JP2006305333A - Module for hemofiltration or hemodiafiltration - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a module for hemofiltration or hemodiafiltration dialysis which is a module using hollow fiber membrane which consists of a polysulfone polymer and polyvinylpyrrolidone, is hard to increase pressure of the blood in extracorporeal circulation circuit during a long treatment, has a long life time (membrane duration life) and a reduced albumin loss. <P>SOLUTION: In a module for extracorporeal circulation of a hollow fiber membrane type, the hollow fiber membrane consists of the polysulfone polymer and polyvinylpyrrolidone and the inside diameter of the hollow fiber membrane is 205-250 μm, elevated liquid level of the hollow fiber membrane measured by the capillary ascending method is 60 mm-120 mm in terms of the hollow fiber membrane having an inside diameter of 230 μm, furthermore, when the distance between opening ends of the hollow fiber membrane is defined as L and the minimum inside diameter of the cylindrical container is defined as D, the ratio of L/D is 3.5-6.5, and the sieving coefficient of albumin (Alb-Sc) after 3 hours in the bovine plasma filtering performance test in vitro is 0.0054 or less. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention is unlikely to cause an increase in blood pressure in the extracorporeal circuit during a long period of time, has a long lifetime (membrane life), and can be extracorporeally circulated safely and efficiently without using a replacement fluid such as albumin. The present invention relates to a module for hemofiltration or hemodiafiltration. More specifically, a hollow fiber membrane made of a polysulfone polymer and polyvinyl pyrrolidone that does not easily cause clogging or increase in blood pressure in the blood circuit due to long-term blood circulation and does not require a replacement fluid such as albumin. The present invention relates to a module for blood filtration or hemofiltration dialysis used.

  Until now, various blood purification methods using membrane separation technologies such as hemodialysis, blood filtration, and hemofiltration dialysis have been devised and technically established, but these blood purification therapies are only available for patients with chronic renal failure. In addition, it has been widely applied to patients with acute renal failure, congestive heart failure, and the like, and in recent years, it has been widely applied to lifesaving emergency and ICU. When the blood purification method using membrane separation is performed on patients with acute renal failure, the extracorporeal circulation is basically performed in the same manner as that for conventional patients with chronic renal failure. Since there are many cases where the condition is worse compared to patients with chronic renal failure, such as complications and unstable circulatory dynamics, it is necessary to adopt a short and intermittent treatment mode such as normal hemodialysis Was impossible.

Therefore, especially for patients with acute renal failure, as a more detailed treatment using a dedicated blood purifier, a treatment mode called “continuous blood purification therapy” in which water removal and liquid replacement are performed in small amounts over a long period of time. Is mainly adopted. Specifically, “continuous hemofiltration” and “continuous hemofiltration dialysis” that perform filtration and dialysis under these conditions are performed. In “continuous hemofiltration”, the blood flow rate is 50 to 150 ml / The filtration rate is set to 5 to 50 ml / min lower than that of normal blood filtration or hemodialysis. In addition, a dedicated continuous blood filter is often used, and a smaller module (with a membrane area of approximately 1.5 m ² ) than a normal hemodialyzer (membrane area of approximately 1.3 to 2.1 m ² ). 1 m ² or less) is used. In the “hemofiltration dialysis”, hemodialysis is also used together with the above-mentioned hemofiltration by flowing a dialysate at a low flow rate. Here, however, a continuous hemofilter is also used exclusively.

  Such a continuous treatment mode is applied to, for example, severe trauma, SIRS (systemic inflammation response syndrome) after acute cardiovascular surgery, acute renal failure associated with severe heart failure, and the like.

  By the way, the duration of the continuous operation is much longer than the normal hemodialysis time of 4 to 5 hours in both cases of blood filtration and hemofiltration dialysis, and often extends from 20 hours to several days. In addition, the continuous hemofilter may become clogged in the blood flow path during the operation, and the pressure loss on the blood inlet side and the blood outlet side becomes high, so the treatment must be stopped during the extracorporeal circulation. There were some cases that could not be obtained or that the continuous blood filter had to be replaced during the operation.

  In order to extend the lifetime of the extracorporeal circulation module such as a continuous blood filter, the membrane material and the container member are improved in antithrombogenicity, and clogging due to blood coagulation is prevented. There are many ideas to improve. However, it is not easy to obtain a medical material that can satisfy all requirements such as membrane separation performance, biological safety, and manufacturing cost, and there are many cases that have not yet been put into practical use.

  On the other hand, a report example is known in which several commercially available continuous blood filters are comparatively evaluated from the viewpoint of lifetime, and guidelines for selecting an appropriate blood filter in clinical practice are given ( Non-patent document 1). In this document, the lifetime of various continuous blood filters as viewed from the circuit internal pressure is clinically evaluated. Blood filters using polyacrylonitrile (PAN) hollow fiber membranes and polysulfone (PS) hollow fibers It has been reported that a blood filter using a membrane has a long lifetime. However, according to the in vitro lifetime evaluation method found by the present inventors, the lifetime of the blood filter described in this document cannot be said to be sufficiently long. In particular, a continuous blood filter incorporating a polysulfone-based hollow fiber membrane generally has a hollow fiber membrane formed of a polysulfone-based polymer that is a hydrophobic polymer and a polyvinyl pyrrolidone that is a hydrophilic polymer. Although it is considered to have a good balance of low-molecular-weight protein permeation performance, ultrafiltration amount, and biocompatibility, this polysulfone-based blood filter still has a lifetime that takes into account long-term administration over 2 days. I had to say that is still inadequate.

  Naturally, in continuous blood purification therapy, it is not preferable that useful proteins such as albumin leak out of the body (loss) during the operation. Therefore, in general, an ICU that is well managed by a patient may perform a replacement fluid such as albumin in such a situation. However, if possible, it is desirable to suppress the loss of useful proteins such as albumin as much as possible, and it is desirable that complicated fluid replacement operations such as albumin are unnecessary. Therefore, performance characteristics desired for a continuous blood filter include albumin and the like. Filtration performance to the extent that no replacement fluid is required is desired, but the lifetime is sufficiently satisfactory, and it cannot be said that the filtration performance of albumin is also satisfactory.

As described above, in a long-term extracorporeal circulation treatment such as continuous blood purification therapy, a hollow fiber membrane composed of a hydrophobic polymer and a hydrophilic polymer, especially a hollow fiber composed of a polysulfone polymer and polyvinylpyrrolidone. A module using a membrane, which has a long lifetime that does not cause an increase in blood pressure in the extracorporeal circuit and has little loss of albumin, a useful protein, is known for blood filtration or hemofiltration dialysis. There wasn't.
Yoshihisa Yamashita, Hiromichi Suzuki, Intensive Care vol. 12 s15-s16 separate volume 2000

  The present invention is a module using a hollow fiber membrane made of a polysulfone polymer and polyvinyl pyrrolidone in view of the problems of the prior art, and increases blood pressure in the extracorporeal circuit during long-term treatment. It is an object of the present invention to provide a module for blood filtration or hemofiltration dialysis that has a long lifetime (membrane life) that does not cause a loss and has little loss of albumin, which is a useful protein.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the hollow fiber membrane incorporated is made of a polysulfone polymer and polyvinyl pyrrolidone, the inner diameter of the hollow fiber membrane is 205 to 250 μm, and the capillary rises. When the liquid level rise value of the hollow fiber membrane measured by the method is converted to a hollow fiber membrane having an inner diameter of 230 μm, it becomes 60 mm to 120 mm, the distance between the open end faces of the hollow fiber membrane is L, and the minimum inner diameter of the cylindrical container is D L / D is 3.5 to 6.5, and the sieving coefficient (Alb-Sc) of albumin after 3 hours in the in vitro bovine plasma filtration performance test is 0.0054 or less. It has been found that a module for hemofiltration dialysis has an excellent lifetime and a small amount of albumin loss, and the present invention has been completed.
That is, the present invention relates to the following blood filtration module.

