JPH09266948A - Blood purifying device and blood purifying equipment - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe and simple blood purifying device and blood purify ing equipment capable of sufficiently removing a low-molecular weight protein typified by β2-microglobnulin from the blood. SOLUTION: Cellulose to which a compound having logP value (wherein P is a distribution coefficient in an octanol-water system) not less than 2.50 is fixed, with a ratio to water ranging from 1:9 to 3:7 by weight, and 700,000 to 20,000,000 spherical hydrogels having an average particle size ranging from 300 to 600μm are stored together with a solution in a container provided with a device for preventing the hydrogels from flowing, having an inlet and an outlet for the blood, at least the outlet being passable for the blood but not for the hydrogels. The container is sealed, at least the inner part thereof is sterilized, and a blood purifying device is connected to a hemodialyzer.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a blood purifier and a blood purification device. More specifically, the present invention relates to a blood purifier and a blood purification device used for extracorporeal circulation treatment.

[0002]

2. Description of the Related Art Blood purification technology by extracorporeal circulation has made remarkable progress in the last quarter century. Among them, hemodialysis is widely used as a blood purification method to substitute the renal function of patients with renal failure. This hemodialysis is based on the principle that blood and dialysate are brought into contact with each other through a dialysis membrane, and unnecessary components in blood are discharged to the dialysate side due to the difference in the concentration of solutes in both solutions. Various hemodialyzers using hollow fiber dialysis membranes have been developed and clinically used. Further, as in the case of hemodialysis, as a blood purification method using a membrane, hemofiltration, hemodiafiltration and the like are performed. On the other hand, various blood purifications using an adsorbent have been studied, and adsorbers filled with granular activated carbon for assisting renal function are commercially available.

[0003]

In recent years, in the field of hemodialysis, it has been regarded as a problem that small molecular weight proteins are accumulated in the blood of patients with renal failure who are undergoing hemodialysis treatment. This accumulation is believed to be a problem that occurred because these small molecular weight proteins, which were originally metabolized in the kidney, could not be removed by traditional hemodialyzers. One example of such a small molecular weight protein is a protein that constitutes amyloid deposits in patients with dialysis amyloidosis.
An example is β2-microglobulin which was clarified by Shimojo et al. In 985. The molecular weight of β2-microglobulin is reported to be 11,731 (F. Gejyo et al., B
iochemical and Biophysical Research Communication
s, Vol.129, No.3, Pages 701-706, 1985). In order to improve the removal performance of such small molecular weight proteins, a means of increasing the pore size of the hemodialysis membrane is taken, and a hemodialyzer using a so-called high performance membrane is developed and clinically used, At present, it is hard to say that sufficient removal capacity has been obtained. In addition, hemofiltration and hemodiafiltration methods are becoming able to remove these small molecular weight proteins with considerably high efficiency, but these methods require a large amount of replacement fluid that is not required in normal hemodialysis. However, there is a problem in that it cannot be handled by a dialysis device which is widely used alone, and an additional device is required. Further, in the method using these membranes, there is a concern that contamination with toxic substances such as endotoxin derived from bacteria from the dialysate side may occur as the pore size increases. On the other hand, the adsorber filled with granular activated carbon is not originally intended for adsorbing proteins, and the adsorbing ability for small molecular weight proteins is poor, so that it cannot be sufficiently removed at present.

The present invention solves the above problems and provides a safe and simple blood purifier and a blood purification device capable of sufficiently removing small molecular weight proteins represented by β2-microglobulin from blood. It is intended.

[0005]

[Means for Solving the Problems] We have found that β2- in blood
As a result of extensive studies on a safe and simple blood purifier capable of sufficiently removing small molecular weight proteins typified by microglobulin, a logP (P is a partition coefficient in an octanol-water system) value of 2.50 or more Which is a hydrogel having a colloidal solid phase composed of celluloses (hereinafter referred to as “C-celluloses”) having the compound of claim 1 fixed thereto and water, wherein the weight ratio and particle size of the C-celluloses and water are in a specific range. It was found that by storing a certain amount of the above in an aqueous solution in a container having an inlet and an outlet, sealing the container, and sterilizing the inside, a device that meets the purpose can be obtained, and blood used for extracorporeal circulation treatment. Invented the purifier.

