JPS6333872B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an adsorbent that is effective in removing bilirubin present in the blood of patients with liver failure. During liver failure, metabolic abnormalities increase in the patient's blood, and in severe cases, induce hepatic coma. The so-called coma factor that causes such hepatic coma is still unknown, but bilirubin has been cited as one of its indicators, and an increase in bilirubin in the blood can significantly worsen the condition. It is thought that they are related. As a treatment for liver failure, auxiliary liver therapy is used to detoxify patients by extracorporeal blood perfusion using adsorbents such as activated charcoal, and has been shown to be effective in helping patients wake up from coma. However, the ability to adsorb albumin-binding substances is low, and the survival rate remains low. In addition, attempts have been made to use anion exchange resins and various synthetic adsorbents to remove albumin-binding substances such as bilirubin, but they all have poor adsorption capacity for bilirubin and are not yet practical. Not enough to serve. Therefore, it is desired to develop a new adsorbent with high adsorption efficiency for bilirubin and the like. The present inventor conducted intensive studies to develop an adsorbent that can efficiently adsorb and remove harmful substances in the blood such as bilirubin that have albumin-binding properties. as well as/
Alternatively, the present invention was achieved by discovering that a polymer containing an imino group efficiently adsorbs an albumin-binding substance. That is, the present invention uses a water-insoluble addition polymer obtained by addition polymerizing a polyvalent amine compound and a polyvalent epoxy compound, or a crosslinked polymer obtained by polymerizing a polyvalent amine compound, a polyvalent epoxy compound, and a crosslinking agent. An adsorbent having bilirubin adsorption ability; and a water-insoluble addition polymer obtained by addition polymerizing a polyvalent amine compound and a polyvalent epoxy compound, or a crosslinked polymer obtained by polymerizing a polyvalent amine compound, a polyvalent epoxy compound, and a crosslinking agent. Bilirubin adsorption capacity using an albumin-binding polymer consisting of a polymer and albumin, wherein the addition polymer or the crosslinked polymer accounts for at least 40% by weight and albumin accounts for 60% by weight or less. The present invention provides an adsorbent having the following properties. The present invention will be explained. Non-limiting examples of the polyvalent amine compound, which is a necessary component for producing the adsorbent used in the present invention, include the following compounds. H ₂ N(-CH ₂ ) _-o NH ₂ , R-NH(-CH ₂ CH ₂ NH)- _n R' (However, n and m represent integers from 1 to 10, and R and R' are independently Represents a hydrogen atom or an alkyl, alkenyl, aryl, alkanol or aralkyl group having 1 to 20 carbon atoms.)

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Examples of the polyvalent epoxy compound used in producing the adsorbent of the present invention include, but are not limited to, the following substances. (However, p and q are integers of 1 to 10) Glycerol diglycidyl ether, glycerol triglycidyl ether, 1,1,1-trimethylolpropane triglycidyl ether, sorbitol polyglycidyl ether, bisphenol-A-diglycidyl ether, Hydroquinone diglycidyl ether, resorcin diglycidyl ether, phloroglycinol triglycidyl ether, triglycidyl isocyanurate, etc. The addition polymer of the present invention needs to be water-insoluble. Although the method of the addition polymerization reaction between the polyvalent amine compound and the polyvalent epoxy compound in the present invention is arbitrary, in order to synthesize such a water-insoluble polymer, it is necessary to form a crosslink between polymer molecules. A suitable formulation is required. That is, when a divalent amine compound and a divalent epoxy compound are reacted, it is desirable to add 1 equivalent or more of epoxy group to 1 equivalent of amino group. In this case, the excess epoxy group reacts with the imino group generated by the reaction between the epoxy group and the amino group to form a crosslink. When using a compound having a valence of 3 or higher, there is no problem with an excess of amino groups, but in general, it is preferable for the blending ratio of amino groups and epoxy groups to have an excess of epoxy groups. That is, the blending ratio of amino groups and epoxy groups is as follows for 1 equivalent of amino group:
The amount of epoxy group is 0.8 to 2.0 equivalents, preferably 1.05 to 1.5 equivalents. Further, when the above-mentioned addition polymer is made water-insoluble using a crosslinking agent, it is not necessary to synthesize the water-insoluble polymer by reacting an amino group with an epoxy group. For example, it is also possible to react equivalent amounts of a divalent amine compound and a divalent epoxy compound to produce a linear polymer, and then add a crosslinking agent to make the polymer crosslinked and insolubilized. Therefore, the blending ratio of amino groups and epoxy groups is as follows:
It is 0.5 to 2 equivalents, preferably 0.8 to 1.5 equivalents. The addition polymerization reaction is generally carried out in an aqueous solvent, but if the reaction reagent has low water solubility, the reaction can be carried out smoothly by adding a water-soluble organic solvent such as tetrahydrofuran or dioxane. can.