(1) The inside of the cylindrical container is filled with a bundle of hollow fiber membranes, and both ends of the hollow fiber membrane are potted to both ends of the cylindrical container with a curable resin to form open end surfaces at both ends of the container. In the hollow fiber membrane type extracorporeal circulation module, a header cap having a blood inlet or outlet is attached to each of the open end faces, and further has a filtrate circulation port communicating with the hollow fiber membrane filtrate side space.
The hollow fiber membrane comprises a polysulfone polymer and polyvinyl pyrrolidone,
The hollow fiber membrane has an inner diameter of 205 to 250 μm,
When the liquid level rise value of the hollow fiber membrane measured by the capillary rise method is converted to a hollow fiber membrane having an inner diameter of 230 μm, it becomes 60 mm to 120 mm.
Blood filtration or blood filtration dialysis, wherein L / D is 3.5 to 6.5, where L is the distance between the open end faces of the hollow fiber membrane, and D is the minimum inner diameter of the cylindrical container Module.
(2) The module for blood filtration or blood filtration dialysis according to (1), wherein the sieve coefficient of albumin after 3 hours in an in vitro bovine plasma filtration performance test is 0.0054 or less.
(3) A module for blood filtration or blood filtration dialysis,
Lifetime evaluation conditions for an extracorporeal circulation module comprising:
a) Warm blood pool to 30-37 ° C .:
b) Connect a filtration circuit with a blood filtration pump to the filtration side of the extracorporeal circulation module:
c) While circulating blood at a blood flow rate of 50 ml / min with a blood circulation pump and returning the filtrate obtained at a flow rate of 10 ml / min with a blood filtration pump to the blood pool:
d) After 30 minutes from the start of blood circulation, add calcium ionophore A23187 to the circulating blood to 10 μM:
The blood according to any one of (1) to (2), wherein the time required for the pressure loss between the blood inlet side and the outlet side of the extracorporeal circulation module to reach 150 mmHg is 200 minutes or more. Module for filtration or hemofiltration dialysis.
(4) The module for blood filtration or blood filtration dialysis according to any one of (1) to (3), wherein a filling rate of the hollow fiber membrane into the cylindrical container is 50% or more and less than 75%.
(5) The module for blood filtration or blood filtration dialysis according to any one of (1) to (4), which is sterilized by irradiation.
(6) The blood filtration or blood filtration dialysis module according to any one of (1) to (5), which is filled with an antioxidant solution.

  According to the present invention, the hollow fiber membrane incorporated in the module is made of a polysulfone polymer and polyvinyl pyrrolidone, the inner diameter of the hollow fiber membrane is 205 to 250 μm, and the hollow fiber membrane measured by the capillary ascending method is used. When the liquid level rise value is converted to a hollow fiber membrane having an inner diameter of 230 μm, it becomes 60 mm to 120 mm, L / D is 3 when the distance between the open end faces of the hollow fiber membrane is L, and the minimum inner diameter of the cylindrical container is D. A module for hemofiltration or hemofiltration dialysis that has a sieve coefficient (Alb-Sc) of albumin after 3 hours in an in vitro bovine plasma filtration performance test of .5 to 6.5 is 0.0054 or less. In addition, the loss of albumin is small, so it is difficult for blood pressure in the extracorporeal circuit to increase during a long period of time, and the lifetime is long. Without liquid, etc., it can provide a module for hemofiltration or hemodiafiltration which can safely and efficiently extracorporeal circulation.

The present invention will be described in detail below.
The blood filtration or blood filtration dialysis module referred to in the present invention is for performing long-time blood filtration such as continuous blood purification therapy, or blood filtration dialysis using dialysis in combination with filtration. As for the module, there is no module dedicated to blood filtration dialysis, and the current situation is that the module for blood filtration is exclusively used. Therefore, in the following description, it is simply referred to as “blood filtration module”, but this naturally includes a module for hemofiltration dialysis.

The capillary rise method referred to in the present invention is a method in which one end of a hollow opening of a hollow fiber membrane is immersed in an aqueous solution, and the height from the water surface of the liquid level that has risen by a capillary action after a certain time has risen from the water surface. Say.
Specifically, pre-processing of the following (1) and (2), that is, (1) 500 mL of distilled water for injection is flowed from each of the blood outflow inlet and the liquid inlet / outlet of the blood filtration module. (2) After thoroughly discarding the water in the blood filtration module, disassemble the module, take out the hollow fiber membrane and dry it, and then dry the hollow opening of the hollow fiber membrane Is a method of immersing one end of the liquid in an aqueous solution and measuring the height from the water surface of the liquid surface that has risen through the hollow portion of the tubular structure by capillary action after a certain time. The reason why such pretreatment is performed is that it is more appropriate that the hollow fiber membrane contains glycerin or a filling liquid so that the surface characteristics cannot be accurately evaluated, and that the evaluation is performed in a state where blood actually contacts. It depends.

Regarding capillary rise, it is generally known that there is the following relational expression.
h = 2γ cos θ / rρg (1)
h: Ascending position from the liquid level
γ: Surface tension of liquid
θ: Contact angle (angle from contact surface of solid and liquid to contact surface of liquid and gas)
r: Pipe radius
ρ: Liquid density
g: Gravity acceleration

  That is, the surface tension of the liquid can be measured by measuring r (tube radius), ρ (liquid density), and h (ascending position from the liquid surface). From this relational expression (1), The ease of wetting of the surface with respect to the liquid, that is, the degree of hydrophilicity and hydrophobicity, can be evaluated by the degree of increase in the liquid level in the capillary tube.

  Therefore, also in the case of a hollow fiber membrane, the ease of wetting of the inner surface of the hollow fiber with respect to the aqueous solution, that is, the degree of hydrophilicity (hydrophobicity) can be measured by the above capillary ascending method. Moreover, even for hollow fiber membranes having different inner diameters, the liquid level rise value and inner diameter in each capillary are measured, and correction is made to convert them into the reference inner diameter of the hollow fiber membrane from the relationship of equation (1). Thus, it becomes possible to make an absolute comparison of the degree of hydrophilicity (hydrophobicity) of each hollow fiber as the liquid level increase value of the hollow fiber membrane having the reference inner diameter. In the present invention, a correction value obtained by converting the inner diameter of the hollow fiber membrane to 230 μm is used as the liquid level rise value.

  When measuring the capillary rise value of the hollow fiber membrane, the moisture content and the inner diameter of the hollow fiber membrane need to be measured because the moisture content and the inner diameter of the hollow fiber membrane affect the measurement value. The moisture content of the hollow fiber membrane needs to be 5% or less, and if the moisture content is greater than 5%, the hydrophobic nature of the inner surface inherent to the hollow fiber membrane is less likely to appear. The capillary rise value shows a large measured value, which makes it difficult to compare the samples.

  When measuring the level rise of an aqueous solution due to capillary action, the measurement time is also important. When the inner surface of the hollow fiber membrane is more hydrophilic, the speed of the aqueous solution rising up the hollow portion is increased, and the measurement value varies in a short time measurement. Moreover, it becomes difficult to measure many samples at once. Practical measurement time is preferably the time when 5 seconds or more have passed since the hollow fiber membrane was immersed in the aqueous solution, and more practically, it is preferably set to an appropriate time within 3 minutes. In the present invention, the value after 1 minute is shown.

  The liquid level of the aqueous solution in the hollow portion can be observed with the naked eye if the hollow fiber membrane has a certain degree of transparency. However, the more porous the hollow fiber membrane is, the lower the transparency becomes and the observation with the naked eye becomes difficult. In that case, if the aqueous solution is colored by adding a dye such as Congo Red to the aqueous solution in an amount that does not affect the surface tension of the aqueous solution, the observation becomes easy.

  In the hollow fiber membrane composed of the hydrophobic polymer and the hydrophilic polymer incorporated in the blood filtration module of the present invention, the inner diameter of the hollow fiber membrane of the rising value of the aqueous solution measured by the capillary ascending method was converted to 230 μm. The correction value needs to be 60 mm or more. If it is lower than 60 mm, the lifetime will be extremely low, so it is not suitable as a blood filtration module that is performed for a long time. The rising value of the aqueous solution is more preferably 70 mm or more, and is preferably 120 mm or less in consideration of handleability and manufacturability due to the hygroscopic property of the hollow fiber membrane.

