JP2007014666A - External perfusion based blood purifier - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a blood purifier, wherein a large membrane area can be obtained, a film mass transfer coefficient is high, channeling of a dialysate is controlled, and internal filtration can be enhanced while keeping high safety. <P>SOLUTION: The present invention provides a external perfusion based blood purifier, wherein, in a blood purifier including a hollow fiber film, blood passes outside of the hollow fiber film, the dialysate passes inside of the hollow fiber film, and when the blood is filtrated through the hollow fiber film, a filtration coefficient in the case that the blood is filtrated from the outside to the inside of the hollow fiber film is higher than that in the case that the blood is filtrated from the inside to the outside of the hollow fiber film. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a blood purifier used for the treatment of renal failure and the like. More specifically, the present invention relates to a blood purifier that is compact, has high dialysis efficiency, and can safely promote internal filtration.

  A blood purifier using a hollow fiber membrane is generally used for blood purification treatment of patients with renal failure. These blood purifiers bundle thousands to tens of thousands of hollow fiber membranes, and these are arranged in a substantially parallel, cylindrical jacket so that blood flows inside the hollow fiber membrane, and the dialysate is hollow fiber. It has a mechanism that flows outside the membrane in the opposite direction to blood. The inside diameter of a general blood purification hollow fiber membrane is 200 μm, and at a blood flow rate of 200 mL / min to 500 mL / min, the blood flow inside the hollow fiber membrane is laminar and the membrane resistance is less Although it exhibits a large resistance, it is difficult to increase the blood flow rate to reduce the membrane resistance for safety.

  Synthetic polymer membranes typified by polysulfone membranes have a skin layer inside the hollow fiber membrane, and this skin layer acts as a separation active layer, so it has excellent fractionation performance and clogging of blood cell components and protein components. Has few features. On the other hand, the synthetic polymer membrane has relatively large pores on the outer side of the hollow fiber, and when filtration is performed from the outer side to the inner side of the hollow fiber, the components in the liquid to be treated are trapped in the membrane. There is a problem that the filtration resistance is remarkably increased due to clogging.

  Patent Document 1 discloses an internal filtration accelerating dialyzer that increases the pressure loss of blood flowing inside the hollow fiber membrane and promotes internal filtration by reducing the inner diameter of the hollow fiber membrane or increasing the length of the hollow fiber membrane. Is disclosed. This is because the removal performance of low molecular weight proteins such as β2 microglobulin (hereinafter abbreviated as β2MG) is improved by increasing the filtration amount. However, when the hollow fiber membrane inner diameter is reduced or the hollow fiber membrane length is increased to increase blood pressure loss, the blood may be damaged, and hemolysis or clotting may occur.

As another method for promoting internal filtration, Patent Document 2 discloses a method of increasing the pressure loss of dialysate by installing a plug or the like outside the hollow fiber membrane. Increased dialysate pressure loss has also been shown to be effective in promoting internal filtration. However, the installation of the plug for increasing the pressure loss on the dialysate side lowers the blood purifier assembly efficiency and increases the cost.
In order to prevent channeling of dialysate and increase dialysis efficiency, crimping to hollow fiber membranes and insertion of spacer yarns are carried out. There is a case.
JP 2002-143298 A Japanese Patent Laid-Open No. 11-9684

Techniques for improving blood compatibility by controlling irregularities on the blood contact surface have been disclosed (see Patent Documents 3 and 4). In these techniques, the unevenness of the surface is defined from values measured by a white interference microscope. In Patent Document 3, it is said that the adhesion of platelets is preferably 10 ⁻⁶ cells / membrane area (cm ² ) or less. A membrane having this characteristic is estimated to have a platelet retention rate (details will be described later) of approximately 100% in the present invention. However, in membranes with extremely high platelet retention, platelets activated by contact with the membrane are released into the blood, which triggers activation of the entire circulating blood in the body, resulting in biocompatibility. It may cause deterioration, which is not preferable.
Moreover, as can be said in common with the technique of the above-mentioned patent document, a blood contact surface that is too smooth may have a large contact area with blood cells, which may cause blood cell activation. Control of the physical properties of the surface is considered to be effective as a technique for improving blood compatibility, but this approach alone has its own limitations as long as it uses materials that are essentially foreign to the living body. I must say that there is.
JP 2000-126286 A JP-A-11-309353

  The present invention has been made against the background of the problems of the prior art, and aims to reduce the resistance of the membrane, promote the internal filtration safely, and suppress the channeling of the dialysate.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have reached the present invention. That is, the present invention has the following configuration.
(1) In a blood purifier including a hollow fiber membrane, when blood flows outside the hollow fiber membrane, dialysate flows inside the hollow fiber membrane, and the hollow fiber membrane filters the blood, the hollow fiber membrane An external perfusion type blood purifier, wherein the filtration coefficient BFRin when filtering from the inside toward the outside and the filtration coefficient BFRout when filtering from the outside to the inside of the hollow fiber membrane are BFRout ≧ BFRin.
(2) The outside described in (1), wherein the hollow fiber membrane has an inner diameter of 50 μm to 300 μm, the hollow fiber membrane has an outer diameter of 80 μm to 400 μm, and the hollow fiber membrane has a thickness of 10 μm to 100 μm. Perfusion blood purifier.
(3) The external reflux blood purifier according to (1) or (2), wherein the outer surface irregularity of the hollow fiber membrane is 0.1 μm or less.
(4) The external perfusion blood purifier according to any one of (1) to (3), wherein the hollow fiber membrane has a crimp.
(5) The external perfusion blood purifier according to any one of (1) to (4), wherein the hollow fiber membranes are arranged in a crosswind manner.