Further, it was found that a system acting as a substitute for the kidney function can be obtained by using this blood purifier in connection with a dialyzer, and a blood purification device used for direct blood perfusion type extracorporeal circulation treatment was completed. It was

That is, according to the present invention, (1) a weight ratio of water to celluloses (C-celluloses) to which a compound having a log P (P is a partition coefficient in an octanol-water system) value of 2.50 or more is fixed is 1: A spherical hydrogel in the range of 9 to 3: 7 and having an average particle size of 300 to 600 μm has an inlet and an outlet for blood, and at least the outlet side allows blood to pass but hydrogel cannot pass. The present invention relates to a blood purifier, characterized in that 700,000 to 20 million pieces are stored together with an aqueous solution in a container equipped with, and the container is sealed and at least the inside thereof is sterilized.

Further, according to the present invention, (2) the logP value is 2.
The blood purifier according to (1) above, wherein the compound having 50 or more is a compound having a hydrocarbon moiety having 8 to 18 carbon atoms.

Further, the present invention relates to (3) the blood purifier according to the above (1) or (2), wherein the pH of the aqueous solution in the container is in the range of 5 to 8.

The present invention further relates to (4) the blood purifier according to the above (1) or (2), wherein the aqueous solution in the container is an aqueous solution of a compound having a buffering effect on pH.

The present invention further relates to (5) the blood purifier according to the above (1) or (2), wherein the aqueous solution in the container is an aqueous solution containing citric acid and sodium citrate.

Further, the present invention relates to (6) the blood purifier according to the above (1) or (2), wherein a container having an inlet and an outlet is partially or entirely made of a transparent resin molded product.

Further, the present invention relates to (7) a blood purification apparatus in which the blood purification device according to any one of items (1) to (6) is connected to a hemodialyzer.

Further, the present invention relates to (8) the blood purification device according to the above (7), wherein the blood purification device and the hemodialysis device are connected in series.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Blood in the present invention includes not only whole blood but also plasma, serum and the like obtained by removing blood cell components from whole blood.

The hydrogel to be filled in the blood purifier of the present invention is composed of celluloses (C-celluloses) and water on which a compound having a log P (P is a partition coefficient in an octanol-water system) value of 2.50 or more is fixed and water or. It is composed of an aqueous solution.

The log P value of the compound is determined by the following method. First, the compound is octanole (or water)
Dissolve in water, add equal amount of water (or octanol) to it, and add Griffin Flask Shaker (Grif
fin flash shaker
And George Limited (Griffin & Ge
orge Ltd. )) For 30 minutes. Then, the mixture is centrifuged at 2,000 rpm for 1 to 2 hours, and the concentration of the compound in the octanol layer and the aqueous layer is measured by various methods such as spectroscopic analysis or GLC.

P = Coct / Cw Coct: Concentration of compound in octanol layer Cw: Concentration of compound in water layer Logs of various compounds by many researchers so far.
P-values have been measured, but those measured values have been arranged by C. Hansch et al. (“Partition Co-Efficients and There Uses; Chemical Reviews (PARTITIO
N COEFFICIENTS AND THEIR U
SES; Chemical Reviews), 71
Vol. 525, 1971 ").

Further, regarding compounds whose actual measured values are not known, R.F.
r) is his book ("The Hydrophobic Fragment Constant (THE HYDROPHOBI)
C FRAGMENTAL CONSTANT) ", Elsevier Scientific Publishing Company (Elsevier Sci. Pub. Co.)
m. ), Amsterdam (1977)) calculated using the hydrophobic fragment constant f (Δf)
Will be helpful. The hydrophobic fragment constant is
It is a value that shows the hydrophobicity of various fragments determined by statistical processing based on the measured value of gP, and it is reported that the sum of the f values of each of the fragments constituting the compound is almost the same as the logP value. ing. In the present invention, lo
The gP value means a Σf value for a compound whose logP value is unknown.