Further, the reaction conditions can be carried out at a temperature range of -30°C to 100°C, but most preferably it is carried out at a temperature of 20°C to 60°C. In the production of the crosslinked polymer as the adsorbent used in the present invention, the crosslinking agent used is a polyvalent organic isocyanate compound, such as hexamethylene diisocyanate, lysine diisocyanate, hydrogenated diphenylmethane diisocyanate, isophorone diisocyanate, hydrogenated tolylene diisocyanate, etc. isocyanate,
Tolylene diisocyanate, diphenylmethane diisocyanate, naphthylene diisocyanate,
Examples include, without limitation, xylylene diisocyanate, tolidine diisocyanate, and the like. Similarly, examples of the polyvalent organic isothiocyanate used as a crosslinking agent include hexamethylene diisothiocyanate, tolylene diisothiocyanate, diphenylmethane diisothiocyanate, and the like. Furthermore, polyhydric carboxylic acid halides that can also be used as crosslinking agents include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, azelaic acid, sebacic acid, brassic acid, phthalic acid,
Isophthalic acid, terephthalic acid, trimellitic acid,
Non-limiting examples include chlorides or bromides of trimesic acid and the like. This crosslinking reaction is performed on an addition polymer of a polyvalent amine compound and a polyvalent epoxy compound,
It does not matter whether the addition polymer has already been crosslinked and has become water-insoluble, or it may be an uncrosslinked polymer or a solution thereof. When the addition polymer is uncrosslinked, after forming the polymer into a film, coating, fiber, etc.
The polymer may be cross-linked and insolubilized by treatment with a cross-linking agent solution, and further, an aqueous solution of the polymer is added dropwise to an organic solvent solution of the cross-linking agent in the presence of a surfactant and the like under stirring to react in an emulsified and dispersed state. It is also possible to adopt a method of obtaining spherical polymer particles. Suitable solvents for crosslinking agents in these reactions include methylene chloride, chloroform, cyclohexane, toluene,
Examples include organic solvents such as xylene, or mixtures of two or more thereof. The crosslinking agent concentration in the crosslinking agent solution is usually 0.05 to 5% by weight, and the contact time with the polymer is 5 minutes to 5 hours. The reaction conditions can be carried out at a temperature of -30°C to 100°C, but a temperature of 20°C to 30°C is preferred. Addition polymers that have not been crosslinked with the crosslinking agent of the present invention (including those that are partially crosslinked and exhibit water insolubility) and crosslinked crosslinked polymers can be used as adsorbents in blood. Adsorbs to bilirubin. The method of adsorbing and removing bilirubin, etc. in blood using such an adsorbent is arbitrary;
For example, this can be done by bringing the adsorbent into efficient contact with blood. An example is a method in which blood or plasma is continuously passed through a column filled with a polymer or a tube or hollow fiber coated with a polymer. The polymer produced by the reaction of a polyvalent amine compound and a polyvalent epoxy compound has a positive charge in its molecule, so it adsorbs bilirubin through an anion exchange action, and also absorbs the amino groups present in large amounts in its molecule. And/or due to the action of imino groups and hydroxyl groups, it has a high affinity for albumin in blood and has the property of adsorbing it. As a result, it has the ability to adsorb bilirubin bound to albumin in blood in an equilibrium manner. As described above, adsorbents made of polymers exhibit excellent adsorption performance for bilirubin due to the synergistic effect of electrical performance and adsorption ability for organic residues. Next, the albumin-binding polymer will be explained.
Reactions between water-insoluble addition polymers or crosslinked polymers and albumin can be easily carried out. For example, by immersing this polymer in an aqueous solution of albumin, a composition in which the polymer and albumin are combined can be obtained. The albumin concentration of the aqueous albumin solution that can be used is preferably 0.5 to 5% by weight, and the reaction temperature is 5% by weight.
~30℃ is best. The reaction treatment time varies depending on the shape of the polymer and the contact efficiency, but since the binding reaction rate between the polymer and albumin is very fast, it generally takes 1 minute to 1 hour when the polymer is immersed in the solution. The reaction is complete. The bond between the polymer and albumin is due to the ionic bond between the secondary or tertiary amino group in the polymer and the negative charge of albumin. Due to its high affinity, which is thought to be caused by hydrogen bonds between amino groups, etc. and albumin, it tends to bind to albumin in an amount never seen in conventional polymers. The amount of albumin in the composition is preferably about 20 to 60% by weight. Since bilirubin in blood has the property of being adsorbed via albumin, when an albumin-binding polymer is used as an adsorbent, bilirubin in blood can be highly adsorbed. The adsorbent in the present invention, whether a polymer or an albumin-binding polymer, can be treated with an isotonic buffer solution with a pH of 7.4 and brought into contact with blood or plasma to adsorb and remove bilirubin from the blood. In addition to bilirubin, the adsorbent in the present invention includes hepatic coma factor, thyroxine, triiodothyronine, uric acid, bile acid, guanidine, indole compounds, and acetylcholine, which are present in the blood and are difficult to remove by operations such as activated carbon adsorption or dialysis. It is also extremely useful as an adsorbent for barbituric acid, digitoxin, salicylic acid, etc. The present invention will be explained below with reference to Examples. Note that "%" in the examples is based on weight, and the bilirubin concentration in blood was measured by the Evelyn-Malloy method. Example 1 3.2 g of hexamethylene diamine was placed in a 300 ml three-neck separable flask equipped with a stirrer and a thermometer.