  The blood purifier of the present invention can obtain a dialysate flow without channeling, can increase the dialysate pressure loss, can promote internal filtration without imposing a burden on the blood, Since the side membrane resistance can be lowered, high removal efficiency of a wide range of solutes from low molecular weight substances to low molecular weight proteins can be obtained safely.

Hereinafter, the present invention will be described in detail.
The present invention is a hollow fiber membrane having specific properties in contrast to the conventional blood purifier using a hollow fiber membrane that has a structure in which blood flows inside the hollow fiber membrane and dialysate flows outside. Is used, and blood is flowed outside the hollow fiber membrane and dialysate is flowed inside. By adopting such a mechanism, unprecedented dialysis performance and safety can be achieved. Since the blood purifier of the present invention allows blood to flow outside the hollow fiber membrane, the hollow fiber membrane is crimped in order to suppress the occurrence of channeling of the blood flow, the filling rate is set within an appropriate range, In order to wind up the thread membrane into a crosswind, and to suppress the retention and coagulation of blood, the inner surface of the housing that is in direct contact with blood is made smooth, antithrombotic, and the dead space is minimized. It is a point that is different from the conventional blood purifier to be a preferable form.

In the present invention, when blood is filtered, the filtration coefficient BFRin when filtering from the inside to the outside of the hollow fiber membrane and the filtration coefficient BFRout when filtering from the outside to the inside of the hollow fiber membrane are BFRout ≧ BFRin In the blood purifier using the hollow fiber membrane having the above relationship, an external perfusion blood purifier is characterized in that blood flows outside the hollow fiber membrane and dialysate flows inside the hollow fiber membrane. The membrane having such characteristics indicates that the filtration performance is higher when the blood is filtered from the outside to the inside than when the blood is filtered from the inside to the outside of the hollow fiber membrane. By using such a membrane, clogging of the membrane can be prevented when the outer surface of the hollow fiber membrane comes into contact with blood, and the membrane performance is effectively expressed. The performance can be improved drastically compared to passing through.
In addition, by using such an external perfusion type blood purifier, for example, the following secondary effects can be expected.
-The surface area of the hollow fiber membrane is naturally larger in the outer surface area than in the inner surface area. Therefore, the permeation performance of the uremic substance is higher when blood is in contact with the outer surface.
-By flowing the dialysate inside the hollow fiber membrane, the occurrence of channeling is suppressed, the flow of dialysate becomes uniform, and the performance of the membrane can be fully demonstrated.
-Since blood freely flows outside the hollow fiber membrane, the boundary membrane outside the hollow fiber membrane is thinned. As a result, the overall mass transfer coefficient is improved and the performance as a blood purifier can be improved.
-If the hollow fiber membrane inner diameter is reduced, the pressure loss of the dialysate flow increases, and as a result, internal filtration in the blood purifier is promoted. At this time, since all the pressure loss for promoting internal filtration is applied to the dialysate, safety is dramatically improved as compared with the case where a large pressure loss is applied to the blood side.
If a hollow fiber membrane of BFRin> BFRout is used, the membrane may be clogged when the outer surface of the hollow fiber membrane comes into contact with blood, and the effect of external perfusion may not be obtained.

As the BFRout value increases, the blood filtration coefficient increases, so the permeation of medium high molecular weight substances such as β2MG increases, and the internal filtration rate also increases. Therefore, 10 mL / (Hr · mmHg) or more is preferable, and 15 mL / (Hr · MmHg) or more is more preferable, and 20 mL / (Hr · mmHg) or more is particularly preferable. On the other hand, if BFRout becomes too large, leakage of useful substances such as albumin may not be suppressed, and is preferably 500 mL / (Hr · mmHg) or less, more preferably 350 mL / (Hr · mmHg) or less, and 200 mL / ( Hr · mmHg) or less is particularly preferable.
When internal filtration occurs in the blood purifier, it is necessary that water can permeate, and BFRin is preferably 5 mL / (Hr · mmHg) or more, particularly preferably 10 mL / (Hr · mmHg) or more, but BFRout It is necessary to be smaller.
In the present invention, BFRin and BFRout are physical property values of the blood purifier itself and are not converted by the membrane area. This is based on the hollow fiber membrane inner and outer diameters, and the membrane area of the hollow fiber membrane is different, and even if the same hollow fiber membrane is used and the number and membrane area are different, BFRin and BFRout are different. In addition, it is difficult to compare.

  The sieving coefficient of β2MG (hereinafter abbreviated as SC), which is an index indicating the pore diameter of the hollow fiber membrane to be used, is preferably 0.10 or more, since the substance removal performance when internal filtration is promoted increases. 0.30 or more is more preferable, and 0.50 or more is particularly preferable. On the other hand, the theoretical maximum value of β2MG SC is 1.0, but if it is too large, leakage of useful substances such as albumin may not be suppressed, and is preferably 0.99 or less, preferably 0.97 or less. More preferred is 0.95 or less.

  In the present invention, the pressure loss of the dialysis fluid when the dialysis fluid flows inside the hollow fiber membrane is preferably higher because internal filtration is promoted, and when 37 ° C dialysis fluid is flowed at a flow rate of 500 mL / min, 10 mmHg or more is preferable, and 30 mmHg or more is more preferable. On the other hand, if the pressure loss is too large, the pump for feeding the dialysate may be overloaded, preferably 750 mmHg or less, more preferably 500 mmHg or less.