In the present invention, in searching for a compound effective for adsorbing β2-microglobulin, various log
As a result of fixing and studying a compound having a P value, a compound having a logP value of 2.50 or more, preferably 2.70 or more, more preferably 2.90 or more is effective for adsorbing β2-microglobulin, and a logP value of 2 It was found that the compounds having a ratio of less than 0.50 showed almost no β2-microglobulin adsorption ability. For example, when alkylamine is immobilized, the alkylamine is converted into n-hexylamine (logP =
2.06) to n-octylamine (logP = 2.9)
It was found that when the value was changed to 0), the adsorption capacity of β2-microglobulin dramatically increased during this period. From these results, the adsorption ability of β2-microglobulin in the blood purifier of the present invention was determined by the fixation of the compound having a logP value of 2.50 or more and the atomic group introduced into cellulose and β2-microglobulin.
It is considered to be due to hydrophobic interaction with microglobulin, and it is considered that the compound having a logP value of less than 2.50 does not exhibit β2-microglobulin adsorption ability because the hydrophobicity is too small.

On the other hand, when n-octylamine is changed to cetylamine (Σf = 7.22) which has a longer alkyl chain length and is considered to have higher hydrophobicity, the adsorption capacity of β2-microglobulin is further increased. I found out that From these results, β in the blood purifier of the present invention
The adsorption of 2-microglobulin is achieved by immobilizing a compound having a logP value of 2.50 or more.
It was found that the larger the P value is, the more preferable it is. For example, octadecylamine (Σf = 8.8), which is considered to have a longer alkyl chain length and higher hydrophobicity than cetylamine.
It is considered that the immobilization of a compound such as 28) exhibits β 2 -microglobulin adsorption equivalent to or higher than that when immobilizing cetylamine. The upper limit of the logP value is not particularly limited, but is practically about 15.

In the present invention, as a compound fixed to cellulose, any compound having a logP value of 2.50 or more can be used without particular limitation. However, when the compound is bonded to the cellulose by the chemical bonding method, a part of the compound is often desorbed,
When the leaving group greatly contributes to the hydrophobicity of the compound, that is, when the hydrophobicity of the atomic group fixed to the cellulose by elimination becomes smaller than Σf = 2.50, the present invention From the point of view of the above, it is unsuitable as a compound used in the present invention. A typical example thereof is the case where isopentyl benzoate (Σf = 4.15) is immobilized on celluloses having a hydroxyl group by transesterification. In this case, the atomic group actually fixed to the cellulose is C ₆ H ₅ CO-, Σf of the atomic group is 1 or less. Whether such a compound is suitable as a compound to be used in the present invention may be judged by whether or not the logP value of the compound in which the leaving group portion is replaced with hydrogen is 2.50 or more.

Among the compounds having a log P value of 2.50 or more, those having a hydrocarbon moiety having 7 to 20 carbon atoms, especially 8 to 18 carbon atoms are preferable, and further unsaturated hydrocarbons, alcohols, amines, thiols, Compounds having a functional group that can be used for binding to cellulose, such as carboxylic acid and its derivatives, halides, aldehydes, isocyanates, oxirane ring-containing compounds such as glycidyl ether, and halogenated silanes are preferably used.

As the unsaturated hydrocarbon, 1-heptene, 1-octene, 1-decene, 1-dodecene, 1-tetradecene, 1-hexadecene, 1-octadecene, 1
-Examples include Eikosen.

Examples of the alcohol include n-octyl alcohol, dodecyl alcohol, hexadecyl alcohol, 1-octen-3-ol, naphthol, diphenylmethanol and 4-phenyl-butanol.

Examples of the amine include n-octylamine, decylamine, dodecylamine, hexadecylamine, octadecylamine, naphthylamine, 2-aminooctene, diphenylmethylamine and the like.

Examples of the thiol include octanethiol, decanethiol, dodecanethiol, tetradecanethiol, hexadecanethiol and octadecanethiol.

Examples of the carboxylic acid and its derivative include n-octanoic acid, nonanoic acid, 2-nonenoic acid, decanoic acid, dodecanoic acid, stearic acid, arachidonic acid, oleic acid, diphenylacetic acid, and the like. Examples thereof include acid halides, esters, amides and hydrazides of the above carboxylic acids.

Examples of the above-mentioned halides include octyl chloride, octyl bromide, decyl chloride and dodecyl chloride.

Examples of the aldehyde include octyl aldehyde, n-caprin aldehyde and dodecyl aldehyde.

Examples of the above-mentioned isocyanates include dodecyl isocyanate, hexadecyl isocyanate, octadecyl isocyanate and the like.