  Here, the lifetime means that during the extracorporeal circulation therapy such as hemofiltration therapy, the hollow fiber membrane of the hemofiltration module and other blood flow channels are clogged with blood cells and plasma proteins, resulting in increased pressure, and treatment cannot be continued. It is the time that can be enforced without becoming, and it means the film life.

  The lifetime during clinical use can be estimated by an in vitro evaluation method developed by the present inventors. The method involves pooling anticoagulant-containing blood containing a specific concentration of platelets, adding a platelet activating reagent in a state where this blood is circulated through the blood flow path, and changing the pressure loss of the blood filtration module ( Monitor). In other words, when the activated blood is circulated, the time required for the pressure loss of the blood filtration module to reach a specific value is measured, and this is an accelerated test that evaluates the lifetime based on the length of the time. The longer the module is evaluated as a module for extracorporeal circulation, the shorter the module is, the shorter the module is evaluated as a module having a shorter lifetime, i.e., a high clogging tendency. At that time, the specific time required for the pressure loss to reach a specific value is determined to be a blood filtration module having an excellent (inferior) lifetime, for example, based on clinical experience. What is necessary is just to make a relative comparison with the index for blood filtration modules that are known to be bad.

  Hereinafter, the in vitro lifetime evaluation method according to the present invention will be described more specifically. The lifetime evaluation method developed by the present inventors comprises a closed circuit similar to normal extracorporeal circulation such as hemodialysis in vitro, and monitors the increase in pressure while circulating blood. . FIG. 1 shows a schematic configuration diagram thereof, in which an arterial blood circuit 3 provided with a blood circulation pump 5 and a blood inlet side pressure detector 6, an extracorporeal circulation module 2, and a vein side provided with a blood outlet side pressure detector 7. The blood circuit 4 is connected in this order to prepare the blood channel 1, and the arterial side and vein side ends of the blood channel 1 are set in the blood pool 8 to form a closed circuit.

The individual members and devices constituting the blood flow path may be known ones that are used in normal extracorporeal circulation treatment, such as a blood circuit composed of a soft tube, a liquid delivery device such as a roller pump, a mercury manometer, A pressure detector such as a digital manometer may be used. Also,
Parts such as a clamp and a drip chamber which are preferably attached for blood circulation may be appropriately attached. Furthermore, in order to simulate actual blood filtration and hemodialysis, a filtration circuit and a dialysis circuit may be provided in the blood flow path. For example, a filtration circuit 9 provided with a blood filtration pump 10 is connected to a nozzle on the filtration side of the extracorporeal circulation module, and blood circulation is performed while filtering at a constant flow rate, or a dialysate introduction circuit and a discharge circuit are used for extracorporeal circulation. If connected to the nozzle on the filtration side of the module, the lifetime can be evaluated under the conditions of hemodiafiltration.

  The extracorporeal circulation module used in the lifetime evaluation method according to the present invention includes a hollow fiber membrane blood purifier such as a hemofiltration dialyzer, hemofilter, hemodialyzer, plasma separator, and plasma component separator, and a nonwoven fabric. Either a cell adsorber filled in a cylindrical shape or a component adsorber filled with an adsorbent made of particles or fibers may be used. However, as described below, this lifetime evaluation method is performed for a long time in a clinical field. Since it is suitable for evaluating the lifetime of the extracorporeal circulation module, a hollow fiber membrane type continuous blood filter is preferred. The continuous hemofilter is generally used for continuous hemodiafiltration, and is not limited to filtration.

  In the lifetime evaluation method according to the present invention, when blood is circulated through the blood flow path, it is necessary to pool blood with a specified platelet concentration in the blood pool 8, and to add a platelet activator thereto.

  The anticoagulant used in this lifetime evaluation method is a drug that prevents the blood taken outside the body from coagulating, such as citrate anticoagulants (sodium citrate, ACD-A, CPD, etc.), ethylenediamine Examples include chelating agents such as tetraacetic acid (EDTA), heparin anticoagulants (such as heparin and low molecular weight heparin), anticoagulants such as nafamostat mesylate and gabexate mesylate. Among them, heparin anticoagulants (heparin, low molecular weight heparin, etc.) do not chelate calcium essential for the coagulation system, and are therefore most preferably used when calcium ionophore is used as a platelet activator described below.

  The blood used in this lifetime evaluation method is whole blood collected, and it is preferable to use blood of mammals such as humans, cows and pigs. Of these, bovine blood is preferably used. This is because it is easy to obtain a sufficient amount of fresh blood for the test, and it is often just a good platelet concentration to evaluate the lifetime. This is because there is no need to make adjustments. Blood platelets with anticoagulant added should have a platelet concentration of 100,000 cells / μL or more, and at lower concentrations, it is difficult to increase pressure even when platelet activator is added. Can not be done. On the other hand, if the platelet concentration is too high, the pressure increase tends to be accelerated, and if it exceeds 300,000 / μL, for example, the required time to reach a predetermined pressure value is shortened and the tendency to vary is increased. Therefore, it is preferable to pool blood with a platelet concentration in the range of 100-300,000 / μL, blood with a platelet concentration of 150-300,000 / μL is more preferable, and a platelet concentration of 22-300,000 / μL. The blood is particularly preferred.

  The platelet activating reagent used in this lifetime evaluation method is a substance that acts on platelets and promotes platelet aggregation and thrombus formation. Illustrative examples include calcium ionophore, PAF (platelet-activating factor), thrombin, endotoxin, and the like, but calcium ionophore has a relatively slow effect on the increase in pressure of circulating blood compared to the non-added system. It is preferable in that it can cause a clear pressure rise and can measure the pressure rise stably and with high sensitivity. Of these, calcium ionophore A23187, which has a function of increasing the membrane permeability of calcium ions, has a particularly high specificity for calcium ions, and is often handled as a model for carrier transport of substances in biological membranes, is particularly preferable.

  As described above, this lifetime evaluation method pools anticoagulant-added blood containing a specific concentration of platelets, adds a platelet activating reagent in a state where this blood is circulated through the blood flow path, and is used for extracorporeal circulation. Monitors the change (increase) in the pressure loss of the module. In other words, when the activated blood is circulated, the time required for the pressure loss of the extracorporeal circulation module to reach a specific value is measured, and this is an accelerated test that evaluates the lifetime according to its length. The longer the module is evaluated as a module for extracorporeal circulation, the shorter the module is, the shorter the module is evaluated as a module having a shorter lifetime, i.e., a high clogging tendency. At that time, the specific time required for the pressure loss to reach a specific value is determined to be a module for extracorporeal circulation with an excellent (inferior) life time. What is necessary is just to make a relative comparison with the index for the extracorporeal circulation module whose badness is known.

The pressure loss here refers to the pressure at the blood inlet side and the blood outlet during circulation of blood using a pressure detector attached to the blood flow path near the inlet and the outlet of the extracorporeal circulation module. The side pressure is measured and calculated by the following equation (2).

Pressure loss of extracorporeal circulation module = Blood inlet side pressure-Blood outlet side pressure (2)

  In this lifetime evaluation method, it is preferable to set the upper limit of pressure loss to 100 to 300 mmHg in order to perform more stable evaluation. If the pressure loss is lower than 100 mmHg, it may be difficult to clearly detect the presence or absence of pressure rise. Conversely, if the pressure loss exceeds 300 mmHg, the normal extracorporeal circulation module is already clogged and becomes normal. This is because blood circulation may not be possible, which is not preferable as an evaluation method. More preferably, it is the range of 100-250 mmHg, Most preferably, it is the range of 100-200 mmHg.

  About the above-mentioned platelet activating reagent, it is preferable to adjust the concentration added to blood, and the concentration of platelets in the blood is set to 10 to 10 in pooled blood (concentration A) having a platelet concentration of 100,000 / mL or more. What is necessary is just to add the platelet activation reagent of the density | concentration which makes 200,000 piece / microliter (concentration B) decrease, and becomes A> = B. This is because the time required for the pressure loss to reach a predetermined value tends to be shortened, and the measurement sensitivity can be increased and the evaluation time can be shortened. Specifically, the platelet activating reagent may be added so that the blood concentration after addition is about 2 to 15 μM.

