl polymer having an aromatic nucleus is a functional group represented by the following general formula (1). [In the above formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and R ₃ represents an alkylene group having a methylene chain length of 2 or more. In addition, R ₅ is an alkyl group, an alkenyl group, an acyl group,

【formula】

[Formula] is shown. Moreover, R ₆ and R ₇ represent an alkenyl group or an alkyl group. R ₄ represents R ₅ or a hydrogen atom or a lower alkyl group. ] In the above formula, R ₃ has a longer methylene chain, since the adsorption capacity increases, so it is preferably 6 or more methylene chains, more preferably 12 or more methylene chains. Also,
The longer the methylene chain length of _R5 , the better the affinity with lipids such as cholesterol, but raw materials with a methylene chain length of 24 or more are difficult to obtain. Specific examples when R ₅ is an acyl group include lauric acid, palmitic acid, stearic acid, oleic acid, linoleic acid,
Examples include acyl groups such as linoleic acid, elaidic acid, and glucuronic acid. If the density of the functional groups represented by general formula (1) is too low, the adsorption capacity will be low, so preferably the polymer 1
0.2 mmol or more per g, more preferably 1.0
Make it present in millimoles or more. Furthermore, when a functional group having a tertiary amino group is present as a side chain in the vinyl polymer having an aromatic nucleus of the present invention in addition to the functional group represented by the above general formula (1), the adsorption capacity is increased. It is preferable because it has the characteristic of increasing. Although there is no particular limitation on the chemical structure of such a functional group, a functional group represented by the following general formula (2) is usually preferably selected from the viewpoint of ease of production. [In the above formula, R ₈ and R ₉ represent a hydrogen atom or a lower alkyl group. ] Even when such a functional group is present, it is preferable that the functional group of general formula (1) is present in an amount of at least 0.01 mmol per 1 g of the polymer. When the functional groups represented by general formula (2) are present together, the sum of the functional groups represented by general formulas (1) and (2) is at least 1.0 per gram of the polymer.
The amount is selected from the viewpoint of adsorption capacity, preferably 2.0 mmol or more. An example of the production of the blood treatment agent of the present invention is as follows:
A molded article made of an α-haloacetamidomethylated aromatic vinyl polymer (JP-A-57-12008) is mixed with a solution of an amine represented by the general formula (3), or a solution of the amine and the general formula (4). First, a carrier is obtained by immersing it in a mixed solution with an amine. R ₈ -NH-R ₉ (4) Next, the following general formula (5 The blood treatment agent of the present invention can be produced by immersing the above-mentioned carrier in a mixed solution of a long-chain carboxylic acid represented by the following formula and N,N'-dicyclohexylcarbodiimide. R ₅ COOH (5) When R ₅ is the following functional group, it is prepared as follows. (a) When using an alkyl group: Mix the alkyl halide and the carrier. Alternatively, an alkylated diamine is reacted. B

When [expression]:

[Formula] (chlorocarbonate) and carrier Just mix it up. C

When [expression]:

[Formula] (isocyanate) and a carrier may be mixed. (Example) Example 1 Polypropylene (Mitsui “Noblen” J3HG)
50 parts as an island component, polystyrene (“Styron”)
666) 46 parts, polypropylene (Sumitomo “Noblen”)
Sea-island composite fiber containing 4 parts of WF-727-F) as a sea component (number of islands: 16, monofilament fineness: 2.6 denier,
Tensile strength 2.9g/d, elongation 50%, number of filaments
42) 100g, N-methylol-α-chloroacetamide 120g, nitrobenzene 800g, 98% sulfuric acid
It was immersed in a mixed solution consisting of 800 g and 1.7 g of paraformaldehyde, and reacted at 20°C for 1 hour. The fibers were taken out from the reaction solution and poured into ice water at 0° C. to stop the reaction, washed with water, and then nitrobenzene adhering to the fibers was extracted and removed with methanol. This fiber (fiber A) was vacuum-dried at 50°C, and the chloroacetamide methylated fiber 140
I got g. Dodecamethylene diamine 23.7g 50% of 2100ml
68 g of the fiber A obtained above was added to the mixed solution obtained by dissolving it in a dimethylamine aqueous solution, and the mixture was heated to 48 g at room temperature.
Allowed time to react. The fibers were taken out and thoroughly washed with dilute hydrochloric acid and water to obtain mixed aminated fibers (fiber C). The amount of dimethylamino groups in this fiber C was 2.51 meq/g, and the amount of dodecamethylenediamine was 0.18 meq/g. After treating 30 g of fiber C with a 1N-NaOH aqueous solution, it was thoroughly washed with water and then dried to obtain an aminated fiber (fiber D). Next, 2.35 g of stearic acid was dissolved in 200 ml of N,N dimethylformamide (hereinafter referred to as DMF) (solution E). On the other hand, 2.05 g of N,N'-dicyclohexylcarbodiimide (DCCD) was dissolved in 20 ml of DMF and added to the above solution E. The mixture was immediately stirred to obtain a homogeneous solution, into which 6 g (dry weight) of fiber D was added and reacted at room temperature for 72 hours. The reaction fibers were taken out, packed into a chromatography column, and washed with 250 ml of DMF, washed with a 1N-NaOH aqueous solution, and further washed with water to obtain fibers (1), which are the blood treatment agent of the present invention. This product had an exchange capacity of 2.39 meq/g and a Cl type water content of 0.71. The difference between this exchange capacity and the exchange capacity of fiber C was regarded as the amount of stearic acid immobilized on the fiber. The immobilized amount was 33 mg/g. Example 2 2.33 g of elaidic acid was dissolved in 200 ml of DMF (solution F). On the other hand, 2.05 g of DCCD was dissolved in 20 ml of DMF and added to the above solution F. Stir immediately to make a homogeneous solution, and add 6.5 g (dry weight) of fiber D into it.
was added and allowed to react at room temperature for 72 hours. The reaction fibers were taken out, packed into a chromatography column, and washed with 250 ml of DMF, washed with a 1N-NaOH aqueous solution, and further washed with water to obtain fibers (2), which are the blood treatment agent of the present invention.
This product had an exchange capacity of 2.51 meq/g and a Cl type water content of 0.74. The immobilized amount was 25 mg/g. Example 3 Fibers of the blood treatment agent of the present invention obtained in Examples 1 and 2
The following adsorption experiments were conducted for (1) and (2). Add the sample (the above fiber (1) or
(2)) After adding 200mg and shaking at 37℃ for 3 hours,
The amount of blood components in the supernatant was examined, and the adsorption rate for each component was determined. The results are shown in Table 1. however,
HDL-cholesterol was determined by heparin manganese precipitated enzyme method.