Examples of the glycidyl ether include dodecyl glycidyl ether, hexadecyl glycidyl ether, octadecyl glycidyl ether and the like.

Examples of the halogenated silane include n-octyltrichlorosilane and octadecyltrichlorosilane.

In addition to these, among the compounds in which the hydrogen atom of the hydrocarbon moiety of the above-exemplified compounds is substituted with a substituent containing a hetero atom such as halogen, nitrogen, oxygen or sulfur, or another alkyl group, etc. , Compounds having a logP value of 2.50 or more, the aforementioned C. Hansch
"Partition Co-Efficients and There Uses; Chemical Reviews (PARTI)
TION COEFFICIENTS AND THE
IR USES; Chemical Review
s), 71, 525, 1971 ”, the compounds having a logP value of 2.50 or more shown in the table on pages 555 to 613 can be used, but in the present invention, only these compounds can be used. It is not limited.

These compounds may be used alone, in any combination of two or more kinds, and may be used in combination with a compound having a logP value of less than 2.50.

The log P value is 2.5 for celluloses.
As a method for immobilizing 0 or more compounds, various known methods such as a method of physically binding, a method of binding via an ionic bond, a method of binding via a covalent bond, etc. can be used. Since it is important that the bound compound is hard to be released, it is most preferable to immobilize it via a covalent bond. As a specific means, a method of directly bonding the compound through an ester bond, an amide bond, an ether bond, a thioether bond, a urethane bond or the like using a hydroxyl group of celluloses, or an amino group to celluloses, A method in which a functional group such as an aldehyde group, an epoxy group, or a carboxyl group is introduced to make the compound highly reactive (activated), and then the compound is bound can be mentioned. Further, as a specific method for introducing a functional group into cellulose to activate it, cyanogen bromide method, epoxy method, tresyl chloride property, periodate oxidation method and the like can be mentioned as specific examples. It is not limited to.

Further, the fixed amount of the compound having a logP value of 2.50 or more in the hydrogel shown in the present invention is 10 to 100 per dry weight (1 g) of the cellulose as the carrier.
0 μmol is preferable, but it is more preferably 50 to 500 μmol, and most preferably 100 to 300 μmol from the viewpoint of having sufficient adsorption ability and preventing adhesion and adhesion of platelets when treating whole blood.

The term "celluloses" as used in the present invention means at least one of natural cellulose, regenerated cellulose and cellulose derivative. Examples of natural cellulose include defatted cotton fiber, hemp fiber and wood. Examples include pulp obtained by removing lignin and hemicellulose, and purified cellulose obtained by further refining the pulp. In addition, regenerated cellulose is cellulose obtained by once converting natural cellulose into a cellulose derivative and then regenerating it by hydrolysis or the like. Examples of the cellulose derivative include those obtained by esterifying and / or etherifying some or all of the hydroxyl groups of natural or regenerated cellulose. Specific examples of those in which a part or all of the hydroxyl groups of the cellulose are esterified, for example, cellulose acetate, cellulose propionate, cellulose butyrate, nitrocellulose, cellulose sulfate, cellulose phosphate, cellulose acetate butyrate, cellulose nitrate, of cellulose. Examples thereof include, but are not limited to, dicarboxylic acid esters. Specific examples of those in which a part or all of the hydroxyl groups of the cellulose are etherified include, for example, methyl cellulose,
Examples thereof include, but are not limited to, ethyl cellulose, benzyl cellulose, cyanoethyl cellulose, carboxymethyl cellulose, aminoethyl cellulose, oxyethyl cellulose and the like. Further, in the present invention, it is an essential requirement that a compound having a logP value of 2.50 or more is fixed, and in addition to this, there is no limitation on fixing other atomic groups.

The hydrogel as referred to in the present invention means a colloidal solid phase containing water or an aqueous solution as an essential component as described above, and the gel skeleton left after drying the hydrogel to remove water, that is, the xerogel is This is outside the concept of hydrogel in the invention.