  In the present invention, the inner diameter of the hollow fiber membrane is preferably 50 μm or more and 300 μm or less. By reducing the inner diameter of the hollow fiber membrane, the pressure loss when the dialysate flows increases, and internal filtration in the blood purifier can be promoted. However, when the inner diameter of the hollow fiber membrane is smaller than 50 μm, the pressure loss of the dialysate becomes too large and it may be difficult to flow the dialysate. Therefore, the inner diameter of the hollow fiber membrane is more preferably 60 μm or more, and further preferably 70 μm or more. On the other hand, when the inner diameter of the hollow fiber membrane is larger than 300 μm, the number of hollow fiber membranes for obtaining a required membrane area increases, and the size of the blood purifier may become too large. Therefore, the inner diameter of the hollow fiber membrane is more preferably 290 μm or less, and further preferably 280 μm or less.

  In the present invention, the outer diameter of the hollow fiber membrane is preferably 80 μm or more and 400 μm or less. If the outer diameter of the hollow fiber membrane is reduced, the gap between the hollow fiber membranes is reduced and the boundary membrane resistance can be reduced. However, if the diameter is less than 80 μm, the pressure loss of the blood becomes too large and blood clots occur. , Blood may be difficult to flow uniformly. Therefore, the outer diameter of the hollow fiber membrane is more preferably 100 μm or more, and further preferably 120 μm or more. Moreover, when the outer diameter of the hollow fiber membrane is larger than 400 μm, the number of hollow fiber membranes for obtaining a required membrane area increases, and the size of the blood purifier may become too large. Therefore, the outer diameter of the hollow fiber membrane is more preferably 380 μm or less, and further preferably 350 μm or less.

  In the present invention, the thickness of the hollow fiber membrane is preferably 10 μm or more and 100 μm or less. It is preferable to reduce the film thickness of the hollow fiber membrane because the mass transfer resistance is reduced. However, if the thickness is less than 10 μm, the yarn strength may be reduced or the hollow fiber membrane may be crushed by external pressure. Therefore, the film thickness of the hollow fiber membrane is more preferably 11 μm or more, and further preferably 12 μm or more. On the other hand, if it is thicker than 100 μm, the mass transfer resistance may become too large. Therefore, the film thickness is more preferably 90 μm or less, and further preferably 80 μm or less.

  Blood purification in the present invention refers to treatment by flowing blood and dialysate through a blood purification device such as hemodialysis, hemodiafiltration, continuous hemodialysis, and continuous hemodiafiltration.

In the present invention, it is preferable to apply crimp to the hollow fiber membrane. By applying the crimp, the flow of blood flowing outside the hollow fiber membrane can be made uniform. The hollow fiber membrane of the present invention is preferably provided with a crimp having an amplitude of 0.1 mm or more. The number of crimps per 10 cm of the hollow fiber membrane is preferably 5 or more. If the crimp of the hollow fiber membrane is less than 0.1 mm in amplitude and less than 5 (per 10 cm of hollow fiber length), the assembly of the blood purifier deteriorates due to the displacement of the hollow fiber membrane in the blood purifier assembly process, or the hollow fiber Permeation performance of small molecular weight substances such as urea may deteriorate due to adhesion between membranes and blood drift. Therefore, the crimp amplitude is more preferably 0.12 mm or more, and further preferably 0.15 mm or more. Further, the number of crimps is more preferably 7 or more, and further preferably 10 or more. On the other hand, since the hollow fiber membrane bundle becomes bulky if the amplitude of the crimp becomes too large, the resistance when inserting the hollow fiber membrane bundle into the blood purifier container in the blood purifier assembly process increases, and the hollow fiber membrane surface It may cause scratches and cause leaks. Accordingly, the crimp preferably has an amplitude of 5 mm or less, more preferably an amplitude of 4 mm or less. Further, the number of crimps is preferably 50 or less, and more preferably 45 or less.
Further, as another embodiment for making the blood flow flowing outside the hollow fiber membrane uniform, it is also possible to suitably employ a spacer yarn.

  In the present invention, the filling rate of the hollow fiber membrane is an important factor that determines the blood flow path width and the blood volume in the blood purifier. When the hollow fiber membrane filling rate is high, the gap between the hollow fiber membranes is reduced and the blood flow path width is reduced, so that the membrane resistance is reduced and the blood volume in the blood purifier is also reduced, but the hollow fiber membranes are in close contact with each other. 80% or less is preferable, and 70% or less is more preferable. On the other hand, if the hollow fiber membrane filling rate is low, end bonding becomes easier, but the hollow fiber membrane gap becomes larger and the blood flow path width becomes larger, so that the membrane resistance increases and the blood volume in the blood purifier Therefore, the filling rate of the hollow fiber membrane is preferably 40% or more, more preferably 45% or more.

In the present invention, the arrangement of the hollow fiber membranes may be parallel to the blood flow. However, when a cross arrangement is adopted and the hollow fiber membranes are arranged obliquely or perpendicularly to the direction of blood flow, the blood is outside the hollow fiber membranes. It is more preferable because it strikes the surface diagonally or vertically, and the blood-side film can be effectively peeled off. Such a structure can be obtained, for example, by winding a plurality of hollow fiber membranes into a crosswind type or arranging the hollow fiber membranes vertically and horizontally.
In the blood purifier of the present invention, a sufficient effect can be obtained simply by replacing the blood inlet / outlet and the dialysate inlet / outlet of a blood purifier using a commercially available hollow fiber membrane. In order to maximize the concentration difference between the solutes of the dialysate, it is preferable that the blood and the dialysate flow in countercurrent.
Further, in order to reduce the blood-side membrane resistance, it is also recommended as a preferred embodiment to have the same structure as that of a commercially available external reflux oxygenator and to flow the dialysate through a flow path for oxygen in the oxygenator.