[Table] Comparison sample in the table 1: Ion exchange resin (manufactured by Organo; IRA-938)
was used. This one has an exchange capacity of 3.7 milliequivalents/
g, and the water content was 2.4 (PH7.4). Comparative sample 2: 100g of fiber A containing 100g of potassium iodide
Iodoacetamide methylated fibers were obtained by soaking in 2% aqueous ethanol and heating at 50°C for 4 hours, and 5 g of this fiber was soaked in a solution consisting of 30 g of tri-n-propylamine, 60 g of dimethyl sulfoxide, and 60 g of ethanol. Tri-n-propylammonium chloride acetamidomethylated fiber obtained by heating at ℃ for 12 hours and washing with dilute hydrochloric acid and 1M saline. The neutral salt decomposition capacity of this product is
The amount of weak basic groups was 1.64 meq/g, and the Cl type water content was 1.57. From Table 1, fibers (1) and (2) that are blood treatment agents of the present invention
is a toxic substance represented by bilirubin and HDL-
It can be seen that both cholesterol and lipid peroxide are adsorbed well. Example 4 Fibers of the blood treatment agent of the present invention obtained in Examples 1 and 2
The following endotoxin adsorption experiments were conducted for (1) and (2). Prepare 5 test tubes (outer diameter 24 mm) for each sample, and hold 20 mg, 40 mg, 60 mg, 100 mg, and 200 mg in each tube.
Then add 10 ml of lipopolysaccharide aqueous solution (E.Coli 055:B5, trichloroacetic acid extraction method, manufactured by Deifco Laporatories, 0.11 mg/ml) and shake at 37°C for 4 hours. Thereafter, it was filtered through No. 2 qualitative filter paper, and the concentration of lipopolysaccharide in the filtrate was measured by the phenol/sulfuric acid method (2 ml of sample + 1 ml of 5% phenolic water + 5 ml of 98% sulfuric acid; 485 mμ). Lipopolysaccharide concentration in mother liquor and initial concentration (0.11mg/ml)
The isothermal adsorption line was determined by regarding the difference between the two as the amount of lipopolysaccharide adsorbed. In order to compare the adsorption capacity of each sample, the adsorption capacity when the mother liquor concentration was 0.05 mg/ml was determined from the isothermal adsorption curve, and the results are shown in Table 2.

[Table] Comparative sample (3) in the table: Results using ion exchange resin (manufactured by Organo Corporation; Amberlite XAD-2). Comparative sample (4): 10 g of the fiber B obtained in Example 1 was immersed in a mixed solution of 30 g of N,N-dimethyllaurylamine and 270 g of DMF, heat-treated at 80°C for 5 hours, and then
After extracting this fiber with methanol for 10 hours using a Soxhlet extractor, it was packed into a chromatography column and
1N-hydrochloric acid aqueous solution, 5. water, 1.1N-NaOH
N,N-dimethyl-N-lauryl ammonium chloride acetamidomethylated fibers obtained by washing with an aqueous solution, 5 and 10 1M saline solutions.
The neutral salt decomposition capacity of this fiber is 0.73 meq/g
There was no weak basic group content, and the Cl type water content was 0.71. Table 2 shows that fibers (1) and (2), which are blood treatment agents of the present invention, have excellent adsorption properties for endotoxins. (Effects of the Invention) The blood treatment agent of the present invention has the characteristic that it can selectively adsorb and remove harmful components and endotoxins in the blood represented by vinyl vinyl, as well as lipids such as cholesterol in the blood, plasma, or serum. It can be applied to the treatment of jaundice and endotoxemia, as well as hyperlipidemia and hypercholesterolemia.

Claims (1)

[Scope of Claims] 1. A blood treatment agent comprising a vinyl polymer having an aromatic nucleus into which a functional group represented by the following general formula (1) is introduced as a side chain. [In the above formula, R ₁ and R ₂ represent a hydrogen atom or a lower alkyl group, and R ₃ represents an alkylene group having a methylene chain length of 2 or more. R ₅ is an alkyl group,
Indicates an alkenyl group, an acyl group, [Formula] [Formula]. Moreover, R ₆ and R ₇ represent an alkenyl group or an alkyl group. R ₄ represents R ₅ or a hydrogen atom or a lower alkyl group. ]