The weight ratio of C-cellulose to water is the weight (wet weight W) when the water adhered to the hydrogel and the interstitial water between the hydrogel particles are removed by a suction filtration method or a centrifugal method.
w) and the weight (dry weight Wd) when the weight is no longer changed by subsequent drying. That is,
Wd: (Ww-Wd) is the weight ratio of C-cellulose and water in the present invention. As a specific method for obtaining the wet weight, for example, take a hydrogel in a glass filter,
There is a method in which suction is performed using an aspirator and the weight is measured after the elapse of the suction time when the weight decrease curve showing the relationship between the suction time and the weight is created and the slope of the curve becomes gentle. Further, the drying method is not particularly limited as long as constant weight can be achieved, but atmospheric pressure drying at a temperature of about 105 ° C. can be simply adopted without a special device. The weight ratio of C-cellulose and water constituting the hydrogel of the present invention is in the range of 1: 9 to 3: 7. This weight ratio of hydrogel is due to the pressure loss when blood is passed through the blood purifier. From the viewpoint of preventing deformation and accompanying consolidation.
It is preferable that the ratio of C-celluloses is 1/9 or more, and further that the ratio of C-celluloses is preferably 3/7 or less from the viewpoint of preventing the reduction of the purification rate.

The hydrogel particles housed in the blood purifier of the present invention have a spherical shape, and the spherical shape includes not only spherical shapes but also widely spheroids. The average particle size of this type of hydrogel is generally 3 when treating a body fluid containing almost no cell components such as plasma.
Those having a particle size of 00 μm or less are adopted from the viewpoint of high purification rate, and when used in a direct blood perfusion system, 250 to 10 μm in order to secure a sufficient passage channel for blood cell components.
Those having a diameter of 00 μm are preferably used. As for the spherical hydrogel particles of the present invention, those having a particle size of 300 to 600 μm are more preferable from the viewpoint of compatibility between the permeability of blood cell components and the purification rate. The average particle size as used herein refers to the number average particle size, for example, 10 times to 5 times with a stereoscopic microscope.
It can be determined by observing and measuring the particle size of 20 to 50 hydrogel particles at a magnification of about 0 and averaging the measured values. If the hydrogel particles are spheroids,
The major axis is taken as the particle diameter, and the average particle diameter is determined by the same method as described above. If the particle size is within the above range, the particle size distribution can be used without any particular limitation, but uniform droplets are formed by using the vibration method described in, for example, JP-A-63-117039. However, particles having a narrow particle size distribution, which are produced by coagulation under appropriate conditions, are particularly preferable when used in the direct blood perfusion method.

As a method for producing hydrogel particles composed of C-cellulose of the present invention, cellulose is used as C-cellulose.
Either a method of forming celluloses and then forming them into hydrogel particles, or a method of preparing hydrogel particles of celluloses and immobilizing a compound having a logP value of 2.50 or more thereto is possible.

More specifically, the method of forming C-celluloses from celluloses and forming them into hydrogel particles will be described. C-celluloses are prepared by fixing compounds having a logP value of 2.50 or more to celluloses. After that, the C-celluloses are dissolved in a solvent to form a solution, and then the droplets are solidified to form hydrogel particles. If there is no suitable solvent for forming the C-celluloses into a solution, C is used. Examples of the method include, but are not limited to, a method in which cellulose is further esterified or etherified to make it easily soluble in a solvent, and then hydrogel particles are formed.

In the method of preparing hydrogel particles of cellulose and fixing the compound having a logP value of 2.50 or more to the hydrogel particles of cellulose, as a method of preparing hydrogel particles of cellulose, after dissolving the cellulose in a solvent, There is a method of forming hydrogel particles by dropletizing and coagulating, and a method of using a cellulose derivative as the celluloses is preferably used because the selection range of the production conditions is widened due to the variety of types of solvents. Examples of the cellulose derivative include those in which a part or all of the aforementioned hydroxyl groups of cellulose have been esterified and / or etherified. Among them, cellulose acetates such as cellulose acetate and cellulose propionate are soluble in various solvents. Therefore, it is more preferably used. After these cellulose derivatives are hydrogel particles, they are hydrolyzed as they are or, if necessary, after which the logP value is 2.
By fixing 5 or more compounds, hydrogel particles of C-cellulose are prepared.