  The material of the hollow fiber membrane used in the blood purifier of the present invention is not particularly limited, and regenerated cellulose, cellulose acetate, cellulose triacetate, polysulfone, polyethersulfone, polyamide, polymethylmethacrylate, ethylene vinyl alcohol copolymer, A polyether sulfone / polyarylate polymer alloy or the like can be used.

The method for obtaining the membrane used in the blood purifier of the present invention is not particularly limited. For example, when producing a hollow fiber membrane, an inert fluid such as liquid paraffin or nitrogen gas is used as a hollow forming material. The hollow forming material can be discharged from the nozzle together with the film forming solution into the air, and then the solvent can be removed in a coagulation bath by a dry and wet spinning method. In this case, the hollow forming material inside the hollow fiber membrane is non-solidifying, and after entering the coagulation liquid, a membrane structure is formed from the outside of the hollow fiber membrane, so that the pore diameter outside the hollow fiber membrane is smaller than the inside. As a result, clogging of blood proteins and the like is reduced with respect to filtration from the outside, and the structure becomes more stable.
On the other hand, when a solidifying liquid such as an aqueous solution is used for the hollow forming material, a skin layer is formed on the inner surface of the hollow fiber membrane, the pore diameter on the outer side of the hollow fiber membrane is increased, and a membrane of BFRin ≧ BFRout is likely to be formed. Performance may be reduced. However, even with such a method, for example, it is possible to produce a film having a structure having a skin layer on the outer surface by increasing the solvent concentration in the hollow forming material, shortening the air gap, and decreasing the concentration of the coagulating liquid. Such an outer skin film can also be suitably used in the present invention.

Moreover, it is preferable that the unevenness | corrugation degree (PV value) of the outer surface of a hollow fiber membrane is 0.1 micrometer or less. If the unevenness of the outer surface of the hollow fiber membrane is too large, platelets may be stimulated when blood is flowed to cause residual blood. Accordingly, the degree of unevenness on the outer surface of the hollow fiber membrane is more preferably 0.07 μm or less, and even more preferably 0.05 μm or less. The lower limit is not limited, but in view of cost and productivity in industrial production, about 0.001 μm seems to be the lower limit.
The PV value represents a difference between the maximum value and the minimum value of the unevenness at all measurement points with respect to the reference point when the unevenness on the film surface is measured. Further, the smoothness of these film surfaces can be obtained from an analysis device such as a three-dimensional surface structure analysis microscope using a scanning white interference method, and can be calculated from measured values. For example, interference images are collected while scanning the interference objective lens in the optical axis direction with a scanning white interference microscope on the test piece, and the digitized interference intensity information is processed on the workstation. PV value can be obtained.

The hollow fiber membrane of the present invention has a heparin-added human whole blood of 150 mL / min on the outside of the hollow fiber membrane of a blood purifier having a membrane area of 1.5 m ² (hollow fiber membrane inner diameter standard) prepared using the hollow fiber membrane. When perfused at a flow rate, the platelet retention after 60 minutes is preferably 70% or more and 98% or less.

  As an index indicating blood compatibility, there is a method for evaluating adhesion of platelets when contacted with blood. Conventionally, in order to improve blood compatibility, studies have been made with the goal of reducing the amount of platelet adhesion (improving platelet retention). Activation is considered unavoidable in some sense, even if the degree of difference. In the case of a membrane with a very high platelet retention rate, the apparent blood compatibility is judged to be good, but if the view is changed, even the platelets activated by contact with foreign materials are in the blood. May have been released. From such a viewpoint, as a result of further intensive studies, it was found that the retention rate of platelets is actually preferably 70% to 98%, and the present invention has been achieved. If the platelet retention rate is less than this range, the amount of platelet adhesion increases, and blood clots may be easily formed or the blood purification function may be reduced. Therefore, the platelet retention rate is more preferably 75% or more, and further preferably 80% or more. In addition, if it is larger than this range, activated platelets are also released into the blood, so blood components such as blood cells and plasma circulating in the living body are stimulated, and the whole blood in the living body is activated Therefore, there is no denying the tendency to clot and in some cases the risk of embolization. Therefore, the platelet retention is more preferably 97% or less, still more preferably 96% or less, and even more preferably 95% or less.

The platelet retention in the present invention indicates a value calculated from the number of platelets in blood before and after blood perfusion by the following method.
(1) Heparin calcium is put in advance in a blood collection bag so that the concentration becomes 5 U / mL, and blood of healthy adults is collected from the vein inside the elbow into this blood collection bag. Prior to blood perfusion, blood is sampled for analysis of blood components.
(2) Priming by flowing an appropriate amount of physiological saline inside and outside the hollow fiber membrane of a blood purifier with an outer surface reference membrane area of 1.7 ± 0.5 m ² , and the heparin-added human whole blood into the blood purifier Perfuse at a flow rate of 150 mL / min. At this time, a circuit is constructed so that the blood flowing out of the blood collection bag passes through the outside of the blood purifier and returns to the blood collection bag.
(3) After blood perfusion for 60 minutes in an environment of 37 ° C., blood sampling is performed, and blood components are analyzed.
(4) The platelet retention rate per 1.7 m ² is calculated from the number of platelets in the blood before and after perfusion by the following formula.
(Platelet retention) [%] = 100 × [1-{(1-Y) × (1.7 / A)}]
Y = {(number of platelets in blood after perfusion) × (hematocrit of blood before perfusion)} / {(hematocrit of blood after perfusion) × (number of platelets in blood before perfusion)}
A = membrane area