(0.028 mol), diethylenetriamine 0.96 g
(0.0094 mol) and 40 ml of distilled water were added thereto, and while stirring at a temperature of 25°C, 9.36 g (0.046 mol) of glycerol diglycidyl ether was gradually added. Stirring was continued for 20 minutes at the same temperature, and when the viscosity of the system increased, 300 ml of a 0.6% toluene solution of 4,4'-diphenylmethane diisocyanate and polyoxyethylene sorbitan monopalmitate were added as a surfactant.
20 mg was added and stirring was continued for 1 hour at a temperature of 25°C. After the reaction was completed, the particulate polymer was separated, thoroughly washed with methanol, and then dried to obtain 13.0 g of a water-insoluble polymer. After immersing 1.0 g of this polymer in a phosphate buffer solution with a pH of 7.4, it was packed into a column, and 100 ml of plasma containing 11.5 mg/dl of total bilirubin was circulated and perfused at a flow rate of 2 ml/min for 6 hours. Ta. The bilirubin concentration in plasma after perfusion was 6.5 mg/dl. Example 2 Polymer particles produced in the same manner as Example 1
1.0 g was immersed in a phosphate buffer solution with a pH of 7.4, washed separately, and immersed in 100 ml of an aqueous solution containing 1.0 g/dl of plasma albumin, and stirred slowly for 1 hour to form a polymer. It adsorbed albumin.
Next, after washing this separately, fill it into a column and
2 100 ml of plasma containing mg/dl total bilirubin
Circulatory perfusion at a flow rate of ml/min for 6 hours reduced the total bilirubin concentration in plasma to 4.5 mg/dl. Example 3 2.9 g of hexamethylene diamine was placed in a 300 ml three-neck separable flask equipped with a stirrer and a thermometer.
(0.025 mol), 1.9 g (0.005 mol) of bisphenol-A-diglycidyl ether, and 4.04 g (0.02 mol) of glycerol diglycidyl ether were reacted at 30°C for 6 hours in a mixed solvent consisting of 8 ml of chloroform and 4 ml of cyclohexane. I let it happen. Next, after adding 1.0 g of triglycidyl isocyanurate, 100 ml of water containing 10 g of sodium chloride and 0.5 g of bentonite as a dispersant was added to suspend and disperse the polymer solution, and the reaction temperature was raised to 40°C. By reacting for a period of time, a spherical water-insoluble polymer was obtained. After immersing 1.0 g of this polymer in a phosphate buffer solution with a pH of 7.4, it is packed into a column, and 100 ml of plasma containing 10.8 mg/dl of total bilirubin is circulated and perfused at a flow rate of 2 ml/min for 8 hours. As a result, the total bilirubin concentration in plasma decreased to 6.7 mg/dl. Example 4 In a 300 ml three-necked flask equipped with a stirrer and a thermometer, 3.2 g (0.028 mol) of hexamethylene diamine and 0.96 g (0.0094 mol) of diethylenetriamine were added.
Add 9.36 g (0.046 mol) of glycerol dicrycidyl ether and stir at the same temperature for 20 minutes at a temperature of 25°C. When the viscosity increased, 160 ml of toluene containing 2.0 g of benzoic acid and 0.1 g of ethyl cellulose as a dispersant was added and stirred to suspend and disperse the aqueous polymer solution.
By raising the temperature to 40°C and reacting for 1 hour, 13.0 g of spherical water-insoluble polymer particles were obtained. After immersing 1.0 g of this polymer in a phosphate buffer solution of pH 7.4, it was packed into a column, and 100 ml of plasma containing 10.2 mg/dl of total bilirubin was perfused at a flow rate of 2 ml/min. , total bilirubin concentration in plasma decreased to 4.7 mg/dl.

Claims (1)

[Scope of Claims] 1. A water-insoluble addition polymer obtained by addition polymerizing a polyvalent amine compound and a polyvalent epoxy compound, or a crosslinked polymer obtained by polymerizing a polyvalent amine compound, a polyvalent epoxy compound, and a crosslinking agent. The used adsorbent has bilirubin adsorption ability. 2. A water-insoluble addition polymer obtained by addition polymerizing a polyvalent amine compound and a polyvalent epoxy compound, or an albumin bond consisting of albumin and a crosslinked polymer obtained by polymerizing a polyvalent amine compound, a polyvalent epoxy compound, and a crosslinking agent. An adsorbent having bilirubin adsorption ability using the albumin-binding polymer, which is a polymer, and the addition polymer or the crosslinked polymer is at least 40% by weight and the albumin is 60% by weight or less.