JPH0356741B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD OF THE INVENTION The present invention relates to adsorbents for endotoxins. [Prior art and its problems] Endotoxin is a substance that exhibits pyrogenicity and toxicity when it enters the blood of mammals. This is a lipopolysaccharide or a lipopolysaccharide-protein complex derived from the outer membrane of the cell wall of Gram-negative bacteria such as Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa. It is a stable substance. Therefore, water for injection, physiological saline, which is administered directly into the body without passing through the gastrointestinal tract, ring fluid containing nutrients such as glucose and vitamins, dialysate for hemodialysis, and proteins such as albumin. Endotoxin must not be mixed into the ring fluid. Ion exchange resins are known as adsorbents for endotoxins, but
Its adsorption capacity is small and it has 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 provides an endotoxin adsorbent 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 represents an alkyl group having a methylene chain length of 4 or more and 10 or less carbon atoms,
R ₂ and R ₃ represent a methyl group or an ethyl group.
Further, R ₄ and R ₅ represent a hydrogen atom or a lower alkyl group. X represents a normal anion represented by a chlorine ion. ). [Summary of Effects] The polymer of the present invention and its molded product can be used to treat endotoxemia in addition to removing endotoxins ten times more than ion exchange resins. [Description of composition and effects] 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. It refers to a copolymer as a component, and it is more preferable if 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. In the above general formula (1), if the methylene chain length of the alkyl group R ₁ is too short or too long, the adsorption capacity will be reduced. The alkyl group for R ₂ and R ₃ is best a methyl group. It is easiest to manufacture when the alkyl groups of R ₄ and R ₅ are hydrogen atoms. If the surface area of the molded article using the polymer 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 molding The surface area of the product is 0.01
50 m ² /g or less, more preferably 0.05 or more 10
m ² /g or less is preferable. 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 formed products with the solution will deteriorate, resulting in endotoxin adsorption. The polymer 1
0.5 mmol or more, more preferably 1.0 per g
It is preferable that the amount is present in millimoles or more. Examples are shown below. Example 1 Polypropylene (Mitsui “Noblen” J3HG)
50 minutes as an island component, polystyrene (Styron)
666) 46 minutes, polypropylene (Sumitomo “Noblen”)
WF-727-F) Sea-island type composite fiber containing a 4-minute mixture as a sea component (number of islands: 16, monofilament fineness: 2.6 denier,
Tensile strength 2.9g/d, elongation 50%, number of filaments 42)
100 g is immersed in a mixed solution consisting of 120 g of N-methylol-α-chloroacetamide, 800 g of nitrobenzene, and 1.7 g of paraformaldehyde,
The reaction was carried out 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. to obtain 71 g of chloroacetamidomethylated fiber (fiber A). 100 g of the fiber A obtained above was immersed in 10% aqueous ethanol 2 containing 100 g of potassium iodide and heated at 50° C. for 4 hours to obtain iodoacetamide methylated fiber (fiber B). 10g of fiber B to N,N-dimethylhexylamine
It was immersed in a solution consisting of 30 g and 170 g of dimethylformamide and heated at 80° C. for 5 hours. Furthermore, this fiber was packed in a chromatography column, and 1 part of 1N hydrochloric acid, 5 parts of water, 1 part of 1N-caustic soda water, 5 parts of
of water and 10 portions of 1M saline solution to obtain N,N-dimethyl-N-hexylammonium chloride acetamidomethylated fiber (sample 1 of the present invention). This one has a neutral salt decomposition capacity of 1.83
milliequivalent/g, weak basic group amount 0.05 milliequivalent/g
The Cl type water content was 1.9. Example 2 10 g of the fiber B obtained in Example 1 was mixed with 30 g of N,N-dimethyloctylamine and dimethylformamide.
It was immersed in 270g of the mixed solution and heated at 80°C for 5 hours.
Furthermore, this fiber was extracted using a Soxhlet extractor for 10
After methanol extraction for 1 hour, it was packed into a chromatography column, 1 part of 1N-hydrochloric acid, 5 part of water, 1 part of 1N-hydrochloric acid, 1 part of 1N-
The fibers were washed with caustic soda water, 5 parts of water, and 10 parts of 1N saline solution to obtain N,N-dimetal-N-octylammonium chloride acetamide methylated fibers (Sample 2 of the present invention). This product has a neutral salt decomposition capacity of 1.72 milliequivalents/g and a weak basic group content of 0.05.
In milliequivalents/g, the Cl type water content was 1.3. Example 3 Present invention sample 1, present invention sample 2, and comparative sample 1
The following endotoxin adsorption experiment was conducted for Prepare six test tubes (outer diameter 24 mm) for each sample, put 15 mg, 30 mg, 50 mg, 80 mg, 160 mg, and 300 mg of the sample into them, and then add 10 ml of lipopolysaccharide aqueous solution (E.Coli 055). :B5, trichloroacetic acid extraction method, manufactured by Deifco Laboratories, 0.11mg/
ml) and shaken at 37℃ for 6 hours.
The mixture was filtered through qualitative filter paper No. 2, and the concentration of lipopolysaccharide in the filtrate was measured by the phenol/sulfuric acid method (2 ml of sample + 1 ml of 5% phenol water + 5 ml of 98% sulfuric acid; 485 mμ). The difference between the lipopolysaccharide concentration in the mother liquor and the initial concentration (0.11 mg/ml) was regarded as the amount of lipopolysaccharide adsorbed, and an isothermal adsorption line was determined. 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 1.