  In addition, there is a C characteristic as an index of blood compatibility performance retention. The C-characteristic is the percentage of the value measured 120 minutes after the start of blood perfusion with respect to the value of the water permeability measured using blood, 15 minutes after the start of blood perfusion. It means that the performance decreases with time. From the viewpoint of performance retention, the C characteristic in the hollow fiber membrane of the present invention is preferably 70% or more, more preferably 75% or more, and further preferably 80% or more. In normal hemodialysis, a treatment time of about 3 to 5 hours is common, and when the C characteristic is less than this, the performance retention is low, so that a sufficient therapeutic effect may not be obtained. In addition, since water permeability decreases with time due to adsorption of blood components during blood perfusion, high C characteristics can be regarded as low blood component adsorption, which is considered to be a value indicating blood compatibility. You can also.

  As a feature of the production method for imparting the above-described properties to the hollow fiber membrane, it is preferable that the hollow fiber membrane structure is not substantially stretched after being fixed. “Substantially no stretching” means that the hollow fiber membrane drawn from the external coagulation liquid is run with only a tension that does not cause slack in the hollow fiber membrane that runs in the subsequent process, and is finally wound on a bag. Means that. When a hollow fiber membrane having a completely fixed membrane structure is stretched, pore deformation, crushing, tearing, and orientation may occur, and endotoxin in the dialysate may easily leach out to the blood side. Due to friction with the contact member and liquid resistance during the film forming process, elongation occurs in the hollow fiber film during travel, and it is difficult to form a film with all the roller speeds being constant. The tension that does not cause slackness specifically means that the roller speed during the spinning process is controlled so that slackness or excessive tension does not occur in the film forming solution discharged from the nozzle. The drawing ratio here is the speed ratio between the rollers. A preferable range of the stretch ratio between the rollers is 0.01 to 1.5%. A more preferable range is 0.03 to 1%, and a further preferable range is 0.05 to 0.5%.

  Furthermore, as a measure for controlling the degree of unevenness on the outer surface of the hollow fiber membrane, it is also an effective method to reduce potential defects by reducing flaws, foreign matter and bubbles on the surface of the hollow fiber membrane. As a method for reducing the occurrence of scratches, the material and surface roughness of the rollers and guides in the hollow fiber membrane manufacturing process are optimized, and the container is inserted when the hollow fiber membrane bundle is inserted into the blood purifier housing when the blood purifier is assembled. It is effective to devise such that contact between the hollow fiber membranes and rubbing between the hollow fiber membranes is reduced. In the present invention, it is preferable to use a roller having a mirror-finished surface in order to prevent the traveling hollow fiber membrane from slipping and scratching the outer surface. Further, it is preferable to use a guide whose surface is textured or knurled in order to avoid contact resistance with the hollow fiber membrane as much as possible. When the hollow fiber membrane bundle is inserted into the blood purifier housing, the hollow fiber membrane bundle is not directly inserted into the housing, but a film whose contact surface with the hollow fiber membrane is, for example, satin-finished is used as the hollow fiber membrane bundle. It is preferable to use a method in which the wound material is inserted into the housing, and after insertion, only the film is removed from the housing.

  In the present invention, since the blood flows outside the hollow fiber membrane, the housing and the blood in which the hollow fiber membrane is housed are in direct contact with each other. Therefore, the material and shape of the housing are important for the blood compatibility of the blood purifier. Polyester, polycarbonate, ABS resin, polystyrene, polypropylene, etc. can be used for the housing that comes into contact with blood, as well as smoothing the blood contact surface and applying anti-thrombotic treatment such as heparin coating and polyurethane coating are more suitable. it can. Moreover, it is also possible to suitably employ the suppression of blood coagulation by reducing the retention of blood flow.

  An example of the shape of the blood purifier of the present invention is shown in FIG. The blood purifier 1 is loaded with a selectively permeable hollow fiber membrane bundle 3 in a cylindrical housing 2, and both ends of the hollow fiber membrane bundle 3 are fixed to both ends of the housing 2 with an adhesive 4 or the like. The both ends of 2 are covered with caps 5a and 5b. A blood inlet 6a for introducing blood into the housing 2 and a blood outlet 6b for discharging blood are formed in the vicinity of one end of the housing 2 and in the vicinity of the other end, respectively. It is. One cap 5a is formed with a dialysate inlet 7a for introducing dialysate into the housing 2, and the other cap 5b is formed with a dialysate outlet 7b for discharging dialysate.

  Then, the blood enters the housing 2 from the blood inlet 6a as shown by the arrow A, flows outside the hollow fiber membrane bundle 3, and is discharged from the blood outlet 6b as shown by the arrow B. On the other hand, the dialysate enters the space formed by the cap 5a and one end face of the hollow fiber membrane bundle 3 from the dialysate introduction port 7a as shown by an arrow C, and passes through the inside of the hollow fiber membrane bundle 3. The hollow fiber bundle 3 enters the space formed by the other end face of the hollow fiber bundle 3 and the cap 5b, and is discharged from the dialysate discharge port 7b as indicated by an arrow D. At this time, the flow of blood to be dialyzed and the flow of dialysate are opposite so-called opposite flows. During this time, waste in the blood flowing outside the hollow fiber membrane is dialyzed into the inner dialysate through the hollow fiber membrane.