  Further, when the platelet activating reagent is added at least 30 minutes after the start of blood circulation where the pressure loss of the extracorporeal circulation module is stabilized, the pressure change can be stabilized and the evaluation accuracy can be improved. The addition method is not particularly limited, but the platelet activation reagent is dissolved in physiological saline or a buffer solution and prepared as an addition solution with a known concentration, and this is added to any place such as an injection port of a blood flow path or a heparin injection circuit. The platelet concentration in the circulating blood may be confirmed with a blood cell counter or the like.

  Regarding the blood circulation conditions, a more reliable evaluation method can be obtained by reflecting as much as possible the implementation conditions of the extracorporeal circulation module in the actual clinical site. For example, the blood pool is preferably heated to 30 to 37 ° C., more preferably 35 to 37 ° C., which is close to body temperature and facilitates platelet activation.

  In addition, the blood flow rate that flows to the extracorporeal circulation module by the blood circulation pump is preferably 50 to 100 ml / min, and more preferably 50 to 60 ml / min when assuming continuous hemofiltration. In that case, it is preferable to perform filtration at a filtration flow rate of 1 to 20 ml / min by connecting a filtration circuit provided with a blood filtration pump to the filtration side nozzle of the extracorporeal circulation module, and more preferably 8 to 12 ml / min. The resulting filtrate is returned to the blood pool so that blood cells are not concentrated.

  By the lifetime evaluation method described above, an extracorporeal circulation module having an excellent lifetime can be selected. According to the knowledge of the present inventors, as a specific condition, the blood pool is heated to 30 to 37 ° C., and a filtration circuit provided with a blood filtration pump is connected to the filtration side of the extracorporeal circulation module. While circulating blood at a blood flow rate of 50 ml / min and performing blood circulation to return the filtrate obtained at a flow rate of 10 ml / min to the blood pool by a blood filtration pump, 30 minutes after the start of blood circulation, calcium ionophore A23187 Under the evaluation conditions in which the blood concentration is 8 to 15 μM (the concentration at which the platelet concentration decreases by 100 to 200,000 / μL), the time required for the pressure loss of the extracorporeal circulation module to reach 150 mmHg is 200. If it was more than minutes, the extracorporeal circulation module showed a sufficiently long lifetime even in clinical practice.

Next, the manufacturing method of the blood filtration module of the present invention will be described.
A hollow fiber membrane comprising a polysulfone polymer and polyvinyl pyrrolidone incorporated in the module can be obtained by using a known dry and wet spinning method. The hollow fiber membrane having such a composition has a structure in which the membrane surface is hydrophilized, so that it is difficult to activate the blood coagulation system on the blood contact surface, and the lifetime of the blood filtration module can be prolonged.

  Examples of the polysulfone-based polymer include polysulfone, polyethersulfone, and polyallyl ether sulfone. These are preferable from the viewpoints of film forming properties and strength, and among them, they are also preferable because they are excellent in sterilization resistance against radiation and are excellent in controlling a wide range of pore diameters from low water permeability type to high water permeability type. Typical structural formulas of polysulfone polymers are shown in [Chemical Formula 1] and [Chemical Formula 2].

  Polyvinyl pyrrolidone is preferable because it is excellent from the viewpoint of compatibility with the polysulfone polymer and blood compatibility.

  When dry-wet spinning is performed using a polysulfone-based polymer as the hydrophobic polymer and polyvinylpyrrolidone or polyethylene glycol as the hydrophilic polymer, the hydrophilic polymer becomes the pore size forming material and the hydrophilizing material when the membrane structure is formed. Responsible for both. As a result, a membrane structure excellent in all of low-molecular-weight protein permeability, ultrafiltration amount, and biocompatibility is easily obtained, and this combination is most preferable. Hereinafter, the case of a polysulfone polymer and polyvinylpyrrolidone will be described as an example.

  As a film-forming stock solution for dry-wet film formation, a solution in which a polysulfone polymer and polyvinylpyrrolidone are dissolved and mixed in a solvent that dissolves in common is used. As the solvent, N, N-dimethylacetamide is preferable in view of solubility of the polymer, safety to living bodies, cost and the like.

  If the concentration of the polysulfone polymer in the membrane forming stock solution is too low, membrane formation becomes difficult and the strength of the membrane becomes weak. On the other hand, if the concentration is too high, phenomena such as poor spinnability and small pore size occur. Therefore, it is generally 12 to 25% by weight, more preferably 15 to 20% by weight. Moreover, a part of polyvinylpyrrolidone remains in the membrane in the process of forming the hollow fiber membrane. Since the ratio varies depending on the molecular weight of polyvinyl pyrrolidone and the spinning conditions, the optimum concentration of polyvinyl pyrrolidone should be appropriately examined. For example, when the number average molecular weight of polyvinyl pyrrolidone is 300,000 or more, 1 to 15 weights %, More preferably 3 to 7% by weight.

  A hollow fiber membrane is formed when the membrane-forming stock solution is discharged from the double annular nozzle simultaneously with the internal coagulation solution and guided to the coagulation bath through the aerial running section. As the internal coagulation liquid and the coagulation bath, a liquid mainly composed of water is used, but it is preferable to use a mixed liquid of a polysulfone polymer solvent and water. In order to obtain permeability and filterability as a blood filtration module, for example, when N, N-dimethylacetamide is used as the internal coagulation liquid, an aqueous solution of 45 to 80% by weight is preferably used.

  In order to express the characteristics of the inner surface of the hollow fiber membrane in the present invention, that is, to correct the liquid level rise value of the aqueous solution measured by the capillary rise method to 60 mm or more when the inner diameter of the hollow fiber membrane is converted to 230 μm. The important point is to control the coagulation conditions of the film-forming stock solution.

  The first point is the control of the travel time of the aerial travel unit. The film-forming stock solution is preferably solidified appropriately from the time it is discharged from the spinning nozzle until it is immersed in the coagulation bath, and for that purpose, the running time of the aerial running section should be 0.4 seconds or more. Is more preferable, and more preferably 0.5 seconds or more. The traveling time of the aerial traveling unit can be managed by the spinning speed. If the running time in the air is less than 0.4 seconds, especially 0.1 seconds or less, the hollow fiber membrane is immersed in the coagulation bath in an insufficiently coagulated state and eluted into the water-soluble polyvinylpyrrolidone coagulation bath. The amount increases, the amount of polyvinylpyrrolidone remaining in the hollow fiber membrane decreases, and hydrophilicity may become insufficient. That is, it may be difficult to ensure that the correction value obtained by converting the inner diameter of the hollow fiber membrane to 230 μm in the liquid level rise value of the aqueous solution measured by the capillary rise method is 60 mm or more. On the contrary, although the upper limit differs depending on the aerial travel distance, it is preferably within a range not exceeding 2.0 seconds when the aerial travel distance is 50 cm.

  The second point is the control of the humidity of the airborne part. The relative humidity of the aerial travel part is preferably 70 to 95%, more preferably 75 to 90%. If the relative humidity is lower than this range, the hollow fiber membrane may not be sufficiently formed before being immersed in the coagulation bath, and an appropriate membrane structure governing the membrane surface characteristics of the present invention may not be formed. Stable spinning is not possible, such as causing sticking in between. On the other hand, if the relative humidity is too high, the coagulation from the outer surface is promoted, the pore diameter in the hollow fiber membrane is reduced, and the permeability of the low molecular protein is deteriorated.

  In the blood filtration module of the present invention, the hollow fiber membrane has the above composition and characteristics, and its inner diameter is 205 to 250 μm, which is somewhat larger than that of a normal hemodialysis membrane. Is particularly important. That is, when the inner diameter of the hollow fiber membrane is smaller than 205 μm, in the lifetime evaluation method of the present invention, the time required for the pressure loss of the blood filtration module to reach 150 mmHg from the start of blood circulation is shorter than 200 minutes, It is not a blood filtration module that is satisfactory in terms of points. On the other hand, when the inner diameter of the hollow fiber membrane is larger than 250 μm, the blood priming capacity per membrane area increases although the time required for the evaluation method exceeds 200 minutes. For patients with poor circulatory dynamics such as applying continuous blood filtration, the volume of blood drawn out of the body should be kept as low as possible, and excessively large internal diameters should be avoided. Therefore, the more preferable inner diameter of the hollow fiber membrane is 210 to 245 μm, and the more preferable inner diameter is 220 to 240 μm. Further, if the inner diameter is increased more than necessary, the dialysis efficiency is lowered. Therefore, assuming the use in hemofiltration dialysis, it is preferable to set the inner diameter to 250 μm as the upper limit.