[Table] 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 acetamide methylated fiber, its neutral salt decomposition capacity is 0.73 meq/g,
There were no weak bases, and the Cl type water content was 0.71. Comparative sample 2 was prepared by adding fiber B obtained in Example 1 to tri-n-butylamine in 15% DMSO/ethanol (1:1).
Tri-n-butylammonium chloride acetamidomethylated fiber obtained by heating in a solution at 55°C for 8 hours,
Its neutral salt decomposition capacity is 1.50 meq/g, weak basic group content is 0.02 meq/g, and Cl type water content is 1.57.
It was hot. Comparative sample 3 is a tri-n-propylammonium chloride acetamidomethylated fiber obtained by heating the fiber B of Example 1 at 55°C for 8 hours in a 20% DMSO/ethanol (1:1) solution of tri-n-propylamine. Its neutral salt decomposition capacity is 1.64 meq/g, there is no weak basic group, and the Cl type water content is
It was 1.57. Comparative sample 4 is fiber B of Example 1.
is a triethylammonium chloride acetamidomethylated fiber obtained by heating the above in a 25% ethanol solution of triethylammonium at 55°C for 5 hours, and its neutral salt decomposition capacity is 1.56 milliequivalents/g, and the amount of weak basic groups is 0.09 In milliequivalents/g, the Cl type water 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. Moreover, although Comparative Samples 1 to 4 are almost the same as the samples of the present invention in terms of the types of functional groups and the number of carbon atoms, their adsorption ability for endotoxins is much lower. This shows that the structure of the functional group represented by general formula (1) of the polymer of the present invention has a special affinity for endotoxins. Example 4 A fibrous polystyrene derivative (sample 3 of the present invention) having a functional group represented by the following general formula () was prepared in the same manner as in Example 1. For comparison, a fibrous polystyrene derivative (comparative sample 5) having a functional group represented by the following general formula () was prepared. E-coli055: B5B-derived lipopolysaccharide was dissolved in distilled water for injection to prepare a 0.1 mg/ml solution. 10 ml of this solution was dispensed into dry and sterilized test tubes. 20 samples each of inventive sample 3 and comparative sample 5.
Prepare mg, 30 mg, 60 mg, 100 mg, and 200 mg, add them to each test tube, shake at 37℃ for 10 hours, quantify the lipopolysaccharide concentration in the remaining solution using the phenol-sulfuric acid method, and find equilibrium using the isothermal adsorption line. The amount of adsorption was calculated. For polystyrene derivative fibers having the general formula (), when the residual liquid concentration was 0.055 mg/ml, the equilibrium adsorption amount was 48.4 mg/g fiber. On the other hand, in the case of (), the equilibrium adsorption amount is 5.2 mg/g
The polystyrene fiber having the general formula () according to the present invention had a much higher adsorption capacity for lipopolysaccharide, which is an endotoxin.

Claims (1)

[Scope of Claims] 1. An endotoxin adsorbent 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 represents an alkyl group having a methylene chain length of 4 or more and 10 or less carbon atoms,
R ₂ and R ₃ represent a methyl group or an ethyl group.
Further, R ₄ and R ₅ represent a hydrogen atom or a lower alkyl group. X represents a normal anion represented by a chlorine ion. )