JPH0475765B2 - - Google Patents

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.

[Prior Art] 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, peripheral circulation may decrease, which may lead to various postoperative disorders. To prevent this, large amounts of blood transfusion are necessary to secure blood and There are problems with the occurrence of hepatitis. Therefore, a blood dilution extracorporeal circulation method is generally employed in which blood is diluted with dextran, glucose solution, gelatin solution, amino acid solution, or crystalloid or colloid such as polyvinylpyrrolidone. 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, a myocardial purge solution or an ice solution for cooling the myocardium may mix into the blood, and the hematocrit value may further decrease. Even if the hematocrit value decreases like this, 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 will decrease. If it remains low, the oxygen carrying capacity will be insufficient and there is a risk that it will not be able to adequately support metabolism.

Therefore, in the past, diuretics were administered to promote urination and remove excess water from the blood in the form of urine, thereby normalizing the hematocrit value.
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. Another problem was that it was difficult to control the amount of water 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. Hollow fiber membranes are used. Although membranes made of cellulose acetate are used in hemoconcentrators currently in practical use, they have the drawbacks of low water permeation rate and poor waterproofing 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, in JP-A-57-43748, cellulose, polyacrylonitrile,
polycarbonate, polymethyl methacrylate,
The use of membranes for dialysis-type or ultrafiltration-type artificial kidneys made of polyethylene or polypropylene has been proposed, but membranes for dialysis-type artificial kidneys have extremely low water permeation rates, making them impractical; Membranes for type artificial kidneys have the disadvantage that a large amount of protein permeates through them, and are not preferred as hemoconcentrators.

[Problem that the invention seeks to solve]

The present invention solves the problems of the prior art described above, and its 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 polymeric materials and evaluated their performance as hemoconcentrators. As a result, the semipermeable membrane obtained from aromatic polysulfone
We have discovered that the above object is particularly excellent in achieving the above object, and have arrived at the present invention.

In order to solve the above problems, the present invention incorporates a hollow fiber membrane made of aromatic polysulfone having a dense layer on at least the inner surface, and allows blood to flow inside the hollow fiber membrane. A pressure difference is created on both sides, and this pressure difference causes water in the blood to pass through the hollow fiber membrane and drain to the outside.The amount of water discharged is measured and the pressure difference on both sides of the membrane is adjusted to concentrate the blood. A sterilized hemoconcentrator equipped with a rate control system, wherein the hollow fiber membrane has an albumin rejection rate of 95% or more and a water permeation rate of 1/m ² .
It was constructed as a hemoconcentrator characterized by a blood flow rate of 1.0 kg/cm ² or more. The higher the inhibition rate of albumin, the better, and preferably 99% or more. Here, the rejection rate of albumin means that an albumin-containing solution with a concentration of 5 g/dl or less is supplied to a hollow fiber membrane, and cross-flow filtration is performed at a transmembrane pressure difference of about 0.5 Kg/cm ² .
The albumin concentration of each of the outlet liquid and permeate liquid is measured, and the value is calculated using the following formula.

Rejection rate (%) = (1-2 x permeate concentration/feed solution concentration + outlet solution concentration)
×100 As is well known, the structure of the hemoconcentrator is 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 using the pressure difference. It is configured like this.

[Effect]

Semipermeable membranes made of aromatic polysulfone allow water to pass through efficiently, and can form pores that are denser than ever before to block polymers such as albumin. Therefore, while retaining the properties of semipermeable membranes, 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 0.3/ ^m2 .
However, when aromatic polysulfone is used, a water permeation rate of 1/m ^{2 ·} min·Kg/cm ² or higher can be easily obtained. Moreover, even though such a high water permeation rate is achieved, proteins hardly permeate through it. That is, a blocking 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 has the formula Polyether sulfone consisting of repeating units shown and formula Examples include polysulfones consisting of repeating units represented by 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 is suitable, preferably 10-30% by weight.
When the concentration exceeds 35% by weight, the water permeability of the resulting semipermeable membrane decreases to less than 1/m ² ·min ·Kg/cm ² . 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. Additives include inorganic salts, polyhydric alcohols, aliphatic or aromatic carboxylic acids or their esters,
Carboxylic acid amides, sulfonic acids, phosphoric acid alkyl esters, and the like 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. As aliphatic carboxylic acid or its ester,
Examples 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, salicylic acid, terephthalic acid, and trimellitic acid. I can give an example. Further, examples of the carboxylic acid amide include N-methylformamide and N-methylacetamide, examples of the sulfonic acid include benzenesulfonic acid, and examples of the phosphoric acid alkyl ester include trimethyl phosphate and triethyl phosphate. The additives can be used alone or in combination of two or more. By selecting the type and amount of these additives,
Hollow fiber membranes with different membrane properties such as water permeability and protein rejection can be produced.

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 a gas or a non-coagulating solution 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 membrane's shape. 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. The protein in the blood is albumin, which has a molecular weight of 69,000, and has a molecular weight of approx.
Since it is mainly composed of 160,000 globulins and various proteins of higher molecular weight, it must exhibit a high albumin blocking rate in order to prevent blood proteins from permeating through it. Therefore, the membrane used in the present invention needs to have an albumin rejection rate of 95% or more, preferably 99% or more.

