JPS6247367A - Blood concentrator - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a hemoconcentrator for removing water increased in blood due to surgery or disease, and returning the blood to a normal water content.

[Conventional technology]

Conventionally, a heart-lung machine has been used in open heart surgery to temporarily replace the functions of the heart and lungs. An artificial heart-lung machine consists of a pump for transporting blood, an artificial lung for adding oxygen to the blood and removing carbon dioxide, and a blood circuit that connects these to the human body and forms a blood circulation route. There is.

By the way, with the extracorporeal circulation of blood due to the use of a heart-lung machine, there is a risk of a decrease in peripheral circulation, which can lead to various postoperative disorders. To prevent this, large amounts of blood transfusion are
There are problems with securing blood and the occurrence of hepatitis. Therefore, a blood dilution extracorporeal circulation method is generally employed in which blood is diluted with quality substances such as dextran, glucose solution, gelatin solution, amino acid solution, or polyvinylpyrrolidone or colloid. According to this method, the hematocrit value of blood (volume % of blood cells in blood) decreases to about 25%. (Normal value 40-50%). Furthermore, during surgery, myocardial purge fluid or ice solution for cooling the myocardium may mix into the blood, which may further reduce the hematocrit value. Even if the hematocrit value decreases in this way, it is not a big problem because the oxygen intake of the body is reduced by hypothermia during surgery, but when the surgery is over and the metabolism returns to normal, the hematocrit value remains low. However, there is a risk that the oxygen carrying capacity will be insufficient and the body will not be able to adequately support metabolism.

Conventionally, diuretics have been administered to promote urination and remove excess water from the blood in the form of urine, bringing the hematocrit level back to normal. However, such a method not only places a heavy burden on the kidneys, but also has the disadvantage that it cannot be applied to patients who do not respond well to diuretics or whose renal function has decreased.

Another problem is that the use of large amounts of diuretics causes side effects such as increased potassium concentration in the blood. Furthermore, there was also the problem that it was difficult to control the amount of water to be removed.

In order to solve these problems, a hemoconcentrator using a semipermeable membrane has recently been put into practical use. The principle of a hemoconcentrator is to remove water from the blood by flowing blood through one side of a semipermeable membrane and allowing the water in the blood to permeate to the other side of the membrane. A hollow fiber membrane is used. Although membranes made of cellulose acetate are used in currently commercialized hemoconcentrators, they have the drawbacks of low water permeation rate and poor water removal efficiency.

In addition, attempts have been made to use porous polypropylene membranes and polyvinyl alcohol membranes in hemoconcentrators, but while these membranes have a high water permeability rate, they also allow proteins in the blood to pass through them, so useful components from the blood can be removed. The disadvantage is that a large amount of information is lost. Furthermore, JP-A-57-4374
In Publication No. 8, the use of membranes for dialysis-type or ultrafiltration-type artificial kidneys made of cellulose, polyacrylonitrile, polycarbonate, polymethyl methacrylate, polyethylene, or polypropylene is proposed; Membranes have an extremely low water permeation rate, making them impractical, and membranes for ultrafiltration type artificial kidneys have the disadvantage of allowing a large amount of protein to pass through, making them undesirable as hemoconcentrators.

[Problem that the invention seeks to solve]

The present invention solves the problems of the prior art described above,
The purpose is to provide a hemoconcentrator with a high water permeation rate. Another object is to provide a hemoconcentrator that causes less protein loss.

[Means for solving problems]

The present inventors created membranes using various polymer materials,
As a result of evaluating its performance as a hemoconcentrator, it was found that a semipermeable membrane made of aromatic polysulfone is particularly excellent in achieving the above-mentioned objectives, and the present invention was achieved.

The solution to the above problems of the present invention is a semipermeable membrane made of aromatic polysulfone, which has an albumin rejection rate of 95% or more and a water permeation rate of I! ! /m2・min・kg/cm
This is a hemoconcentrator that incorporates two or more hollow fiber membranes.

The higher the rejection rate of albumin, the better, and preferably 99% or more. As is well known, the structure of the hemoconcentrator is such that a large number of hollow fiber membranes are bundled and cut into a certain length, blood is flowed inside each hollow fiber membrane, and water is discharged to the outside by utilizing the pressure difference. be done.

