JP3392707B2 - Hemodialysis machine - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hemodialyzer, and in particular, it is possible to prevent endotoxin existing on the dialysate side from migrating into the blood of a patient even when backfiltration occurs during dialysis. The present invention relates to a hemodialyzer that is highly safe and has excellent permeation performance that can be blocked.

[0002]

2. Description of the Related Art Hemodialysis treatment is carried out as a treatment method for removing waste products in the blood of patients whose kidney function is deteriorated or lost. FIG. 2 is a configuration diagram schematically showing an example of a dialysis treatment apparatus used for such hemodialysis treatment.

The dialysis treatment apparatus 11 includes a hemodialyzer (dialyzer) 12 for dialysis, a device 13 for supplying a dialysate to the hemodialyzer (dialyzer) 12, a monitor unit 14 for monitoring and controlling dialysis conditions, and A pump means 15 for circulating and circulating blood to the dialyzer 12 is provided. FIG. 3 is a schematic configuration diagram mainly showing the configuration of the hemodialyzer (dialyzer) 12.

The hemodialyzer 12 has a housing 12h.
A hollow fiber membrane 12m in which a plurality of hollow fibers are bundled is provided inside. Generally, the hollow fiber 21 for hemodialysis constituting the hollow fiber membrane 12m has a dense layer 23 on the inner surface S21a side forming a hollow 22 formed inside the hollow fiber 21, as shown in FIG. And outside that,
The structure is such that a porous support layer (sponge layer) 24 is provided.

During the dialysis, the hollow fibers 21 of the hollow fiber 21
Blood is flown into the hollow fiber 2, dialysate is flown to the outside of the hollow fiber 21, and the dense layer 23 in direct contact with the blood allows useful proteins contained in the blood having a molecular weight of tens of thousands or more to pass through the hollow fiber 21. It is designed to prevent leakage to the dialysate side. In addition, proteins and blood components having a molecular weight of less than tens of thousands contained in blood permeate the support layer 24 of the hollow fiber 21 and reach the outer surface side of the hollow fiber 21 due to the concentration difference between the blood and the dialysate. The components that are to be mixed into the dialysate and need to be supplied to the blood are exuded to the inner surface S21a side of the hollow fiber 21 and mixed into the blood during dialysis. Has become.

By the way, in a hemodialyzer having a high water removing capability,
The outlet 12e side of the blood, in too much blood is too concentrated by dialysis, unbalanced osmotic pressure between the blood side and the dialysate side, transmission of water or the like to the blood side of the dialysate side, so-called back-Filtration Occurs and endotoxin x present in the dialysate may be mixed into the blood due to this back filtration.
The water removal capacity of the hemodialyzer 12 comes at the expense of permeation performance.
It is controlled below a certain value.

[0007] Here, endotoxin is a complex of lipopolysaccharide and protein, and is a harmful substance that causes fever and shock symptoms when invading the body of a dialysis patient. Therefore, when performing dialysis using a dialyzer with high water removal performance, it is necessary to manage the dialysate free of endotoxin so that endotoxin does not flow from the dialysate into the patient's blood even if backfiltration occurs. There is.

As a technique for solving such a problem,
A system for removing endotoxin contained in dialysate using an endotoxin adsorbent has already been developed.However, even when this system is applied, it is not possible to maintain the dialysate circulation circuit at all times so that it is not contaminated by endotoxin. It's extremely difficult. At present, many dialysis treatment sites do not even have this system.

Due to such a fact, at present, when performing dialysis using a dialyzer having a high water removal performance, it is possible to avoid the risk of endotoxin migrating into the blood of a patient due to backfiltration. Not not.

[0010]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, in which endotoxin existing on the dialysate side is trapped in a dialysis membrane to prevent back filtration. Even if it occurs, it is an object of the present invention to provide a hemodialyzer which is highly safe and has excellent permeation performance, which prevents endotoxin contained in a dialysate from flowing into a patient's blood.

[0011]

As a result of earnest and devoted efforts to study the technology for solving the above-mentioned problems, the present inventor has found that heavy groups in which amino groups or imino groups such as polyamine and polyimine are introduced. Coalescence was found to have excellent adsorption capacity for endotoxin, and further, such material was used as a hollow fiber used as a filter material for a dialyzer having a high water removal capacity in which back filtration may occur. If it is formed by coating or reaction on the surface, it is thought that it is possible to develop a hemodialyzer that adsorbs and removes endotoxin contained in the electrolyte solution, has high safety, and has excellent permeation performance,
As a result of repeated research efforts, the present invention has been completed.

