JPS6311027B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a medical adsorbent used to treat diseases by removing harmful substances from body fluids such as blood, plasma, or ascites. Harmful components in the blood that are thought to cause brain damage and liver necrosis during liver dysfunction or drug addiction, as well as harmful metabolites during renal failure, can be removed by adsorption with activated carbon or ion exchange resin, dialysis, or excessive treatment. Therapies to remove these substances are called artificial livers, artificial liver support, and artificial kidneys, and have been clinically implemented in recent years. Among these, in the blood perfusion method using an adsorbent, adsorbent powder is released into the blood, blood coagulates,
In order to avoid hemolysis, decrease in platelets, etc., adsorbents have been coated with various coating agents.
A typical example is coating with polyhydroxyethyl methacrylate (Journal of the American Society for Artificial Organs 17 , 222
(1971)), and this method has superior blood compatibility compared to methods of coating with collodion, gelatin, etc. However, coating only with hydrophilic acrylates such as polyhydroxyethyl methacrylate has a weak strength of the coating layer, and some of the coating layer peels off, and it is desirable to avoid this. For this purpose, suitable difunctional monomers (crosslinking agents) and curing agents such as dichromates or free radical catalysts are mixed into the polymer solution used to coat the adsorbent. A method of crosslinking and curing by heat treatment after coating is known (Japanese Unexamined Patent Application Publication No. 1989-1999).
76219), but with this method, it cannot be denied that a small amount of the unpolymerized crosslinking agent and curing agent may be mixed into the coating layer and elute into the blood during use. Incidentally, epoxides are known as post-crosslinking agents similar to those used in the present invention (Japanese Patent Laid-Open No. 53-22178). When hydroxyethyl methacrylate is polymerized using this polymerizable monomer having an epoxy group as a copolymerization component, it may become insolubilized during polymerization, purification, or storage. For example, when using more than a few percent of glycidyl methacrylate, problems such as insolubility in the solvent ethanol often occur. Furthermore, many epoxides are poorly soluble in water, and the washing effect with water is small, so the possibility of monomer remaining in the coating layer cannot be denied. The present invention eliminates these possibilities, improves the strength of the coating layer by crosslinking the coating layer after coating, prevents the generation of fine particles from the adsorbent itself and the coating layer, and eliminates unreacted particles. In order to eliminate the elution of the coating polymer (including low molecular weight substances) without using a low molecular weight crosslinking agent or curing agent that may elute if left, N-methylol groups or N
- It is characterized in that a hydrophilic (meth)acrylate polymer containing a polymerizable monomer having a methylol ether group as one of the polymerization components is used as the coating layer of the adsorbent. Below, the structure of the adsorbent for blood purification according to the present invention will be explained in detail. Adsorbents include activated carbon, alumina, silica,
Conventionally used adsorbents such as ion exchange resins and organic synthetic adsorbents (Amberlite XAD, etc.) are used. The shape of the adsorbent is preferably one with no corners or ridges, that is, a true spherical shape or a shape close to it, in order to prevent the generation of fine particles and to prevent blood clotting and hemolysis. Spherical activated carbon made from pitch is suitable. The size of the adsorbent is 0.1 to 5 mm in diameter, especially 0.5 to 5 mm.
A diameter of about 1 mm is preferable because it has high adsorption performance and low pressure loss. Therefore, a spherical activated carbon adsorbent coated with a hydrophilic (meth)acrylate polymer is
This is the most preferable combination for this technology. The hydrophilic (meth)acrylate copolymer that is the base material of the coating layer of the present invention is a hydrophilic acrylate copolymer or a hydrophilic methacrylate copolymer, and the monomer used as the main component of the polymer is is the general formula Or general formula (However, in () and (), R ₁ is hydrogen or a methyl group; R ₂ is a divalent alkylene group or poly(oxyalkylene) group having 2 to 3 carbon atoms with or without a substituent; R ₃ and R ₄ are Substituted or unsubstituted hydroxy or alkoxyalkyl (meth)acrylate represented by hydrogen or an alkyl group having 1 to 3 carbon atoms, which may further have a polar substituent such as a hydroxyl group or an amino group amino or alkylamino(meth)acrylates or poly(alkylene glycols)
One or more monomers selected from the group of monomers consisting of hydrophilic (meth)acrylates such as (meth)acrylates are suitable; specifically, hydroxyethyl methacrylate, hydroxyethyl Acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate, polyethylene glycol monomethacrylate, polyethylene glycol monoacrylate,
polypropylene glycol monomethacrylate,
Examples include polypropylene glycol monoacrylate, methoxyethyl methacrylate, methoxyethyl acrylate, dimethylaminoethyl methacrylate, and dimethylaminoethyl acrylate. In addition, the polymerizable monomer having an N-methylol group or N-methylol ether group that is added to improve the strength of the coating layer and prevent elution, which is a feature of the present invention, has the general formula (However, R ₁ , R ₂ , R ₃ are hydrogen or methyl groups; R ₄