(Measurement of relationship between BFRin and BFRout and calculation of BFRout)
Prepare bovine blood with a hematocrit of 30 ± 2% and a total protein concentration of 6 ± 1 g / dL. The experimental temperature is 37 ± 1 ° C., the blood flow rate is 200 mL / min, and the filtration flow rate is 20 mL / min. ^Two blood purifiers having a membrane area of 1.5 ± 0.5 m ^{2 in} terms of the inner diameter of the hollow fiber are prepared. One of the blood purifiers flows blood inside the hollow fiber membrane, and the intermembrane pressure difference TMPin after one hour is measured. In the other one, blood flows outside the hollow fiber membrane, and the intermembrane pressure difference after 1 hour is defined as TMPout. At this time, when TMPin ≧ TMPout, BFRout ≧ BFRin. This shows the relationship that the lower the pressure, the higher the filtration coefficient in order to obtain the same filtration flow rate.
Also, BFRout is calculated by the following equation.
BFRout (mL / hr / mmHg) = 20 (mL / min) × 60 (min / hr) / ((TMPout (mmHg) −25))
Here, 25 mmHg is subtracted from TMPout because the average colloid osmotic pressure of plasma having a total protein concentration of 6 g / dL is 25 mmHg.

(Measurement of water permeability)
The blood outlet circuit (outlet side from the pressure measurement point) of the blood purifier is sealed with forceps to perform total filtration. Purified water kept at 37 ° C. is put into a pressurized tank, the pressure is controlled by a regulator, pure water is sent to a blood purifier kept at a constant temperature bath at 37 ° C., and the amount of filtrate flowing out is measured with a graduated cylinder. The transmembrane pressure difference (TMP) is TMP = (Pi + Po) / 2
And Here, Pi is the blood purifier inlet side pressure, and Po is the blood purifier outlet side pressure. The TMP is changed at four points, the filtrate flow rate is measured, and the water permeability (mL / m ² / hr / mmHg) is calculated from the slope of the relationship and the membrane area based on the inner diameter of the hollow fiber membrane. At this time, the correlation coefficient between TMP and the filtration flow rate must be 0.999 or more. Further, in order to reduce the pressure loss error due to the circuit, the TMP must be in a range of 100 mmHg or less.

(Measurement of clearance)
Prepare bovine blood with a total protein concentration of 6 ± 1 g / dL in which human β2MG is dissolved. The experimental temperature is 37 ± 1 ° C., the blood flow rate is 200 mL / min, the filtration flow rate is 15 mL / min, the dialysate flow rate is 500 mL / min, and the clearance values at the time of 10 min, 20 min, and 30 min from the start of the experiment are calculated by the following formulas: The average of 3 points is adopted as the clearance of the blood purifier.
Clearance (mL / min) = [(200 × CBi) − (185 × CBo)] / CBi
Here, CBi is the blood purifier inlet side concentration, and CBo is the blood purifier outlet side concentration.

(Measurement of SCβ2MG)
Prepare bovine blood with a total protein concentration of 6 ± 1 g / dL in which human β2MG is dissolved. The experiment temperature is 37 ± 1 ° C, the blood flow rate is 200 mL / min, the filtration flow rate is 15 mL / min, the SC value at 30 min, 45 min, and 60 min from the start of the experiment is calculated by the following formula, and the average of 3 points is adopted as SC To do.
SC = (CBi + CBo) / (2 × Cf)
Here, Cf is the concentration in the filtrate.

(Measurement of inner diameter and film thickness of hollow fiber membrane)
The hollow fiber membrane is cut with a sharp razor perpendicular to the length direction, and the cross section is observed with a microscope at a magnification of 200 times. The inner diameter value and the outer diameter value are measured at n = 5, and the average value is calculated.
Film thickness [μm] = {(outer diameter) − (inner diameter)} / 2

(Maximum protrusion height (PV value) on the outer surface of the hollow fiber membrane)
Ten arbitrary hollow fiber membranes were selected from a bundle consisting of a plurality of hollow fiber membranes, and each hollow fiber membrane was measured at an arbitrary one place by 0.1 mm, and the average degree of unevenness was determined. The measurement was performed using a scanning white interference microscope (NewView 100) manufactured by ZYGO, using a 20 × objective lens under the conditions of a system magnification of 2 times, and the average value was displayed. The measurement was performed without using a filter.

(Platelet retention)
The platelet retention in the present invention indicates a value calculated from the number of platelets in blood before and after blood perfusion by the following method.
(1) Heparin calcium is put in advance in a blood collection bag so that the concentration becomes 5 U / mL, and blood of healthy adults is collected from the vein inside the elbow into this blood collection bag. Prior to blood perfusion, blood is sampled for analysis of blood components.
(2) outer surface reference membrane area 1.7 ± 0.5 m ² hollow fiber membrane inside the blood purifier, flowing appropriate amount of outward saline primed, the heparinized human whole blood to the blood purifier Perfuse at a flow rate of 150 mL / min. At this time, a circuit is constructed so that the blood flowing out of the blood collection bag passes through the outside of the blood purifier and returns to the blood collection bag.
(3) After blood perfusion for 60 minutes in an environment of 37 ° C., blood sampling is performed, and blood components are analyzed.
(4) The platelet retention rate per 1.7 m ² is calculated from the number of platelets in the blood before and after perfusion by the following formula.
(Platelet retention) [%] = 100 × [1-{(1-Y) × (1.7 / A)}]
Y = {(number of platelets in blood after perfusion) × (hematocrit of blood before perfusion)} / {(hematocrit of blood after perfusion) × (number of platelets in blood before perfusion)}
A = membrane area