[Function] A semipermeable membrane made of aromatic polysulfone allows moisture to pass through efficiently, and it is possible to form pores that are denser than ever before to block macromolecules such as albumin, thus retaining the properties of a semipermeable membrane. However, a membrane with high water permeation rate can be obtained. If this semipermeable membrane is formed into a hollow fiber membrane, a hemoconcentrator with a high albumin rejection rate and a high water permeation rate can be obtained.

Conventional hemoconcentrators using cellulose acetate membranes have a water permeation rate of 0.2 to 0.3β/m2.
min.kg/cm2, but when aromatic polysulfone is used, lj! /m2・min・kg/cm2 or higher water permeation rate can be easily obtained. Moreover, even though such a high water permeation rate is achieved, proteins hardly permeate through it. That is, a rejection rate of albumin, which has a small molecular weight among blood proteins, is 95% or more, preferably 99% or more.

〔Example〕

The present invention will be explained in detail by examples.

The aromatic polysulfone used in the present invention includes:
Examples include polyether sulfones consisting of repeating units represented by the formula, polysulfones consisting of repeating units represented by the formula, and mixtures thereof.

To produce a hollow fiber membrane from aromatic polysulfone, a spinning dope in which aromatic polysulfone is dissolved in an organic solvent is extruded through an annular nozzle and brought into contact with a coagulating liquid that is miscible with the organic solvent but does not dissolve the aromatic polysulfone.

As an organic solvent for dissolving the aromatic polysulfone, dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, morpholine, etc. can be used. These may be used alone or in combination of two or more. The concentration of the solution is 5-35% by weight, and 10-30% by weight.
is preferred. When the concentration exceeds 35% by weight, the water permeability of the resulting semipermeable membrane decreases to 11/m"・min・kg/c
n! It becomes below. Furthermore, if the concentration is lower than 5% by weight, a semipermeable membrane with sufficient strength cannot be obtained, so there is a risk of blood leakage. The spinning dope may be a simple solution of aromatic polysulfone, but various additives may be added to change the membrane performance. As additives, inorganic salts, polyhydric alcohols, aliphatic or aromatic carboxylic acids or esters thereof, carboxylic acid amides, sulfonic acids, and phosphoric acid alkyl esters can be used.

More specifically, examples of inorganic salts include sodium chloride, sodium nitrate, potassium nitrate, and sodium sulfate, and examples of polyhydric alcohols include polyethylene glycol.

Examples of aliphatic carboxylic acids or esters thereof include formic acid, acetic acid, propionic acid, methyl formate, ethyl formate, methyl acetate, ethyl acetate, lactic acid, and ethyl lactate. Examples of aromatic carboxylic acids include benzoic acid. ,
Examples include salicylic acid, terephthalic acid and trimellitic acid. Also, as a carboxylic acid amide, N
-Methylformamide and N-methylacetamide, benzenesulfonic acid as the sulfonic acid, and trimethyl phosphate and triethyl phosphate as the phosphoric acid alkyl esters. The additives can be used alone or in combination of two or more. By selecting the types and amounts of these additives, hollow fiber membranes with different membrane performances such as water permeability and protein rejection can be manufactured.

The spinning dope is extruded through a double annular nozzle having an appropriate diameter, and its outer or inner surfaces are brought into contact with the coagulating liquid. As the coagulating liquid, water or a mixture of water and an organic solvent is preferably used. The spinning dope extruded from the annular nozzle may be brought into contact with the coagulating liquid immediately, or may be once extruded into the air and then brought into contact with the coagulating liquid. Further, when the coagulating liquid is not injected from the inner surface of the annular nozzle, it is preferable to inject gas or a non-coagulating liquid in order to maintain a good shape of the fibers. The spinning stock solution that comes into contact with the coagulation liquid immediately coagulates, and the solvent is leached into the coagulation liquid to form hollow fibers.