is hydrogen or an alkyl group having 1 to 4 carbon atoms), specifically N-methylolacrylamide, N-methylolmethacrylamide, N-n-butoxymethylacrylamide, etc. In particular, N-methylol acrylamide and N-methylol methacrylamide are suitable, in which the product produced during crosslinking by heat treatment is water in order to improve the strength of the coating layer and prevent elution. The hydrophilic (meth)acrylate copolymer has a monomer selected from the above () and () as a main component, and a monomer having an N-methylol group or an N-methylol ether group selected from (). It is prepared by polymerizing the polymer as a copolymer component using conventional methods such as solution polymerization and suspension polymerization. The proportion of these monomers having an N-methylol group or N-methylol ether group is preferably 0.1 to 30% by weight, preferably 0.1 to 5% by weight, and usually 0.1 to 1% by weight based on the total monomers. In order to improve the mechanical properties of the hydrophilic polymer, an amount of ethylenically unsaturated monomer (e.g. acrylonitrile, methacrylonitrile, vinyl acetate, alkyl acrylate, alkyl methacrylate, alkoxy It is also possible to add alkyl acrylates, alkoxyalkyl methacrylates, etc.). The amount of these copolymers added is 50 wt% or less, usually 30% or less, which can sufficiently contribute to mechanical properties. Furthermore, in order to improve blood compatibility, polymerizable monomers having a sulfonic acid group (for example, p-styrene sulfonic acid, allyl sulfonic acid, sulfoethyl (meth)acrylate, etc.) within a range that can maintain insolubility in water, Alternatively, it is also possible to add an alkali salt of the monomer, etc.). Taking solution polymerization as an example of a polymerization method,
Azobisisobutyronitrile, azobis-2,4-dimethylvaleronitrile, diisopropyl peroxycarbonate, tert-butyl peroctoate in a solvent such as methanol, ethanol, dimethylformamide or a mixed solvent thereof with water, acetone, etc. 100℃ or less, preferably 30 to 30℃ using a normal radical polymerization initiator such as
Obtained by polymerization at 70℃. The resulting polymer is purified by washing or repeated precipitation in a non-solvent. A preferred purification method is to precipitate the polymer in water and wash it. Polymerizable monomers having an N-methylol group or N-methylol ether group have extremely high solubility in water, and are much less likely to remain behind than similar post-crosslinking agents, such as poorly water-soluble epoxides. It is a copolymerization additive component. The obtained polymer can be made into a solution in a suitable solvent such as methanol, ethanol or acetone, and coated on the adsorbent by dipping, spraying or wet coagulation. The polymer concentration of the solution at that time is 0.01 to 5%, preferably 0.2 to 2%.
It is. After coating, the polymer constituting the coating layer is crosslinked and insolubilized due to the reaction of the N-methylol groups or N-methylol ether groups contained therein by air drying and heat treatment at 70 to 150°C. Abrasion properties are improved, the generation of fine particles is greatly reduced, and elution from the coating layer can be suppressed during sterilization operations (especially high-pressure steam sterilization) that are essential for medical applications. In addition, by performing the coating process twice or more,
This effect can be further ensured. The coated adsorbent obtained in the present invention can be sterilized by high-pressure steam, dry heat, drugs such as ethylene oxide or formalin, or radiation irradiation, and then subjected to direct perfusion adsorption of blood, perfusion adsorption of plasma, and ultraviolet adsorption. Due to perfusion adsorption of ascites and ascites, etc.
It is used to treat poisoning, hepatic coma, renal failure, etc., and to prevent and treat diseases by removing harmful substances from body fluids, such as removing harmful substances from stored blood. Examples will be shown below to more specifically illustrate the present invention. Example 1 and Comparative Examples 1 to 4 99.0 parts of hydroxyethyl methacrylate, N-
Methyloacrylamide 0.9 parts, azobis-2,
0.1 part of 4-dimethylvaleronitrile, ethanol
600 parts (or more parts by weight) of the mixture was heated at 50°C in argon.
The copolymer solution obtained by stirring for 16 hours was poured into water, and the resulting precipitate was crushed into small pieces and thoroughly washed with water. The water-containing polymer, which was washed and drained by centrifugation, was dissolved in ethanol to prepare a coating solution as a 0.5% dry polymer solution. Spherical activated carbon BAC-MUL manufactured by Taiyo Kaken Co., Ltd. (particle size 0.4
After pre-cleaning and drying, the spherical particles (~0.8 mm) were immersed in activated carbon:coating liquid at a ratio of 1:2. After filtering and air drying this activated carbon, and drying it at 80℃ overnight,
It was further heat treated at 120°C for 1 hour and then thoroughly washed in water. For comparison purposes, this sample, the above spherical activated carbon which had been thoroughly washed with water but was not coated (Comparative Example 1), the above spherical activated carbon coated with a homopolymer of hydroxyethyl methacrylate only (Comparative Example 2), and the above spherical activated carbon coated with a homopolymer of hydroxyethyl methacrylate only (Comparative Example 2), Crushed charcoal used in Smith &Nephew's blood purification column "Hemocol" (Comparative Example 3) and
0.5% collodion solution (ethanol/ether)
A total of 5 spherical activated carbons (Comparative Example 4) coated with
Using the seeds, adsorption performance, generation of fine particles, and elution properties were evaluated as follows. 1 Adsorption performance 2.5 g of sample activated carbon was added to 150 ml of a phosphate buffered saline solution of pH 7.4 containing 20 mg/dl of creatinine and 1 g/dl of albumin, and the mixture was heated at 37°C for 100 r.p.m.
Adsorption was carried out for 2 hours under low pressure. Table 1 shows the amount of creatinine adsorbed at that time. Add 2.5 g of sample activated carbon to 150 ml of AK Sorita solution (35 times diluted solution of artificial kidney dialysate manufactured by Shimizu Pharmaceutical Co., Ltd.) containing ₄₀ mg/dl of vitamin B-12.
Adsorption was carried out at 100 r.p.m. for 2 hours at .degree. Table 1 shows the adsorption amount of vitamin B ₁₂ at that time.