(C characteristic value)
Using a blood purifier, hematocrit 35% bovine blood was perfused outside the hollow fiber membrane at a flow rate of 200 mL / min. At the same time, filtration was performed at a flow rate of 20 mL / min from the outside of the hollow fiber membrane toward the inside of the hollow fiber membrane. The water permeability in the bovine blood system (hereinafter abbreviated as MFR) was calculated from the transmembrane pressure and the amount of filtrate 15 minutes after the start of perfusion / filtration. With this value as (A), 120 minutes after the start of perfusion / filtration, the C characteristic value is calculated by the calculation of 100 (%) × (B) / (A) from the MFR value (B) obtained by the same operation. Calculated.

Example 1
Cellulose triacetate (LT105 manufactured by Daicel Chemical Industries, Ltd.) 20 wt%, N-methylpyrrolidone (hereinafter abbreviated as NMP) 56 wt%, triethylene glycol (hereinafter abbreviated as TEG) 24 wt% (made by Mitsui Chemicals) The film was dissolved and defoamed, and the insoluble content was removed with a filter to prepare a film forming solution. From the inside of the tube-in orifice nozzle, liquid paraffin is discharged as the core liquid, the film-forming solution is discharged from the outside, solidified in the coagulation bath, and after removing the solvent and non-solvent in the washing tank, glycerin is applied and dried. And wound it on a bobbin. The bobbin around which the hollow fiber membrane was wound was heat-treated at 80 ° C., thereby crimping the hollow fiber membrane. The roller used in the hollow fiber membrane production process was a mirror-finished surface. The stretching ratio between all the rollers was 0.1%. The hollow fiber membrane had an inner diameter 200 [mu] m, outer diameter 230 .mu.m, the permeability ^{150mL / m 2 / hr / mmHg} , granted crimp amplitude 0.4 mm, crimps per hollow fiber membrane 10cm was 25. The PV value of the outer surface of the hollow fiber membrane was 0.05 μm.
10000 of these hollow fiber membranes are bundled and inserted into a cylindrical housing, both ends are bonded with urethane resin, the ends are cut off to open the hollow fiber membranes at the ends, and the membrane area 1. A 5 m ² blood purifier was made.
Two such blood purifiers were prepared, and the above-mentioned BFRin and BFRout were compared. TMPin was 45 mmHg and TMPout was 40 mmHg, and it was found that the blood purifier comprising the obtained hollow fiber membrane had a relationship of BFRout> BFRin. Further, BFRout was 65 mL / hr / mmHg, SCβ2MG was 0.93 when blood was externally perfused, platelet retention was 96%, and C-characteristic was 92%. On the other hand, BFRin was 42 mL / hr / mmHg, SCβ2MG was 0.82 when blood was internally perfused, platelet retention was 95%, and C-characteristic was 88%.
When blood was sent to the outside of the hollow fiber membrane of the obtained blood purifier at a rate of 200 mL / min and dialysate was sent to the inside of the hollow fiber at a rate of 500 mL / min to conduct a dialysis experiment, β2MG clearance was good at 70 mL / min. Showed a good value. At this time, the pressure loss of the dialysate was 20 mmHg.

(Comparative Example 1)
The blood was purified at 200 mL / min inside the hollow fiber membrane of the blood purifier prepared in Example 1 and the dialysate was sent countercurrently at 500 mL / min outside the hollow fiber membrane to conduct a dialysis experiment. As a result, β2MG clearance was 50 mL / min. min, which is lower than that of Example 1. Despite using the same blood purifier, Example 1 showed higher clearance because the blood was perfused outside, the membrane area increased, and clogging of the membrane was suppressed, This was thought to be because internal filtration was promoted by an increase in the pressure loss of the dialysate.

(Example 2)
A hollow fiber membrane was produced in the same manner as in Example 1 except that the flow rates of the core solution and the membrane forming solution when producing the hollow fiber membrane were adjusted. The hollow fiber membrane had an inner diameter of 150 μm, an outer diameter of 180 μm, a water permeability of 130 mL / m ² / hr / mmHg, an applied crimp of 0.3 mm in amplitude, and 28 crimps per 10 cm of the hollow fiber membrane. The PV value of the outer surface of the hollow fiber membrane was 0.03 μm.
From a bundle of 13300 hollow fiber membranes, a blood purifier having a membrane area of 1.5 m ^{2 in} terms of the inner surface of the hollow fiber membrane was produced in the same manner as in Example 1. TMPin was 48 mmHg, TMPout was 43 mmHg, and BFRout> BFRin. The BFRout was 58 mL / hr / mmHg, the SCβ2MG was 0.92, the platelet retention was 97%, and the C characteristic was 95% when blood was externally perfused. On the other hand, BFRin was 33 mL / hr / mmHg, SCβ2MG was 0.75 when blood was internally perfused, platelet retention was 97%, and C-characteristic was 83%.
When blood was fed to the outside of the hollow fiber membrane of the obtained blood purifier at 200 mL / min and dialysate was sent to the inside of the hollow fiber membrane at 500 mL / min in countercurrent, a dialysis experiment was conducted. As a result, β2MG clearance was 80 mL / min. Good value was shown. At this time, the pressure loss of the dialysate was 40 mmHg, which was larger than that of Example 1, and it was considered that this increase in pressure loss promoted internal filtration and contributed to the improvement of β2MG clearance.