  The blood filtration module of the present invention is formed by filling a hollow bundle of the hollow fiber membrane and filling it into a cylindrical container. The molding method is a known molding method of the hollow fiber membrane module. You can refer to it. For example, a hollow fiber membrane bundle in which several thousand to 20,000 hollow fiber membranes are bundled is inserted and filled into a cylindrical container having one or more filtrate ports, and the end of the hollow fiber membrane bundle and the end of the container And a header cap having a blood circulation port (inlet or outlet) at both ends, after cutting the cured resin layer and opening the hollow fiber membrane at its end. Formed by mounting. The formed module can be used safely for the patient by filling the inside of the container with water or physiological saline as necessary and sterilizing by γ-ray irradiation or the like.

  Here, in the blood filtration module of the present invention, an important point in extending the lifetime is the ratio between the module length and the trunk diameter. That is, it is necessary that L / D is 3.5 to 6.5 when the distance between the open end faces of the hollow fiber membrane is L and the minimum inner diameter of the cylindrical container is D. Here, the distance between the opening end faces of the hollow fibers refers to the distance from one hollow fiber membrane opening end face of the potted resin layer to the opening end face of the other resin layer. Strictly speaking, this is the length of the hollow fiber membrane filled in the module, but the slack of the membrane is ignored and the distance is fixed inside the module. The minimum inner diameter of the cylindrical container refers to the minimum value of the diameter when the cross section of the cylindrical container filled with the hollow fiber membrane bundle is converted into a perfect circle.

  When L / D is less than 3.5, in the lifetime evaluation method described above, the time required for the pressure loss of the blood filtration module to reach 150 mmHg from the start of blood circulation exceeds 200 minutes, and the lifetime of the blood filtration module However, since the module becomes thicker than necessary, the space capacity in the header cap increases and the blood priming capacity increases, which is not preferable for use in patients with poor circulatory dynamics. Further, when the cross-sectional area of the cylindrical container is increased, there is a concern that the adhesive force of the potting resin to the inner wall of the container is reduced. On the contrary, if L / D exceeds 6.5, in the evaluation method, the required time is less than 200 minutes, and the lifetime of the blood filtration module is shortened.

The bovine plasma filtration performance test of the present invention refers to the following method.
First, only plasma components are separated by centrifugation from bovine blood to which CPD solution as an anticoagulant is added to 0.13 ml with respect to 1 ml of blood, and the total protein concentration using physiological saline for the plasma 1 L of plasma adjusted to 6.5 ± 0.5 g / dl is pooled, and then the blood circuit is connected to the header caps that serve as the blood inlet and outlet of the module for hemofiltration or hemodiafiltration, The aforementioned plasma is circulated by a blood circulation pump at a plasma flow rate of 100 ml / min at 37 ° C., and simultaneously filtered by a hemofiltration pump at a flow rate of 10 ml / min, and the filtrate is returned to the aforementioned plasma pool.

For the measurement of the sieving coefficient (Sc) of a solute after a certain time, for example, taking the sieving coefficient (Alb-Sc) of albumin as an example, the filtrate is collected after a certain time, and the concentration of the albumin (CF ), The concentration of albumin in the plasma entering the module from the header cap (CBi), the concentration of albumin in the plasma flowing out from the header cap of the module (CBo), and collecting the filtrate by the following equation (3) The sieve coefficient (Alb-Sc) of albumin at the time can be obtained.

Sieve coefficient of albumin (Alb-Sc) = 2 (CF) / (CBi + CBo) (3)

  In the blood filtration module of the present invention, the sieve coefficient (Alb-Sc) of albumin after 3 hours in the bovine plasma filtration performance test needs to be 0.0054 or less. If Alb-Sc exceeds 0.0054, in the bovine plasma filtration performance test, the total loss of albumin after 30 hours exceeds 3 g, and in actual clinical settings, supplements such as albumin preparations have become necessary. Because it ends up.

The total loss of albumin after 30 hours can be determined according to the following procedures (I) to (IV).
(I) The sieve coefficient is calculated from the measured albumin concentration for 1 to 30 hours.
(II) Draw an approximate curve from the sieve coefficient of (I) and obtain an approximate expression.
(III) From the approximate expression of (II), the sieving coefficient is obtained every 15 minutes for 1 to 30 hours.
(IV) The average sieving coefficient for 1 to 30 hours is determined, and the value is applied to the following formula (4).

Total albumin loss (g)
= Albumin concentration (g / ml) x average sieve coefficient (average value of 1-30Hr)
X Filtration flow rate (ml / min) x Time (min) (4)

  The above procedure will be described in more detail. Since the sieve coefficient (y) can be expressed as y = ax ^ (b) as a function of time (x), the constants a and b are calculated by the least square method from the measured value of the sieve coefficient of the blood filtration module. An approximate expression of the blood filtration module can be obtained. By using this approximate expression and substituting the obtained average sieve coefficient into the above expression (4), the total loss of albumin can be calculated.

  On the other hand, when the total loss of albumin exceeds 3 g, considering that it is necessary to replenish the albumin preparation and the like, from the above approximate expression, the total loss of albumin after 30 hours does not exceed 3.0 g. The sieving coefficient (Sc) of albumin after 3 hours is, for example, when the performance of the module (eg, filtration performance) changes in the direction in which albumin is filtered more, and the curve of the approximate expression based on it does not change It can be determined by simulating assuming that it slides in the y-axis direction.

  The filling rate of the hollow fiber membrane bundle into the cylindrical container refers to the filling density of the hollow fiber membrane bundle filled in the cylindrical container, and the hollow fiber membrane occupies the cross-sectional area of the container at the minimum inner diameter portion of the cylindrical container. It is defined by the ratio (in%) of the cross-sectional area. If the cross-sectional area of the container is too large compared to the cross-sectional area of the hollow fiber membrane, the filling rate decreases, and dialysis efficiency tends to decrease when dialysis is used together as in hemofiltration dialysis therapy. From this viewpoint, the filling rate is preferably 50% or more, and more preferably 65% or more. On the other hand, if the filling rate is too high, the hollow fiber membrane is damaged when the hollow fiber membrane bundle is filled in the container. Therefore, the filling rate is preferably 75% or less, and more preferably 70% or less.

  The blood filtration module thus obtained can be obtained by washing the hollow fiber membrane inside with warmed water or a solvent, a mixture thereof, or the like. It is possible to adjust the rising value. For example, if washing is performed at about room temperature of about 18 to 25 ° C., hydrophilic substances such as polyvinyl pyrrolidone and glycerin existing on the inner surface of the hollow fiber can be washed, which contributes to excessive hydrophilicity and variation between films. Since it can prevent, it is preferable. Further, it is preferable to wash with warm water of about 40 to 50 ° C. because the detergency is further increased, but it hardly affects the heat denaturation of the surface of the hollow fiber membrane, the container and the header cap. It is also preferable to perform these module cleanings with a constant pulse or alternately with reverse cleaning.

  The blood filtration module of the present invention may or may not be filled with an aqueous solution such as water or physiological saline in the space in the container. However, in consideration of performing priming before use in a clinical field, It is preferable to fill the container with an aqueous solution such as water or physiological saline for reasons such as removal. This is a so-called wet type. At that time, it is preferable to use an antioxidant solution containing a radical-capturing organic compound such as glycerin or an antioxidant inorganic salt as the filling liquid, and among them, a sodium pyrosulfite solution having good detergency is used. Most preferred. This is not only convenient for suppressing the oxidation of the hollow fiber membrane when the blood filtration module is sterilized by radiation, but also by appropriately suppressing the crosslinking and modification of the hydrophilic polymer due to the radiation. This is because the liquid level rise value of the aqueous solution measured by the rise method may be adjusted to an appropriate range. The reason is not clear, but when a linear polymer such as polyvinyl pyrrolidone or polyethylene glycol is three-dimensionally structured by crosslinking, it is presumed that the molecular mobility is suppressed and the hydrophilicity is affected.

