JPS60197703A - Polymer excellent in endotoxin adsorptivity and its molding - Google Patents

Abstract

PURPOSE:The titled polymer having a large endotoxin adsorption capacity and useful for the treatment of endotoxinemia, comprising an aromatic vinyl polymer having a specified functional group introduced as a side chain. CONSTITUTION:An aromatic vinyl polymer [e.g., (alpha-methyl)-styrene polymer] reinforced with a poly(alpha-olefin) such as crystalline PP is immersed in and reacted with a solution, in a solvent such as nitrobenzene, of a compound having a functional group of the formula (wherein R1 is an alkyl having 4-10 methylene units, R2-3 are each CH3 or C2H5, R4-5 are each H or a lower alkyl, and X is an anion such as a chloride ion), e.g., N-methylol-alpha-chloroacetamide, at about 20 deg.C for about 1hr to obtain a poly(alpha-olefin)-reinforced aromatic vinyl polymer having at least 0.5mmol, per g of polymer, of the functional groups of the formula introduced as side chains. This polymer is formed into a molding, such as fiber or a membrane, having surface area of 0.01-50m<2>/g.

Description

[Detailed description of the invention] (Technical field of invention) The present invention relates to endotoxin adsorbents.

[Prior art and its problems]

** is a substance that exhibits pyrogenicity and toxicity when it enters the blood of mammals. This is a ribopolysaccharide or ribopolysaccharide-protein complex derived from the outer membrane of the cell wall of Gram bacteria such as Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa. It is a stable substance.

Therefore, water for injection and physiological saline that is administered directly into the living body without passing through the gastrointestinal tract, infusions containing nutritional components such as glucose and vitamins, and white fluid for dialysis.

Dialysate fluids and infusions containing proteins such as albumin must not be contaminated with endotoxins.

Ion exchange resins are known as adsorbents for endotoxins, but their adsorption capacity is small and they have not been put to practical use.

(Objective of the invention) To find an adsorbent with a large adsorption capacity for endotoxins.

(Structure of the Invention) The present invention relates to 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, and a molded product thereof.

In the above formula, R1 represents an alkyl group having a methylene chain length of 4 to 10 carbon atoms, and R2 and R3
represents a methyl group or an ethyl group.

Further, R4 and R5 represent a hydrogen atom or a lower alkyl group. X represents a normal anion represented by a chlorine ion.

It provides:

[Summary of effects]

The polymer of the present invention and its molded product can be used not only to remove endotoxins ten times more than ion exchange resins, but also to treat endotoxin I# collapse disease.

[Composition and effect explanation]

In the present invention, the vinyl polymer having an aromatic nucleus is a vinyl monomer T11 monopolymer having an aromatic nucleus represented by styrene, α-methylstyrene, vinyltoluene, etc., or a copolymer having these as the main component. It refers to polymers, and it is more preferred if these polymers are crosslinked. Further, it is more preferable that the polymer is reinforced with a polyα-olefin such as crystalline polypropylene or polyethylene, since the 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 mei, a membrane, etc., a method of crosslinking after molding is preferably employed.

In the above general formula (1), if the methylene chain length of alkyl JIR1 is too short or too long, the adsorption capacity will be reduced.

The alkyl group for R2 and Rs is preferably a methyl group.

It is easiest to manufacture when the alkyl groups of R4 and R5 are hydrogen atoms.

If the surface area of the molded article 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 filled with the molded article of the present invention will be poor, so the surface area of the molded article will be 0. 01 or more and 50 is /9 or less, more preferably,
It is preferably 0.05 or more and 10 m'/9 or less.

There is no particular limitation on the amount of the functional group represented by the above general formula (1) in the polymer of the present invention, but if it is too small, the affinity of the polymer of the present invention and its molded products with the solution will deteriorate, leading to endotoxic Since the adsorption capacity decreases, it is preferable that the amount is 0.5 mmol or more, more preferably 1.0 mmol or more per 1 g of the polymer.

Examples are shown below.

Example 1 Polypropylene (Mitsui "Noblen" J3HG) 50 minutes was used as the island component, polystyrene (Styron" 666) 4
6 minutes, polypropylene (Sumitomo “Noblen” WF-72
7-F) Sea-island type composite m1l with 4-minute mixture as sea component
I (number of islands 16, single yarn fineness 2°6 denier, tensile strength 2.
9cy/d, elongation 50%, number of filaments 42>100
0, N-methylol-α-chloroacetamide 120
Q. Nitrobenzene 8000. The sample was immersed in a mixed solution consisting of 1.7 g of rose formaldehyde and reacted at 20° C. for 1 hour. The fibers were taken out from the reaction solution and poured into 10 nm of ice water at 0° C. to stop the reaction, and then washed with water, and then the nitrobenzene adhering to the fibers was extracted and removed with methanol. This fiber (fiber 111A) was vacuum dried at 50°C to produce 1ft7 chloracetamide methyl synthetic fiber.
1a (IImA) was obtained.