(Comparative Example 2)
The blood was purified at 200 mL / min inside the hollow fiber membrane of the blood purifier produced in Example 2 and the dialysate was sent countercurrently at 500 mL / min outside the hollow fiber membrane to conduct a dialysis experiment. The β2MG clearance was 52 mL / min. min, which is lower than that of Example 1.

(Example 3)
The hollow fiber membrane produced in Example 2 is woven so as to intersect in the two-dimensional XY direction, this woven fabric is stacked, filled into a rectangular parallelepiped case, the ends are bonded with urethane, and the ends are cut. The hollow fiber membrane was opened. A flow path for the dialysate to flow inside the hollow fiber membrane was created, and a blood flow path was created so that blood would flow perpendicularly to the hollow fiber membrane on the outside of the hollow fiber membrane. A blood purifier with a membrane area of 1.5 m ² was produced. TMPin was 48 mmHg, TMPout was 42 mmHg, and BFRout> BFRin. Further, BFRout was 60 mL / hr / mmHg, SCβ2MG was 0.92 when blood was externally perfused, the retention rate of platelets was 96%, and the C characteristic was 96%.
When blood was fed to the outside of the hollow fiber membrane of the obtained blood purifier at 200 mL / min and dialysate was sent to the inside of the hollow fiber membrane at 500 mL / min in countercurrent, a dialysis experiment was conducted, and β2MG clearance was 90 mL / min. Good value was shown. At this time, the pressure loss of the dialysate was 40 mmHg. It was considered that the blood flow was perpendicular to the hollow fiber membrane, the boundary membrane on the outer surface of the hollow fiber membrane was thinned, the mass transfer was promoted, and the β2MG clearance was improved.

(Comparative Example 3)
A polysulfone blood purifier APS150S manufactured by Asahi Kasei Medical was used. The PV value of the outer surface of the hollow fiber membrane was 1.5 μm. This blood purifier had a TMPin of 40 mmHg and a TMPout of 125 mmHg, and BFRout <BFRin. BFRout was 12 mL / hr / mmHg, SCβ2MG was 0.38 when blood was externally perfused, platelet retention was 48%, and C-characteristic was 38%.
When blood was sent to the outer side of the hollow fiber membrane of this blood purifier at 200 mL / min and the dialysate was sent to the inner side of the hollow fiber membrane at 500 mL / min in countercurrent, a dialysis experiment was conducted. The β2MG clearance was 15 mL / min. The value was lower than in Example 1. On the other hand, blood was sent to the inner side of the hollow fiber membrane of the blood purifier at 200 mL / min, dialysate was sent to the outer side of the hollow fiber membrane at 500 mL / min in countercurrent, and a dialysis experiment was conducted. The β2MG clearance was 65 mL / min. Significantly higher β2MG clearance was obtained compared to external perfusion. The hollow fiber membrane was taken out from this blood purifier, and the inner and outer surfaces of the hollow fiber membrane were observed with an SEM. The inner surface had a skin layer, and pores of 0.1 μm or more were not observed. There were pores of about 1 to 2 μm. Therefore, it was thought that this hollow fiber membrane is prone to clogging because the pore diameter decreases when the substance moves from the outside to the inside, and when the blood is perfused to the outside, the performance is significantly reduced due to clogging. .

  The external reflux blood purifier of the present invention can increase the surface area of the hollow fiber membrane, and blood freely flows outside the hollow fiber membrane, so that the boundary membrane on the outside of the hollow fiber membrane becomes thin. A coefficient improves and the performance as a blood purifier can be improved. In addition, when the dialysate flows inside the hollow fiber membrane, the occurrence of channeling is suppressed and the flow of the dialysate becomes uniform, so that the performance of the membrane can be fully exhibited. If the hollow fiber membrane inner diameter is further reduced, the pressure loss of the dialysate flow increases, and as a result, internal filtration in the blood purifier is promoted. At this time, since all the pressure loss for promoting internal filtration is applied to the dialysate, there is an advantage that the safety is drastically improved as compared with the case where a large pressure loss is applied to the blood side. Therefore, it is important to contribute to the industry.

It is sectional drawing of a blood purifier.

Explanation of symbols

1: Blood purifier 2: Housing 3: Hollow fiber membrane bundle 4: Adhesive resin 5: Cap 6a: Blood inlet 6b: Blood outlet 7a: Dialysate inlet 7b: Dialysate outlet

Claims (5)

  In a blood purifier including a hollow fiber membrane, blood flows outside the hollow fiber membrane, dialysate flows inside the hollow fiber membrane, and when the blood is filtered, the blood is filtered from the inside to the outside of the hollow fiber membrane. The external perfusion type blood purifier, wherein the filtration coefficient BFRin in the case of performing and the filtration coefficient BFRout in the case of performing filtration from the outside to the inside of the hollow fiber membrane are BFRout ≧ BFRin.   The external perfusion type blood purifier according to claim 1, wherein the hollow fiber membrane has an inner diameter of 50 µm or more and 300 µm or less, and the hollow fiber membrane has an outer diameter of 80 µm or more and 400 µm or less.   The external reflux blood purifier according to claim 1 or 2, wherein the hollow fiber membrane has an outer surface irregularity of 0.1 µm or less.   The external perfusion type blood purifier according to any one of claims 1 to 3, wherein the hollow fiber membrane has a crimp.   The external perfusion type blood purifier according to any one of claims 1 to 4, wherein the hollow fiber membranes are arranged to cross each other.

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