  As the sterilization method, radiation sterilization such as γ-ray sterilization and electron beam sterilization is preferable, but γ-ray sterilization is particularly preferable in view of productivity.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail according to an Example, this invention is not limited to these.

[Examples 1, 2, 3, 4 and Comparative Example 1]
18.5 parts by weight of a polysulfone resin (Solvay, P-1700), 6.7 parts by weight of polyvinylpyrrolidone (manufactured by ISP, K-92), 74.8 parts by weight of dimethylacetamide (hereinafter, DMAC) A uniform spinning stock solution was prepared. This spinning solution was discharged from a double annular die having a slit width of 60 μm together with a hollow inner solution having a DMAC concentration of 20% by weight, immersed in water at 60 ° C. provided 105 cm below and wound up at a speed of 70 m / min. The discharge amount of the spinning solution and the hollow inner solution was adjusted so that the hollow fiber film thickness was 45 μm and the inner diameter was 205 μm. When 7100 filaments were wound up, the rope was cut to a length of 300 mm and then shower washed with hot water at 90 ° C. for 24 hours, and it was confirmed that no peak with a UV absorbance of 220 nm was observed in the cleaning liquid. Next, it was impregnated with a 20% aqueous solution of glycerin and dried with hot air at 85 ° C. for 7 hours. After drying, the inner diameter and film thickness were measured again, and it was confirmed that the hollow fiber inner diameter matched 205 μm.

The above 6400 hollow fiber membranes were inserted into a cylindrical container and potted, and molded into a module having an effective membrane area of 0.7 m ² and L / D = 5.3. Header caps were attached to both ends of the cylindrical container, and irradiation sterilization with γ rays (25 KGy) was performed to obtain five continuous blood filters (continuous blood filter 1).
The obtained continuous blood filter was washed with 1 L of physiological saline and connected to a circuit for extracorporeal circulation. In order to confirm the influence of the platelet activating reagent, calcium ionophore A23187 (manufactured by SIGMA) (Example 1), PAF (manufactured by SIGMA) (Example 2), thrombin (manufactured by Pacific Hemostasis) (implemented) Four types of Example 3) and endotoxin (manufactured by SIGMA) (Example 4) were prepared. A continuous blood filter with a blood flow rate of 50 mL / min while maintaining a temperature of 37 ° C. with a blood pool of 2000 mL of bovine blood (platelet concentration 250,000 / μL) to which heparin anticoagulant (manufactured by Mitsubishi Pharma) was added as an anticoagulant The inside was recirculated. At the same time, filtration was performed at a filtration flow rate of 10 mL / min, and the obtained filtrate was returned to the blood pool. Immediately after the start of circulation, calcium ionophore A23187 was added to each blood pool to a blood concentration of 10 μmol / L, PAF 0.5 μmol / L, thrombin 3000 IU / L, and endotoxin 5 μmol / L. Pressure changes on the inlet side and outlet side of the filter were observed. As Comparative Example 1, a test in which no platelet activating reagent was added was also conducted.

  As a result, the pressure loss of the continuous hemofilter of Examples 1 to 4 to which the platelet activating reagent was added increased from the initial pressure, whereas in Comparative Example 1, the pressure loss of the continuous hemofilter changed. There wasn't. The level of pressure increase varies depending on the type of platelet activating reagent, and calcium ionophore A23187 was preferred in that the pressure increase in circulating blood can be measured stably and with high sensitivity. The results are shown in Table 1 and FIG.

[Examples 5, 6, and 7]
Three continuous blood filters obtained by the same production method as in Example 1 were each washed with 1 L of physiological saline and then connected to an extracorporeal circuit.
In order to confirm the effect of the addition amount of calcium ionophore A23187, 2000 mL of bovine blood (platelet concentration 25 / μL) to which heparin anticoagulant was added as an anticoagulant was used as a blood pool, maintained at 37 ° C., and blood flow 50 mL / The inside of the continuous blood filter was recirculated in minutes, filtration was performed at a filtration flow rate of 10 mL / min, and the resulting filtrate was returned to the blood pool. The platelet activating reagent was added 30 minutes after the start with calcium ionophore A23187 in the blood concentration of 2 μM, 8 μM and 10 μM (referred to as Examples 5, 6 and 7 respectively), and the inlet of the continuous hemofilter The pressure change of the side and outlet side was observed, and the time required for the pressure loss of the continuous blood filter to reach 150 mmHg was measured.
As a result, it can be seen that the sensitivity of lifetime evaluation can be adjusted by the blood concentration of the added platelet activating reagent, and the higher the concentration, the higher the sensitivity. The results are shown in Table 2 and FIG.

[Examples 8, 9, 10, and 11 and Comparative Examples 2 and 3]
Six continuous blood filters obtained by the same production method as in Example 1 were each washed with 1 L of physiological saline and connected to a circuit.
Three types of blood with a platelet concentration higher than 300,000 / μL, blood with a platelet concentration of less than 100,000 / μL, and blood with a platelet concentration of 100-300,000 / μL were prepared. In order to confirm the effects of platelet concentration and blood temperature, 2000 mL of bovine blood to which heparin anticoagulant was added as an anticoagulant was used as a blood pool, and the blood temperature was maintained at 25 ° C, 37 ° C, and 40 ° C. Examples 8, 9, and 10) were recirculated through the continuous hemofilter at a blood flow rate of 50 mL / min, filtered at a filtration flow rate of 10 mL / min, and the resulting filtrate was returned to the blood pool. Calcium ionophore A23187 was added 30 minutes after the start so that the blood concentration was 10 μmol / L, and the time required for the pressure loss of the continuous hemofilter to reach 150 mmHg was measured. Further, at a blood temperature of 37 ° C., the same experiment was performed with blood having a platelet concentration higher than 300,000 / μL (Example 11) and blood having a platelet concentration of less than 100,000 / μL (Comparative Example 2). That is, the effects of platelet concentration and blood temperature were evaluated under the conditions shown in Table 3. As Comparative Example 3, a case where no calcium ionophore was added was used as a control.

  As a result, the pressure loss of the continuous blood filter of Comparative Example 3 in which no platelet activating reagent was added did not change, and the pressure loss was also evaluated in evaluation using blood whose platelet concentration was lower than 100,000 / μL (Comparative Example 2). It did not change. On the contrary, in the evaluation using blood whose platelet concentration is higher than 300,000 / μL (Example 11), it can be said that the required time to reach 150 mmHg is shortened and the sensitivity is high. However, when the required time is shortened to about 100 minutes, the evaluation system becomes unstable, and it seems that there are concerns about accuracy such as variations. Moreover, the time required to reach 150 mmHg tended to decrease as the blood temperature increased (Examples 8 to 10). The results are shown in Table 3.

[Examples 12, 13, and 14 and Comparative Examples 4 and 5]
Under the same membrane forming conditions as in Example 1, a hollow fiber membrane in which only the inner diameter was changed was obtained without changing the film thickness of the hollow membrane yarn. The obtained hollow fiber membranes had three types of inner diameters of 205 μm, 230 μm, and 250 μm.
Using the hollow fiber membrane, a continuous blood filter (continuous blood filter 3, Example 12) having a hollow fiber membrane inner diameter of 250 μm and a hollow fiber number of 5800 by the same production method as in Example 1, hollow Continuous blood filter with continuous inner diameter of 230 μm and number of hollow fibers of 6400 (continuous blood filter 2, Example 13), the same continuous blood filter 1 as in Example 1 (Example 14) Prepared. In addition, as a comparison target of a continuous blood filter filled with a polysulfone-based hollow fiber membrane, a blood filter manufactured by X Company (Comparative Example 4) and a blood filter manufactured by Y Company (Comparative Example 5) were prepared. The inside of each continuous blood filter was washed with 500 mL of physiological saline and connected to an extracorporeal circuit. Bovine blood 2000ml (platelet concentration 25 / μL) with heparin anticoagulant added as an anticoagulant is used as a blood pool, maintained at 37 ° C, and recirculated through a continuous blood filter at a blood flow rate of 50mL / min. Filtration was performed at a flow rate of 10 mL / min, and the obtained filtrate was returned to the blood pool. After 30 minutes from the start, calcium ionophore A23187 was added to a blood concentration of 10 μM, and the time required for the pressure loss of the continuous blood filter to reach 150 mmHg was measured.