That is, in the hemodialyzer according to claim 1, as a membrane filter material for hemodialysis, a polymer which adsorbs endotoxin is mainly used as an outer supporting layer which is in direct contact with a dialysate outside the hollow fiber. The formed hollow fiber was used.
Here, the term “support layer on the outside of the hollow fiber” used in the present specification is provided on the outside of a dense layer (also referred to as an active layer) formed on the inner surface of the hollow fiber, and is a hollow fiber. Means a porous layer of hollow fibers forming the outer contour of

In the present specification, the surface of the dense layer forming the hollow formed inside the hollow fiber is referred to as "inner surface".
The surface forming the outer contour of the hollow fiber is referred to as "outer surface". The "polymer that adsorbs endotoxin" must be provided in the support layer outside the hollow fiber so as not to impair the function of the hollow fiber as a permeable membrane. The polymer film that adsorbs endotoxin provided on the outer surface side of the is not a dense film, but rather a film having a fine three-dimensional network structure or a so-called fine porous structure. preferable.

In the present invention, the inner surface of the hollow fiber, which is in direct contact with the blood to be dialyzed, is not provided with a polymer for adsorbing endotoxin, but the support layer outside the hollow fiber is provided with a polymer for adsorbing endotoxin. Since the blood is dialyzed, the blood itself does not come into direct contact with the polymer that adsorbs endotoxin even when the blood to be dialyzed flows in the hollow. Therefore, a part of the polymer film that adsorbs endotoxin does not mix into the blood during dialysis flowing through the hollow of the hollow fiber, which is excellent in safety. Moreover, since endotoxin present in the dialysate is adsorbed by the polymer that adsorbs endotoxin, even if backfiltration occurs during dialysis, there is a significant risk that endotoxin will move into the blood of the patient. Reduce.

A hemodialyzer according to a second aspect is the first aspect.
The polymer that adsorbs endotoxin of the hemodialyzer described in 1., specifically identifies the polymer that adsorbs endotoxin, at least an amino group, a polymer having one type of imino group introduced. Characterize. Claim 3
The hemodialyzer according to claim 2, which is the hemodialyzer according to claim 2,
It is characterized in that the polymer into which at least one of an amino group and an imino group is introduced is a polyalkene polymer.

A hemodialyzer according to a fourth aspect is the second aspect.
Of the hemodialyzer described in, at least, amino group, of the polymer introduced one kind of imino group, to identify a preferred specific example, at least an amino group, a polymer introduced one kind of imino group, the average It is a polymer selected from the group consisting of polyethyleneimine having a molecular weight of 10,000 or more and reactive polyethyleneimine having an epoxy group introduced therein.

Specific examples of the polymer which adsorbs endotoxin include cationic polymers such as polyethyleneimine, polytrimethyleneimine, polyvinylamine and polyallylamine. These polymers have low molecular weights. However, the molecular weight is preferably 10,000 or more. Specifically, a polymer selected from the group of polyethyleneimine having an average molecular weight of 10,000 or more and reactive polyethyleneimine having an epoxy group introduced therein is preferable. This is a polymer that adsorbs endotoxin,
To firmly held on the outer table surface of the hollow fiber, preferably has a molecular weight of as large as possible polymers, and,
This is because those that are insoluble in water by the reaction are preferable.

When a low molecular weight polymer is used as the polymer, a second component as a crosslinking agent may be added,
By forming an ion complex with a cationic compound,
The polymer may be immobilized. In addition, as a hemodialyzer in which back filtration occurs, specifically, a hemodialyzer having a large membrane area or having a high water-removing capacity of 15 ml / m 2 / hour (hr) / mmHg or more in a normal membrane area. Performance hollow fibers are used, and as materials for the hollow fibers constituting the dialysis hollow fiber membrane of such a hemodialyzer, cellulose, cellulose acetate, polysulfone, polymethylmethacrylate (PMMA), ethylene vinyl are used. Alcohol, polyamide, etc. are used.

Therefore, the hemodialyzer according to the present invention is
It is preferable that the hollow fiber is made of such a material, a polymer that adsorbs endotoxin is provided mainly on the outer surface side of the hollow fiber, and the hollow fiber membrane has the above-mentioned membrane area.
As the cross-linking agent used for insolubilizing the endotoxin-adsorbing polymer, diglycidyl ether, diisocyanate, epichlorohydrin and the like are preferable.