[Table] 2 Generation of fine particles Add 5 g of activated carbon sample to 25 ml of Coulter Isoton electrolyte in a Coulter counter, and heat for 100 r at 37°C.
The mixture was shaken for 3 hours under P.M., and the supernatant liquid was measured using a Coulter counter. 1.4～
Measurements of fine particles with a particle size of 28 microns are shown in Table 2 using 5 g of distilled water for injection as a blank.

[Table] 3. Elution property Add 50 ml of water to 10 g of activated carbon sample and sterilize in a steam sterilizer.
Heat sterilize at 121℃ for 20 minutes, and after cooling, take 30ml of the supernatant liquid, add 20ml of 0.01N-KMnO ₄ aqueous solution,
Titration was performed with a 0.01N-Na ₂ S ₂ O ₃ aqueous solution. Table 3 shows the difference in titer between the blank and the sample using 10 g of water.

[Table] From the results in Tables 1 to 3, Example 1 of the adsorbent of the present invention
It can be seen that only the sample showed excellent values for the amount of adsorption of creatinine and vitamin _B12 , the degree of generation of fine particles, and the dissolution property. Example 2 The same procedure as in Example 1 was carried out using a mixed solution of 75 parts of hydroxyethyl methacrylate, 4.9 parts of N-methylolacrylamide, 20 parts of methyl methacrylate, 0.1 part of azobis-2,4-dimethylvaleronitrile, and 600 parts of ethanol. The copolymer prepared by this method was dissolved in a mixed solvent of ethanol/acetone to prepare a coating solution with a concentration of 0.5%. The adsorption performance of activated carbon coated with this coating solution in the same manner as in Example 1 was determined by the adsorption amount of creatinine.
11.5mg/g, vitamin B ₁₂ adsorption amount is high at 16.7mg/g, the generation of fine particles is on the same level as blank distilled water for injection, and the elution property is as low as titration of 0.1ml (difference from blank).
A good coating layer was formed. Example 3 The spherical activated carbon coated with the hydroxyethyl methacrylate/N-methylol acrylamide copolymer obtained in Example 1 was packed into a cylindrical column with an internal volume of 200 ml, and applied to the femoral artery and vein of a dog from which both kidneys had been removed the previous day. It was connected using an artificial kidney dialysis circuit KV-102 (manufactured by Clinical Supply Co., Ltd.), and a blood perfusion experiment was conducted at a flow rate of 200 ml/min. As a result, blood creatinine decreased from 2.3 mg/dl to 0.6 mg/dl, and dogs under Nembutal anesthesia who did not wake up when an activated charcoal column was not connected woke up every 20 minutes in this experiment. It was necessary to additionally administer 1 ml of Nembutal (Dainippon Pharmaceutical Co., Ltd.) each time, and a blood purification effect due to adsorption was observed. During this period, no blood coagulation or hemolysis was observed, and the rate of decrease in platelets was only less than 20%, and stable blood perfusion was achieved.

Claims (1)

[Claims] 1 N-methylol group or N as post-crosslinking agent
- A medical adsorbent coated with a hydrophilic (meth)acrylate copolymer containing a polymerizable monomer containing a methylol ether group as one of the copolymerization components.