  As a result, in the continuous blood filter in which the hollow fiber membrane is filled with a hollow fiber having an inner diameter of 205 to 250 μm and L / D is 5.4, the time required for the pressure loss to reach 150 mmHg is 200 minutes or more. Whereas it was long, a commercially available continuous blood filter filled with a polysulfone-based hollow fiber membrane having an inner diameter of 200 μm and an L / D of 7.5 required less than 200 minutes and had a lifetime of Judged to be short. The results are shown in Table 4.

[Examples 15 and 16 and Comparative Examples 6, 7, and 8]
It consists of 18.5 parts by weight of a polysulfone resin (manufactured by Solvay, P-1700), 6.5 parts by weight of polyvinylpyrrolidone (manufactured by ISP, K-92), and 75 parts by weight of dimethylacetamide (hereinafter referred to as DMAC). A uniform spinning stock solution was prepared. This spinning dope was discharged from a double annular die having a slit width of 60 μm together with an internal coagulation liquid having a DMAC concentration of 22% by weight, immersed in water at 60 ° C. provided 100 cm below and wound up at a speed of 70 m / min. The discharge amount of the spinning solution and the internal coagulation solution was adjusted so that the hollow fiber film thickness was 45 μm and the inner diameter was 230 μm. When 6400 filaments were wound up, the lobe was cut to a length of 300 mm, shower washed with hot water at 90 ° C. for 24 hours, and the fact that unstable water-soluble polymers such as polyvinylpyrrolidone were not present in the filaments, This was confirmed by the absence of a peak with a UV absorbance of 220 nm in the cleaning solution. Next, it was impregnated with a 20% aqueous solution of glycerin and dried with hot air at 85 ° C. for 7 hours. After drying, the inner diameter and film thickness were measured again, and it was confirmed that the hollow fiber inner diameter matched 230 μm.

The above 6400 hollow fibers were inserted into a cylindrical container and potted, and molded into a module having an effective membrane area of 0.7 m ² and L / D = 5.4. After the header caps were attached to both ends of the module, the blood side and filtrate side of this module were (1) washed with 3 L of water at 20 ° C. (Example 15), (2) washed with 3 L of water at 50 ° C. (Example 16), (3) Three types of modules (comparative example 6) were manufactured in which washing with 9 L of water at 60 ° C. was repeated twice. Subsequently, each module was filled with an aqueous solution in which 300 ppm of sodium pyrosulfite and 100 ppm of sodium carbonate were dissolved, and irradiated with 25 kGy of γ rays to obtain three types of polysulfone blood filtration modules.

In addition to this, as a comparative example, a commercially available polysulfone blood filtration module (Comparative Example 7) manufactured by Company X and a commercially available polysulfone blood filtration module (Comparative Example 8) manufactured by Company Y were prepared. In any module, the inner diameter of the hollow fiber membrane was 200 μm, and L / D was 7.5.
The blood side and the filtrate side of the blood filtration module were each washed with 500 ml of distilled water for injection, and after sufficiently discarding the water, the module was disassembled and the hollow fiber membrane was taken out. The hollow fiber membrane was dried with a drier, and it was confirmed that the moisture content of each hollow fiber membrane was 5% or less.
Ten hollow fiber membranes were vertically aligned and attached to a glass plate to which a double-sided tape was attached, so that the ends of the hollow fiber membranes were aligned with one end of the glass plate. After that, about 5 mm of the end of the hollow fiber membrane on the side aligned with the glass plate was immersed in a 0.1% Congo red aqueous solution, and after 1 minute, the distance from the water surface of the liquid surface where the aqueous solution rose, The average value was obtained. Further, for the hollow fiber membranes of Comparative Examples 7 and 8, the correction value of the liquid level increase value was also determined so that the inner diameter thereof corresponded to 230 μm. The results are shown in Table 5.

  On the other hand, in order to evaluate the lifetime of the module in vitro, a blood filtration module equivalent to the above five types of modules was prepared, and the blood side and the filtrate side were respectively washed with 500 ml of physiological saline. Next, using the circulation circuit shown in FIG. 1, 2000 mL of bovine blood (platelet concentration 250,000 / μL) to which heparin-based anticoagulant (manufactured by Mitsubishi Pharma) was added as an anticoagulant was used as a blood pool at 37 ° C. While being maintained, the blood filtration module was recirculated at a blood flow rate of 50 mL / min. At the same time, filtration was performed at a filtration flow rate of 10 mL / min, and the obtained filtrate was returned to the blood pool. Immediately after the start of circulation, calcium ionophore A23187 (manufactured by SIGMA) was added to the blood pool to a blood concentration of 10 μmol / L, and pressure changes on the blood inlet side and blood outlet side of the blood filtration module were observed. The time when the pressure loss reached 150 mmHg was measured, and the time was defined as the lifetime. The results are shown in Table 5.

  From the above results, it can be seen that when the liquid level rise value is 60 mm or more, the lifetime of the blood filtration module is long, and conversely, when it falls below 60 mm, the lifetime is drastically lowered. It can also be seen that the liquid level rise value of the hollow fiber membrane can be adjusted by changing the washing temperature and quantity when washing the module before sterilization.

[Examples 17, 18, and 19 and Comparative Examples 9 and 10]
Five types of hollow fiber membranes having inner diameters of 205 μm, 230 μm, 250 μm, 200 μm, and 180 μm were produced under the same film forming conditions as in Example 15 so that the film thickness of the hollow membrane yarn was not changed at 45 μm.
Using the hollow fiber membrane, a continuous blood filter having a hollow fiber membrane inner diameter of 250 μm and a hollow fiber number of 5800 (sustained) so that L / D is 5.4 by the same production method as in Example 16. Type blood filter 8, Example 17), hollow fiber membrane inner diameter 230 μm, number of hollow fiber 6400 continuous blood filter (continuous blood filter 7, Example 18), hollow fiber membrane inner diameter 205 μm, hollow 7100 continuous blood filter (continuous blood filter 6, Example 19), hollow fiber membrane inner diameter 200 μm, 7300 hollow fiber continuous blood filter (continuous blood filter 5, comparison) Example 9) A continuous blood filter (continuous blood filter 4, Comparative Example 10) having an inner diameter of a hollow fiber membrane of 180 μm and a number of hollow fibers of 8100 was prepared.

The liquid level rise value converted into an inner diameter of 230 μm by the capillary rise method of the hollow fiber incorporated in each continuous blood filter was measured in the same manner as in Example 15.
The bovine plasma filtration performance test of each continuous blood filter was conducted by measuring the total protein concentration of bovine plasma separated from bovine blood to which CPD solution was added to 0.13 ml per 1 ml of bovine blood, at 6.5 g / dl. The plasma was used as a plasma pool and was recirculated through the continuous hemofilter at a plasma flow rate of 100 ml / min while maintaining the temperature at 37 ° C. Simultaneously, filtration was performed at a filtration flow rate of 10 ml / min, and the obtained filtrate was returned to the plasma pool, and the sieving coefficient (Alb-Sc) of albumin after 3 hours was measured.

  For in vitro lifetime evaluation, the inside of each continuous hemofilter was washed with 500 mL of physiological saline and connected to an extracorporeal circuit. A blood pool of 2000 mL of bovine blood (platelet concentration 250,000 / μL) added with a heparin anticoagulant as an anticoagulant is kept at 37 ° C. and recirculated in a continuous hemofilter at a blood flow rate of 50 mL / min. Filtration was performed at a filtration flow rate of 10 mL / min, and the obtained filtrate was returned to the blood pool. After 30 minutes from the start, calcium ionophore A23187 was added to a blood concentration of 10 μM, and the time required for the pressure loss of the continuous blood filter to reach 150 mmHg was measured. The respective results are shown in Table 6.