The blood purifier of the present invention has the above-mentioned hydrogel having an inlet and an outlet for blood, and a container provided with a device for preventing the outflow of the hydrogel to the outside of the container at least on the outlet side through which blood can pass. It is stored in. Examples of the hydrogel outflow preventive device include filters such as mesh, non-woven fabric, and wire plug, and as the material thereof, polypropylene, polyethylene, polyester and the like can be used. The shape, material, and size of the container are not particularly limited, but preferable specific examples include a container of about 150 to 500 ml and a transparent or translucent cylindrical container having a diameter of about 4 to 10 cm. It is preferable that the material has sterilization resistance. Specifically, glass coated with silicone, polypropylene, polycarbonate, polysulfone, polymethylpentene,
Polyvinyl chloride and the like can be mentioned, but polypropylene and polycarbonate are preferable because of good moldability, strength, chemical resistance, and the like, and further, polycarbonate is highly transparent, and before use, during use and after use inside the blood purifier. It is particularly preferably used because abnormalities can be visually confirmed.

The number of hydrogel particles contained in the blood purifier of the present invention can be calculated by converting the number of hydrogel particles contained per unit volume per volume of the blood purifier. The number of hydrogel particles is 70
If the number is less than 10,000, sufficient purification capacity cannot be obtained. If more than 20 million blood purifiers are to be stored, the volume of the blood purifier will exceed 500 ml, and the extracorporeal blood circulation will be very large, which will impose a heavy burden on the patient, which is not practical.

There is no particular limitation on the ratio of the volume of hydrogel to the volume of hydrogel in the container. For example, the volume of hydrogel may be approximately 50%, or the volume of hydrogel may be approximately equal to the volume of hydrogel. However, the latter method of filling the entire storage space with the hydrogel is preferable because it does not unnecessarily increase the extracorporeal blood circulation.

An embodiment of the blood purifier of the present invention is shown in FIG. However, the blood purifier of the present invention is not limited to such a specific example.

In FIG. 1, reference numeral 1 denotes a cylindrical container body, and an upper opening and a lower opening of the container body 1 are liquid-tightly sealed by an upper lid member 2 and a lower lid member 4, respectively. The upper lid member 2 is provided with a blood inflow side nozzle 3, and the lower lid member 4 is provided with a blood outflow side nozzle 5. Reference numeral 7 is a mesh provided on the mesh frame 6. The mesh on the blood inflow side may be omitted. 8 is an aqueous solution (filling liquid), and 9 is a spherical hydrogel.

The aqueous solution stored together with the hydrogel composed of C-cellulose in the blood purifier of the present invention, that is, the filling solution is basically any aqueous solution as long as it does not adversely affect the human body. It does not matter, but the pH is preferably in the range of 5 to 8 in order to prevent damage to the hydrogel during sterilization. Further, when there is a concern that the pH in the blood purifier changes due to temperature changes during sterilization, the fluctuation range of the pH of the filling liquid can be reduced by using an aqueous solution of a compound having a buffering effect on the pH. Therefore, a buffer solution is preferably used as the filling solution. Specific examples of the compound include phosphoric acid, acetic acid, maleic acid, citric acid, boric acid, tartaric acid, glycine, etc.
Alternatively, those which are safe for the human body such as sodium salt, potassium salt, calcium salt and the like are preferable, and these may be used alone or in combination of two or more kinds. Further, an aqueous solution using citric acid and sodium citrate as the compound has a track record as a filling liquid for a commercially available blood purifier for plasma perfusion and is preferably used.

Specific examples of the method for sterilizing the blood purifier of the present invention include high-pressure steam sterilization, γ-ray sterilization, sterilization with a water-soluble drug, and the like, which can kill bacteria in the presence of water. If there is no special restrictions, it will be performed. Among them, high-pressure steam sterilization is preferably used because it does not cause a large damage to the hydrogel and does not use any special chemicals and thus does not leave harmful chemicals.

The blood purifier of the present invention can be used for both the method of perfusing plasma as described above and the method of directly perfusing blood. Further, only the blood purifier of the present invention is incorporated in the blood circuit. It can be used alone or in combination with other blood purifiers such as hemodialyzers and blood adsorbers.

When the blood purifier of the present invention is used in combination with a hemodialyzer, either serial connection or parallel connection can be used, but the series connection is simple and does not lead to a complicated blood circuit or complicated operation. It is preferably used for. The blood purification device of the present invention in which the blood purification device and the hemodialysis device are connected in series can remove small molecular weight proteins such as β2-microglobulin which cannot be sufficiently removed by hemodialysis. It is a simple system that is easy to use and does not require extra fluid replacement, and is a system suitable for purifying blood of patients with renal failure. In addition, as long as they are connected in series, either the blood purifier or the hemodialyzer of the present invention may be located on the upstream side.