In the hemodialyzer according to the present invention, for example, a hollow fiber is dissolved in a solvent in which a polymer which adsorbs endotoxin is dissolved, and a polymer which adsorbs endotoxin is used as a solvent in the hollow of the hollow fiber. The solution dissolved in is soaked so as not to enter, and the hollow fiber dipped in the solution in which the polymer that adsorbs endotoxin is dissolved in a solvent is dried,
It can be produced by removing the solvent and spinning a hollow fiber in which a polymer that adsorbs endotoxin is deposited on the outer surface of the hollow fiber.

In this way, when a polymer that adsorbs endotoxin is deposited on the outer surface of the hollow fiber, the polymer thus deposited has a three-dimensional network structure of polymer chains, and
Since it has a multi-hard structure in which the pores formed when the solvent is removed are formed, the function of the hollow fiber itself as the permeable membrane is not easily impaired.

[0022]

1 is a sectional view schematically showing the structure of a hollow fiber constituting a hollow fiber membrane of a hemodialyzer according to the present invention. In FIG. 1, 1a is a conventional hollow fiber for hemodialysis, 2 is a hollow fiber, and 3 is a dense layer formed on the inner surface S2a side forming a hollow 2 formed inside the hollow fiber 1a. Reference numeral 4 denotes a porous support layer (sponge layer) provided outside the dense layer 2.

The material of the hollow fiber 1a is cellulose,
Cellulose acetate, polysulfone, polymethylmethacrylate (PMMA), ethylene vinyl alcohol, polyamide and the like are used. In this hollow fiber 1, a new support layer 4 on the outer side of the hollow fiber 1 is newly added.
A polymer 5 that adsorbs endotoxin x is provided.

In this example, as the polymer 5 adsorbing endotoxin x, for example, a cationic polymer such as polyethyleneimine, polytrimethyleneimine, polyvinylamine, polyallylamine, or the like is used. These polymers may be of low molecular weight, but the molecular weight is
It is preferably 10,000 or more. Specifically, a polymer selected from the group of polyethyleneimine having an average molecular weight of 10,000 or more and reactive polyethyleneimine having an epoxy group introduced therein is preferable. In order to firmly hold the polymer 5 to which endotoxin x is adsorbed on the outer surface S1b of the hollow fiber 1a, this is preferably a polymer having a molecular weight as large as possible, and is insoluble in water by the reaction. This is because that is preferable.

The polymer 5 which adsorbs endotoxin x is
The conventionally known hollow fiber 1a for hemodialysis is adsorbed with endotoxin x in the hollow 2 of the conventionally known hollow fiber 1a for hemodialysis in a solution of a polymer 5 that adsorbs endotoxin x in a solvent. The hollow fiber 1a for hemodialysis, which is conventionally known, is prepared by immersing the polymer 5 in a solution in which the polymer is dissolved in a solvent so that the solution does not enter, and immersing the polymer 5 in which the polymer 5 adsorbing endotoxin x is dissolved in the solvent. Then, the solvent is removed, and the hollow fiber 1 having the polymer 5 that adsorbs endotoxin x deposited on the outer surface S1b of the hollow fiber 1a is spun.

If desired, the outer surface S1b of the hollow fiber 1a may be heat-treated to heat-bond the polymer 5 that adsorbs endotoxin x. In this way, when the polymer 5 that adsorbs endotoxin x is deposited on the outer surface S1b of the hollow fiber 1a, the polymer 5 that has deposited has a three-dimensional network structure of polymer chains, and when the solvent is removed. It becomes a multi-hard structure in which the pores formed in are formed.

Polymer 5 which adsorbs endotoxin x
Is produced by polymerizing a raw material monomer of a polymer that adsorbs endotoxin x using a crosslinking agent. still,
As the cross-linking agent used for polymerizing the raw material monomer of the polymer 5 that adsorbs endotoxin x, diglycidyl ether, diisocyanate, epichlorohydrin and the like are preferable. As the polymerization method, a conventionally known polymerization method such as bulk polymerization or solution polymerization may be used.