  From the results in Table 6, in the continuous blood filter having an inner diameter of the hollow fiber membrane of 205 μm or more, the time required for the pressure loss to reach 150 mmHg was longer than 200 minutes, whereas the continuous blood filter having an inner diameter of 200 μm or less. The blood filter was judged to have a short lifetime, less than 200 minutes.

[Examples 20, 21, and 22 and Comparative Examples 11 and 12]
A hollow fiber membrane having an inner diameter of 230 μm was produced under the same film forming conditions as in Example 18 so that the thickness of the hollow membrane yarn was not changed by 45 μm.
Using the hollow fiber membrane, by the same manufacturing method as in Example 16, the membrane area of each continuous filter was kept constant at 0.7 m2, and the continuous blood filtration with L / D of 4.3 (Continuous blood filter 9, Example 20), continuous blood filter with L / D of 5.4 (continuous blood filter 10, Example 21), continuous with L / D of 6.5 Blood filter (continuous blood filter 11, Example 22), continuous blood filter with L / D of 7.5 (continuous blood filter 12, comparative example 11), continuous type with L / D of 10 A blood filter (continuous blood filter 13, Comparative Example 12) was prepared.

The liquid level rise value converted into an inner diameter of 230 μm by the capillary rise method of the hollow fiber incorporated in each continuous blood filter was measured in the same manner as in Example 15.
The bovine plasma filtration performance test of each continuous blood filter was conducted by measuring the total protein concentration of bovine plasma separated from bovine blood to which CPD solution was added to 0.13 ml per 1 ml of bovine blood, at 6.5 g / dl. The plasma was used as a plasma pool and was recirculated through the continuous hemofilter at a plasma flow rate of 100 ml / min while maintaining the temperature at 37 ° C. Simultaneously, filtration was performed at a filtration flow rate of 10 ml / min, and the obtained filtrate was returned to the plasma pool, and the sieving coefficient (Alb-Sc) of albumin after 3 hours was measured.
For in vitro lifetime evaluation, the inside of each continuous hemofilter was washed with 500 mL of physiological saline and connected to an extracorporeal circuit. A blood pool of 2000 mL of bovine blood (platelet concentration 250,000 / μL) added with a heparin anticoagulant as an anticoagulant is kept at 37 ° C. and recirculated in a continuous hemofilter at a blood flow rate of 50 mL / min. Filtration was performed at a filtration flow rate of 10 mL / min, and the obtained filtrate was returned to the blood pool. After 30 minutes from the start, calcium ionophore A23187 was added to a blood concentration of 10 μM, and the time required for the pressure loss of the continuous blood filter to reach 150 mmHg was measured.

  As a result, in the continuous hemofilter whose inner diameter of the hollow fiber membrane is 230 μm, the time required for the pressure loss to reach 150 mmHg was longer than 200 minutes in any of the continuous hemofilters of L / D, When L / D was 6.5 or less, the required time was longer than 400 minutes, and the lifetime was judged to be extremely long. The results are shown in Table 7.

[Example 23] <Calculation of albumin Sc over time and total Alb loss in 30 hour test>
Using the continuous blood filter of Examples 15, 16, and 18, a 30-hour bovine plasma filtration performance test was performed using bovine plasma. The total protein concentration of the bovine plasma was adjusted to 6.5 g / dl, 1 L of plasma was used as a plasma pool, and the plasma was recirculated through the continuous hemofilter at a plasma flow rate of 50 ml / min while maintaining 37 ° C. At the same time, filtration was performed at a filtration flow rate of 10 ml / min, and the obtained filtrate was returned to the plasma pool. Thereafter, the sieving coefficient (Sc) of albumin after 1 hour, 3 hours, 10 hours, 20 hours, and 30 hours was measured. The results are shown in Table 8.

From these results, the total loss of albumin (30-hour integrated value) was determined according to the following procedures (I) to (IV).
(I) The sieve coefficient is calculated from the measured albumin concentration for 1 to 30 hours.
(II) Draw an approximate curve from the sieve coefficient of (I) and obtain an approximate expression.
(III) From the approximate expression of (II), the sieving coefficient is obtained every 15 minutes for 1 to 30 hours.
(IV) The average sieving coefficient for 1 to 30 hours is obtained, and the value is applied to the following formula.
Total albumin loss (g) = albumin concentration (g / ml) × average sieve coefficient (average value of 1-30 Hr) × filtration flow rate (ml / min) × time (min)

According to the above procedure, from the measured value of the sieve coefficient of the blood filtration module of the present invention shown in Table 8, the approximate expression of (II) obtained is
y = 0.0066x ^ (-0.4579)
It was calculated. Using this approximate expression, the average sieving coefficient for 1 to 30 hours was calculated to be 0.0022. Using the average albumin concentration 0.045 (g / ml) in human plasma as the albumin concentration, the total loss of albumin calculated from the above formula was calculated to be 1.82 g.
On the other hand, from the above approximate expression, the sieving coefficient (Sc) of albumin after 3 hours in which the total loss of albumin after 30 hours does not exceed 3.0 g was calculated as 0.0054 as a result of simulation.

  The blood filtration module of the present invention has a long module lifetime and a small amount of albumin loss, so that it can be effectively used for long-term blood filtration therapy and blood filtration dialysis therapy like continuous therapy. it can.

It is the schematic which shows the circuit structure which performs the lifetime evaluation method of this invention. It is a graph which shows the change of the pressure loss in a module after platelet activation reagent addition. It is a graph which shows the pressure loss change in a module after adding platelet activating reagent according to concentration.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 ... Blood flow path 2 ... Extracorporeal circulation module 3 ... Arterial side blood circuit 4 ... Vein side blood circuit 5 ... Blood circulation pump 6 ... Blood inlet side pressure detector 7 .. Blood outlet side pressure detector 8 ... Blood pool 9 ... Filtration side circuit 10 ... Blood filtration pump

Claims (6)

The inside of the cylindrical container is filled with a bundle of hollow fiber membranes, and both ends of the hollow fiber membrane are potted to both ends of the cylindrical container with a curable resin to form open end surfaces at both ends of the container, In a hollow fiber membrane type extracorporeal circulation module having header caps having blood inlets or outlets attached to the respective open end faces, and further having a filtrate circulation port leading to the hollow fiber membrane filtrate side space,
The hollow fiber membrane comprises a polysulfone polymer and polyvinyl pyrrolidone,
The hollow fiber membrane has an inner diameter of 205 to 250 μm,
When the liquid level rise value of the hollow fiber membrane measured by the capillary rise method is converted to a hollow fiber membrane having an inner diameter of 230 μm, it becomes 60 mm to 120 mm.
Blood filtration or blood filtration dialysis, wherein L / D is 3.5 to 6.5, where L is the distance between the open end faces of the hollow fiber membrane, and D is the minimum inner diameter of the cylindrical container Module.   The module for hemofiltration or hemodiafiltration according to claim 1, wherein the sieving coefficient of albumin after 3 hours in the in vitro bovine plasma filtration performance test is 0.0054 or less. A module for blood filtration or hemodiafiltration,
Lifetime evaluation conditions for an extracorporeal circulation module comprising:
a) Warm blood pool to 30-37 ° C .:
b) Connect a filtration circuit with a blood filtration pump to the filtration side of the extracorporeal circulation module:
c) While circulating blood at a blood flow rate of 50 ml / min with a blood circulation pump and returning the filtrate obtained at a flow rate of 10 ml / min with a blood filtration pump to the blood pool:
d) After 30 minutes from the start of blood circulation, add calcium ionophore A23187 to the circulating blood to 10 μM:
The blood filtration according to claim 1, wherein the time required for the pressure loss between the blood inlet side and the outlet side of the extracorporeal circulation module to reach 150 mmHg is 200 minutes or more. Module for hemofiltration dialysis.   The module for blood filtration or blood filtration dialysis according to any one of claims 1 to 3, wherein a filling rate of the hollow fiber membrane into the cylindrical container is 50% or more and less than 75%.   The module for blood filtration or blood filtration dialysis according to any one of claims 1 to 4, which is sterilized by irradiation. The module for blood filtration or blood filtration dialysis according to any one of claims 1 to 5, which is filled with an antioxidant solution.