FIG. 2 shows an embodiment of the blood purification apparatus of the present invention.
Another embodiment is shown in FIG.

In FIG. 2, 10 is an arterial circuit including a blood pump 11, and a blood purifier 12 and a hemodialyzer 13 of the present invention are connected in series in this order in the downstream direction of the arterial circuit 10. The hemodialyzer 13 is connected to the venous circuit 14. Reference numeral 15 is a drip chamber. In FIG. 2, arrows indicate the direction of blood flow.

In the embodiment of the blood purifying apparatus shown in FIG. 3, the hemodialyzer 13 and the blood purifier 12 are connected in series in this order in the downstream direction of the arterial circuit 10.

Below, β in the purification of blood of patients with renal failure
The effects of the present invention will be shown in specific examples relating to the removal of 2-microglobulin, but the usage of the blood purifier of the present invention is not limited to these.

Example 1 Commercially available cellulose acetate was dissolved in a mixed solvent of dimethyl sulfoxide and propylene glycol, and this solution was subjected to the method (vibration method) described in JP-A-63-117039.
Were made into droplets and solidified to obtain cellulose acetate spherical hydrogel particles. The hydrogel particles were mixed with an aqueous sodium hydroxide solution and subjected to a hydrolysis reaction to obtain cellulose hydrogel particles. Next, epichlorohydrin was reacted in an aqueous sodium hydroxide solution, and then hexadecylamine was reacted in an alcoholic aqueous solution to obtain spherical hydrogel particles of cellulose (average particle diameter 460 μm) on which hexadecylamine was immobilized.

In this spherical hydrogel of hexadecylamine-immobilized cellulose (immobilization amount: 175 μmol / g-dry weight), the weight ratio of hexadecylamine-immobilized cellulose to water is 2: 8, and the spherical hydrogel has When the number of gel particles contained in 1 ml of sedimentation volume was counted, it was 9,800.

This hydrogel was filled in a 350 ml transparent container (material: polycarbonate) equipped with a mesh (material: polyester) of 150 μm opening on both the blood inlet side and the blood outlet side (calculated gel number in the container: 34
30,000), and the pH of the filling solution was adjusted to 6 to 6.5.
A buffer solution consisting of 00 ppm citric acid and sodium citrate was filled, and high-pressure steam sterilization treatment was performed at 121 ° C. for 20 minutes to prepare a blood purifier.

1 liter of physiological saline was added to this blood purifier,
Then, after washing with 1 liter of a physiological saline solution containing 10 U / ml of heparin, a hemodialyzer (Fi
It was connected in series with the ltral 16 (manufactured by Phospal), and extracorporeal circulation of the patient's blood was performed at a blood flow rate (200 ml / min) during normal hemodialysis. RIA of β2-microglobulin concentration in blood before extracorporeal circulation and after 4 hours of extracorporeal circulation
-It measured by the 2 antibody method. The blood after 4 hours was collected from the upstream side of the blood purifier in FIG. It was 39.4 mg / l before the extracorporeal circulation, but decreased to 7.7 mg / l after 4 hours. In addition, the amount of β2-microglobulin removed was calculated to be 239 mg by the blood purifier and 263 mg by the blood purifier from the temporal changes in the β2-microglobulin concentration before and after the blood purifier and after the hemodialyzer.

Example 2 A blood purifier prepared and washed in the same manner as in Example 1 was connected in series with a hemodialyzer (Filtral 16, manufactured by Phospal Co.) as shown in FIG. 3, and the blood flow rate during normal hemodialysis ( Two
Extracorporeal circulation of the patient's blood was performed at 00 ml / min). The β2-microglobulin concentration in blood before extracorporeal circulation and after 4 hours from extracorporeal circulation was measured by the RIA · 2 antibody method. still,
Blood after 4 hours was collected from the upstream side of the hemodialyzer in FIG. It was 32.6 mg / l before the extracorporeal circulation, but decreased to 7.5 mg / l after 4 hours.
In addition, the amount of β2-microglobulin removed was calculated to be 258 mg by the blood purification device from the temporal transition of the β2-microglobulin concentration before the hemodialyzer and after the blood purifier.