Although the inner diameter and membrane thickness of the hollow fibers are not particularly limited, hollow fibers with an inner diameter of 200 to 1000 μm and a membrane thickness of 100 to 200 μm are preferably used because they are easy to manufacture and have good blood concentration efficiency. Furthermore, hollow fibers are washed with water and thoroughly desolvated before use, but if they are dried before use, they must be impregnated with glycerin or the like to maintain water permeability. It is preferable to make it hydrophilic.

The hemoconcentrator of the present invention is manufactured in the same manner as conventional blood processing devices incorporating 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 total membrane area is approximately 0.8 to 1.5 ^m2 .

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 negative 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 mmHg. Moisture in the blood permeates the membrane and is discharged to the outside of the hollow fiber due to the pressure difference between the two sides of the membrane, thereby 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 to remove water from blood in heart surgery using an artificial heart-lung machine.
It can also be used to treat cases where excess fluid 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 (Union Carbide P-
1700), 7.5 parts by weight of polyvinylpyrrolidone (average molecular weight 10,000), and 74 parts by weight of N,N-dimethylacetamide were mixed and dissolved to prepare a spinning dope. A spinning stock solution and water as a core solution each having a temperature controlled at 15° C. were extruded through a double annular nozzle, and wet-dry 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 microscopic observation, and the inside of the membrane was a finger-shaped porous layer. In addition, the water permeation rate is 3/ ^m2・min・
The albumin rejection rate was 100% at Kg/cm ² and the molecular weight cutoff was about 13,000.

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 ^-1 ), transformer membrane pressure 192mmHg,
When blood was allowed to flow inside the fiber under conditions of a blood hematocrit value of 37% to perform hemoconcentration, the water filtration rate was 61 ml/m ² ·min. 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 a speed of 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. This material had a water permeation rate of 3/m ² ·min·Kg/cm ² and good pressure resistance. The albumin inhibition rate was 100%, and the molecular weight cutoff was approximately 28,000.

When an in vivo hemoconcentration experiment was conducted in the same manner as in Example 1, the water filtration rate was 58 ml/m ² ·min, and no albumin was detected in the filtrate.
At this time, the blood flow rate was 100 ml/min, the transmembrane pressure was 200 mmHg, and the hematocrit value was 32%.

Example 3 Polyether sulfone (ICI 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 stock solution. A spinning stock solution and water serving as a core liquid, each of which was controlled at a temperature of 30° C., were extruded through a double annular nozzle and subjected to dry-wet spinning. The residence time in the air was 2 seconds, after which it was introduced into water at 40°C and wound up at 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. In addition, the water permeability rate is 7/m ² · min · Kg/cm ² ,
Albumin rejection rate is 100%, molecular weight cutoff is approximately 28000
It was hot.

We constructed a hemoconcentrator and performed an in vitro hemoconcentration experiment using bovine blood with a hematocrit value of 40%. Blood flow rate 100ml/min (shear rate within the fiber
320sec ^-1 ), and the water filtration rate at a trans membrane pressure of 200 mmHg was 120 ml/cm ² ·min.
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 built into this blood concentrator is a cellulose acetate hollow fiber membrane, and the water permeation rate is 0.24.
/m ² ·min·Kg/cm ² , albumin inhibition rate is 95%.

Hemoconcentration using extracorporeal circulation was performed using dogs under conditions of blood flow rate of 100 ml/min, transmembrane pressure of 200 mmHg, and hematocrit value of 38%.
The water filtration rate was 27 ml/cm ² ·min. In addition, for plasma albumin concentration of 1.40 g/dl before filtration,
Albumin of 0.09 g/dl 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 hemoconcentrator according to the present invention uses a hollow fiber membrane made of aromatic polysulfone with a water permeation rate of 1/m ² ·min ·Kg/cm ² or more, so that it This hollow fiber membrane has a higher water permeation rate than a membrane made of acetate or the like, and has a dense layer on at least the inner surface.
In addition, it uses a product with an albumin blocking rate of 95% or more, which has the effect of almost completely blocking the passage of proteins in the blood.

Claims (1)

[Claims] 1. A hollow fiber membrane made of aromatic polysulfone having a dense layer on at least the inner surface is built in, blood is allowed to flow inside the hollow fiber membrane, a pressure difference is created on both sides of the hollow fiber membrane, and the Equipped with a system that allows water in the blood to pass through the hollow fiber membrane and discharge to the outside based on the pressure difference, and also measures the amount of water discharged and adjusts the pressure difference on both sides of the membrane to control the blood concentration rate. The hollow fiber membrane has an albumin rejection rate of 95% or more and a water permeation rate of 1/m ² ·min.
A hemoconcentrator characterized in that the hemoconcentrator is Kg/cm ² or more. 2. The hemoconcentrator according to claim 1, wherein the albumin rejection rate is 99% or more. 3 The aromatic polysulfone has the formula The hemoconcentrator according to claim 1 or 2, which is a polyether sulfone consisting of repeating units represented by: 4 The aromatic polysulfone has the formula The hemoconcentrator according to claim 1 or 2, which is a polysulfone consisting of repeating units represented by: 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.