The aromatic polysulfone hollow fiber thus obtained has a dense layer on one or both sides of the membrane, and the inside of the membrane has a porous structure. There may be a cavity inside the membrane. The performance of the membrane is mainly determined by the dense layer on the surface, and the internal porous structure acts as a support layer to maintain the shape of the membrane. When the inner and/or outer surfaces of the fibers are observed with a scanning electron microscope, substantially no pores or gaps should be observed. Proteins in blood have a molecular weight of 69
,000, globulin with a molecular weight of about 160,000, and various proteins with higher molecular weights. Therefore, in order to prevent proteins in the blood from permeating, albumin must have a high blocking rate. No. Therefore, the membrane used in the present invention needs to have an albumin rejection rate of 95% or more, preferably 99% or more.

The inner diameter and film thickness of the hollow fibers are not particularly limited, but the inner diameter is 200 to 1000μ and the film thickness is 100μ.
Hollow fibers with a diameter of ~200μ are preferred because they are easy to manufacture (and have good blood concentration efficiency).Furthermore, hollow fibers are washed with water and thoroughly desolvated before use.
If this is to be used after it has been dried, it is preferable to impregnate it with glycerin or the like to make it hydrophilic in order to maintain water permeability.

The present Song-Ming hemoconcentrator is manufactured in the same manner as conventional blood processing devices containing hollow fibers. In other words, a large number of hollow fibers are bundled and cut into a certain length, then stored in a housing, both ends are fixed with a hardening resin such as polyurethane, and blood inlets and outlets are provided at both ends to allow blood flow inside the hollow fibers. to allow blood to flow. The amount of hollow fibers used is preferably such that the area of the membrane is approximately 0.8 to 1.5 m.

The hemoconcentrator is used after being sterilized, and the device of the present invention can be sterilized using ethylene oxide gas, high-pressure steam sterilization, or radiation sterilization.

In order to remove water from the blood and concentrate the blood using the hemoconcentrator of the present invention, blood is introduced from the inlet of the hemoconcentrator and the blood is pressurized, or the outside of the hollow fiber is placed under positive pressure and the blood side is What is necessary is to make the pressure relatively high. The appropriate pressure difference (trans membrane pressure) is about 200 to 500 mm Hg. Water in the blood permeates the membrane and is discharged to the outside of the hollow fibers due to the pressure difference between the two sides of the membrane, concentrating the blood. The blood concentration rate is controlled by measuring the amount of water discharged and adjusting the pressure difference.

The hemoconcentrator of the present invention can be used not only to remove water from blood during heart surgery using an artificial heart-lung machine, but also to treat cases where excess water accumulates in the body due to disease.

Hereinafter, the present invention will be explained in more detail with reference to specific examples.

Example-1 Polysulfone (P-1700 manufactured by Union Carbide)
18.5 parts by weight, polyvinylpyrrolidone (average molecular weight 1
0.000) and 74 parts by weight of N,N-dimethylacetamide were mixed and dissolved to prepare a spinning dope. 1 each
A spinning dope and water as a core solution whose temperature was controlled to 5° C. were extruded through a double annular nozzle, and dry-wet spinning was performed. The residence time in the air was 0.12 seconds, and then it was introduced into water, which is an external coagulating liquid, and wound up. The winding speed at this time was 29 m/min.

The obtained hollow fiber membrane had an inner diameter of 500 μm and an outer diameter of 700 μm, and had dense layers on both the inner and outer surfaces with no voids observed even by electron microscopy, and the inside of the membrane was a finger-shaped porous layer.

In addition, the water permeation rate is 31/m''・min・kg/cnT, the albumin rejection rate is 100%, and the molecular weight fraction is approximately 1.
It was 3,000.

This hollow fiber membrane was bundled and incorporated into a housing to create a hemoconcentrator, and extracorporeal blood circulation was performed using a dog. Blood flow rate 100ml/min, shear rate 320sec
-') ,) Lance membrane pressure 192mm Hg,
When blood was poured inside the fibers and blood was concentrated under conditions where the blood hematochrysotropy value was 37%, the water filtration rate was 6.
1m1/n?・It was a minute. The albumin concentration in the filtrate was below the detection limit.

Example 2 Spinning was carried out using the same stock solution and core solution as in Example 1, except that morpholine was used instead of N,N-dimethylacetamide. After running in the air for 2.4 seconds, it was introduced into water at 16°C and wound up at 24 m/min.