Example 3 A blood purifier prepared and washed in the same manner as in Example 1 was connected in series with a hemodialyzer (BK-1.6P, manufactured by Toray Industries, Inc.) as shown in FIG. Blood flow at time (200m
Extracorporeal circulation of the patient's blood was performed at 1 / min). When β2-microglobulin concentration in blood before extracorporeal circulation and after 4 hours of extracorporeal circulation was measured by RIA · 2 antibody method, lysozyme concentration was measured by turbidimetric method, and myoglobin concentration was measured by RIA · PEG method, Β2-microglobulin before extracorporeal circulation,
Lysozyme and myoglobin concentrations were 41.5 each
mg / l, 46.0 mg / l and 711.0 ng / m
1 and 11.5 mg each after 4 hours of extracorporeal circulation
/ L, 17.8 mg / l and 212.5 ng / ml.

Comparative Example The same patient shown in Example 3 was subjected to hemodialysis (hemodialyzer: BK-1.6P, manufactured by Toray Industries, Inc.) for 4 hours.
Before hemodialysis and 4 hours after hemodialysis, β2 microglobulin concentration in blood was measured by RIA · 2 antibody method, lysozyme concentration was measured by turbidimetric method, myoglobin concentration was measured by RIA · PEG.
The β2-microglobulin, lysozyme and myoglobin concentrations before hemodialysis were 32.1 mg / l, 43.0 mg / l and 567.0, respectively.
ng / ml, 2 after 4 hours on hemodialysis
2.4 mg / l, 34.0 mg / l and 286.9n
g / ml.

From these results, the blood purifier and the blood purifier of the present invention are safe and simple blood purifiers and blood purifiers capable of sufficiently removing small molecular weight proteins represented by β2-microglobulin. It turns out to be a device.

[0066]

EFFECTS OF THE INVENTION The blood purifier and blood purification device of the present invention have the effect of removing β2-microglobulin and other small molecular weight proteins in blood safely, conveniently and with high efficiency.

[Brief description of drawings]

FIG. 1 is a partial cross-sectional side view showing an embodiment of the blood purifier of the present invention.

FIG. 2 is a schematic explanatory view showing an embodiment of the blood purification device of the present invention.

FIG. 3 is a schematic explanatory view showing another embodiment of the blood purification device of the present invention.

[Explanation of symbols]

 1 Container body 2 Upper lid member 3 Blood inflow side nozzle 4 Lower lid member 5 Blood outflow side nozzle 6 Mesh frame 7 Mesh 8 Aqueous solution 9 Spherical hydrogel 10 Arterial circuit 11 Blood pump 12 Blood purifier 13 Hemodialyzer 14 Vein circuit 15 Drip Chamber

Claims (8)

[Claims] 1. A weight ratio of cellulose and water having a compound having a log P (P is a partition coefficient in an octanol-water system) of 2.50 or more in the range of 1: 9 to 3: 7,
A spherical hydrogel having an average particle size of 300 to 600 μm has an inlet and an outlet for blood, and at least the outlet side allows blood to pass but hydrogel cannot pass. Individual,
A blood purifier which is housed together with an aqueous solution, wherein the container is sealed and at least the inside thereof is sterilized. 2. The blood purifier according to claim 1, wherein the compound having a logP value of 2.50 or more is a compound having a hydrocarbon moiety having 8 to 18 carbon atoms. 3. The blood purifier according to claim 1, wherein the pH of the aqueous solution in the container is in the range of 5 to 8. 4. The blood purifier according to claim 1, wherein the aqueous solution in the container is an aqueous solution of a compound having a buffering effect on pH. 5. The blood purifier according to claim 1, wherein the aqueous solution in the container is an aqueous solution containing citric acid and sodium citrate. 6. The blood purifier according to claim 1 or 2, wherein a part or the whole of the container having an inlet and an outlet is made of a transparent resin molded product. 7. A blood purification apparatus in which the blood purification device according to claim 1 is connected to a hemodialysis device. 8. The blood purification device according to claim 7, wherein the blood purification device and the hemodialysis device are connected in series.