The fiber A10 (l) obtained above was immersed in 10% aqueous ethanol 2Q containing 1009 potassium iodide, and heated to 50℃ for 4 hours.
Heat for a period of time and dry the □ iodoacetamide methylated fiber (1 ftB of fiber).

Fiber $181 (l = N, N-dimedylhexylamine 30
It was immersed in a solution consisting of Q and dimethylformamide 1709 and heated at 80°C for 5 hours. Furthermore, this fiber was packed in a chromatography column, 1N of 1N-hydrochloric acid, 5Q of water, 1
a 1N caustic soda water, 5a water and 10g 1
The mixture was sequentially washed with M-saline solution to obtain N,N-dimethyl-N-hexylammonium acetamidomethyl chloride (sample 1 of the present invention). This product has a neutral salt decomposition capacity of 1.83 milliliters! /Q, the amount of weak basic group was 0.05 milliequivalent 10, and the CI type water content was 1.9.

Example 2 The fiber B10Q obtained in Example 1 was immersed in a mixed solution of 300% N,N-dimethyloctylamine and 2700% dimethylformamide, and heated at 80°C for 5 hours. Furthermore, this fiber was extracted with methanol for 10 hours using a Soxhlet extractor, and then packed into a chromatography column. Wash with N chloride,
N-dimetal-N-octylammonium acetamidol synthetic fiber (sample 2 of the present invention) was obtained. This thing is
The neutral salt decomposition capacity is 1.72 milliequivalent fIi/g, the amount of weak basic group is 0.05 milliequivalent/Q, and the C+ type water content is 1.3.
Met.

Example 3 The following endotoxin adsorption experiment was conducted on Inventive Sample 1, Inventive Sample 2, and Comparative Sample 1.

Prepare 6 test tubes (outer diameter 24 mm) for each sample, and in them 15-g, 30-g, 5010.80 + 16 oz.
01! Insert the samples II and 3.00■9, and then
10-I ribopolysaccharide aqueous solution (E, Co11 055
: B5, trichloroacetic acid extraction method, manufactured by Difco Laboratories, 0, 11 gio/ml), 37
After shaking at ℃ for 6 hours, it was filtered through a No. 2 qualitative filter paper, and the concentration of lipopolysaccharide in the filtrate was determined using the phenol-sulfuric acid method (sample 21 + 5% phenol water 1-1 + 98% sulfuric acid 5).
sl:485-μ). The difference between the ribopolysaccharide concentration in the mother liquor and the initial concentration (0.11 ma/ll) was regarded as the amount of adsorbed ribopolysaccharide, and an isothermal adsorption line was drawn. In order to compare the absorption capacity of each sample, the mother liquor concentration was 0.05 ma/m
Table 1 shows the results of considering the adsorption capacity when 1 is equal to the constant vortex @ wire attachment.

Table 1 However, Comparative Sample 1 is N chloride, prepared in exactly the same manner as in Example 1, except that N,N-dimethyllaurylamine is used instead of N,N-dimethyloctylamine in Example 2. N-dimethyl-N-lauryl ammonium acetamidomethyl compound, its neutral salt decomposition capacity is 0.73
Milliequivalent/Q, no weak base, C1 type water content O,'
It was 71. Comparative sample 2 is fiber 11B obtained in Example 1.
tri-n-butylammonium chloride acetamidomethylated fiber obtained by heating at 55°C for 8 hours in a 15% DMSO/ethanol (1:1) solution of tri-n-butylamine,
Its neutral salt decomposition capacity is 1.50 meq/g, weakly basic IM is 0.02 meq/Q, and type CI water content is 1.5.
It was 7. Comparative sample 3 was prepared by mixing the fiber INIB of Example 1 with tri-n-propylamine in 20% DMSO/ethanol (
1:1) trichloride obtained by heating at 55°C for 8 hours in solution
- propylammonium acetamidomethylated Ill, whose neutral salt decomposition capacity is 1.64 meq. 10;
There were no weakly basic groups, and the CI type water content was 1°57. Comparative sample 4 is a triethylammonium chloride acetamidomethylated mixture obtained by heating the fiber 11B of Example 1 at 55° C. for 5 hours in a 25% ethanol solution of triethylammonium, and its neutral salt decomposition capacity is 1. .56 meq@/g, the amount of weak basic group is 0.09 meq/g,
Type CI moisture content was 1.20.

Table 1 shows that the sample of the present invention has an endotoxin adsorption capacity that is 10 times or more that of the ion exchange resin. In addition, comparative samples 1 to 4
Although it is almost the same as the sample of the present invention in terms of the number of functional groups and the number of carbon atoms, its sensitivity to endotoxin is much smaller. From this, the general formula (
It can be seen that the structure of the functional group shown in 1) has a special affinity for endotoxins.

Patent applicant Higashi Shikikai Co., Ltd.

Claims (1)

[Scope of Claims] 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, and a molded product thereof. In the above formula, R1 represents an alkyl group having a methylene chain length of 4 to 10 carbon atoms, and R2 and R3
represents a methyl group or an ethyl group. Further, R4 and R5 represent a hydrogen atom or a lower alkyl group. X represents a normal anion represented by a chlorine ion.