The obtained hollow fiber membrane had dense layers on both the inner and outer surfaces, and the inside of the membrane was a finger-like porous layer. The water permeability rate of this thing is 11/
The pressure resistance was also good at m''·min·kg/cm2.

The albumin rejection rate is 100%, and the molecular weight cutoff is approximately 2.
It was 8,000.

When an in vivo hemoconcentration experiment was conducted in the same manner as in Example-1, the water filtration rate was 120ml/m2.
・minutes, and no albumin was detected in the filtrate. At this time, the blood flow rate was 100 ml 7 minutes, the trans membrane pressure was 200 mm Hg, and the hematocrit value was 32%.

Example-3 Polyether sulfone (TCI 4800-P) 20
Parts by weight, polyethylene glycol (PEG-600)
16 parts by weight and 64 parts by weight of dimethyl sulfoxide were mixed and dissolved to prepare a spinning dope. A spinning stock solution and water as a core liquid each having a temperature controlled at 30° C. were extruded through a double annular nozzle, and dry-wet spinning was performed. Residence time in the air is 2 seconds, then 40
It was introduced into water at a temperature of 0.degree. C. and wound up at a speed of 10 m/min.

The inner surface of the obtained hollow fiber membrane was dense, the outer surface had many micropores, and the inside of the membrane was a finger-shaped porous layer. Further, the water permeation rate was 3 (1/m2·min·kg/cm2), the albumin rejection rate was 100%, and the molecular weight cut off was 28,000.

A hemoconcentrator was prepared and an in vitro hemoconcentration test was conducted using live blood with a hematocrit value of 40%. Blood flow rate 100 m 127 minutes (shear rate within the fiber 320 se
c-'), 1-Lance membrane pressure 200mm11
The water filtration rate in g was 58 mn/m''·min and no albumin was detected in the filtrate.

Comparative Example-1 An in vivo test was conducted using a commercially available hemoconcentrator (manufactured by CD Medical Co., Ltd., trade name Hemocon).

The membrane installed in this blood concentrator is a cellulose acetate hollow fiber membrane, and the water permeation rate is 0.241/m.
min.kg/cm2, albumin inhibition rate is 95%.

Blood flow 1 t 100 m E 7 minutes using a dog, trans.
Membrane pressure 200mmHg, hematocrit value 38
When hemoconcentration by extracorporeal circulation was performed under conditions of %,
Water filtration rate is 27nj! /m”・min.

Furthermore, while the blood albumin concentration before filtration was 1.40 g/j, 0.09 g of albumin #1 was detected in the filtrate.

As is clear from the above results, a semipermeable membrane with a high water permeation rate and a low molecular weight cutoff can be easily obtained from aromatic polysulfone. The obtained membrane has a high permeation rate of water in the blood even when blood is processed, and can almost completely block the permeation of proteins, so it is extremely useful as a membrane for a hemoconcentrator.

〔Effect of the invention〕

As described above, the present invention has the advantage that it is possible to almost completely block proteins such as albumin and to easily obtain a hemoconcentrator with a high water permeation rate.

Patent applicant: Japan Medical Supply Co., Ltd. (
1 other person) Procedural amendment December 25, 1985

Claims (5)

[Claims] (1) A semipermeable membrane made of aromatic polysulfone with an albumin rejection rate of 95% or more and a water permeation rate of 1 l/m
A hemoconcentrator characterized in that it has a built-in hollow fiber membrane having a rate of at least ^2·min·kg/cm^2. (2) The hemoconcentrator according to claim 1, wherein the albumin rejection rate is 99% or more. (3) The hemoconcentrator according to claim 1 or 2, wherein the aromatic polysulfone is a polyether sulfone consisting of a repeating unit represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼. (4) The hemoconcentrator according to claim 1 or 2, wherein the aromatic polysulfone is a polysulfone consisting of a repeating unit represented by the formula ▲A mathematical formula, a chemical formula, a table, etc.▼. (5) The hemoconcentrator according to any one of claims 1 to 4, wherein the hollow fiber membrane has a dense surface layer and a porous support layer.