In this hollow fiber 1, the polymer 5 adsorbing endotoxin x is not provided on the inner surface S1a which is in direct contact with blood to be dialyzed, but the polymer 5 adsorbing endotoxin x is provided. Since the outer support layer 4 is covered with the polymer 5 which adsorbs endotoxin x, even when the blood to be dialyzed flows in the hollow 2, the blood itself is not converted to the polymer 5 which adsorbs endotoxin x. There is no direct contact. Therefore, a part of the polymer 5 that adsorbs endotoxin x is not mixed in the blood under dialysis flowing in the hollow 2 of the hollow fiber 1, which is excellent in safety. Moreover, since the endotoxin x existing in the dialysate is adsorbed by the polymer 5 which adsorbs the endotoxin x,
Even if backfiltration occurs during dialysis, the risk of translocation of endotoxin x into the patient's blood is significantly reduced.

In the hollow fiber 1, the polymer 5 that adsorbs endotoxin x is not a dense film but a film having a fine three-dimensional network structure or a so-called fine porous structure. The function of the permeable membrane as a whole is unlikely to be impaired. Next, the hemodialyzer according to the present invention will be described based on experimental examples. (Experimental example) Water removal by wet method: 25 ml / m2 / hr / mm
Hg, urea permeability: 24510-6 cm2 / (min),
Vitamin B12 permeability: 39 × 10 -6 cm 2 / min (mi
After spinning the hollow fiber of n), it was immersed in an aqueous glycerin solution containing polyethyleneimine having a molecular weight of 70,000 and dried to obtain a high performance polysulfone hemodialysis membrane capable of adsorbing and removing endotoxin. The resulting hollow fiber has a membrane area of 1.0 m2
To prepare a hemodialyzer.

This was set in a cartridge that had been sterilized by dry heat at 250 ° C. for 1 hour in advance, and then an endotoxin aqueous solution (concentration: 20 EU / ml) was added to the hollow fiber at 12.5 liters / min / 1.0 cm 2. The endotoxin concentration of the filtrate supplied to the outer surface was measured by the gelation inversion method (gelation sensitivity: 0.03 EU / ml).
As a result, the endotoxin concentration in the filtrate was 0.03 EU / ml or less up to 3000 liters, and this hemodialyzer showed a high endotoxin adsorption capacity. (Comparative Example) Using the same hollow fiber material as in the above experimental example, a hemodialyzer similar to that in the above experimental example was prepared without treatment with a polyethyleneimine aqueous solution, and endotoxin adsorption capacity was evaluated by the same method as in the experimental example. . As a result, in the hemodialyzer which was not treated with the polyethyleneimine aqueous solution, the endotoxin concentration in the filtrate became 0.03 EU / ml or more after filtering 30 liters.

As a result of comparison between the experimental example and the comparative example, it was revealed that the hemodialyzer of the experimental example is at least 100 times more excellent in endotoxin adsorption capacity than the comparative example.

[0032]

EFFECTS OF THE INVENTION The hemodialyzer according to the present invention mainly uses a hollow fiber having a polymer for adsorbing endotoxin in a support layer outside the hollow fiber as a membrane filter material for hemodialysis. Even if back filtration sometimes occurs, the transfer of endotoxin into the blood of the patient can be prevented, so that the safety is high and the water removal capacity of the hemodialyzer can be increased.

[Brief description of drawings]

FIG. 1 is a cross-sectional view schematically showing a configuration of hollow fibers constituting a hollow fiber membrane of a hemodialyzer according to the present invention.

FIG. 2 is a configuration diagram schematically showing an example of a dialysis treatment apparatus.

FIG. 3 is a schematic diagram mainly showing a configuration of a dialyzer.

FIG. 4 is a cross-sectional view that schematically shows the configuration of a conventional hollow fiber that constitutes the hollow fiber membrane of a hemodialyzer.

[Explanation of symbols]

1 hollow fiber 2 hollow 3 Dense layer (active layer) 4 Support layer (sponge layer) 5 Polymers that adsorb endotoxin

Claims (4)

(57) [Claims] 1. As a membrane filter material for hemodialysis, mainly on the outer support layer of the hollow fiber which is in direct contact with the dialysate ,
A hemodialyzer using a hollow fiber formed of a polymer that adsorbs endotoxin. 2. A polymer which adsorbs the endotoxin,
The hemodialyzer according to claim 1, wherein the hemodialyzer is a polymer into which at least one of an amino group and an imino group is introduced. 3. The hemodialyzer according to claim 2, wherein the polymer into which at least one of an amino group and an imino group is introduced is a polyalkene-based polymer. 4. A polymer selected from the group consisting of polyethyleneimine having an average molecular weight of 10,000 or more and reactive polyethyleneimine having an epoxy group introduced therein, wherein the polymer having at least one of an amino group and an imino group introduced therein. The hemodialyzer according to claim 2, wherein