JPH023622B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a blood purification device that separates substances dissolved in blood (hereinafter referred to as solutes). More specifically, the present invention relates to a blood purification device incorporating a permselective membrane capable of efficiently filtering and removing soluble high molecular weight solutes such as immune complexes, immunoglobulin aggregates, cold aggregates, and nucleic acids contained in blood. In recent years, with the remarkable development of so-called artificial organs, therapeutic methods that perform operations such as dialysis treatment and adsorption treatment after fractionation on blood taken out of the body through external circulation have been put into practical use, and the importance of such treatment methods is increasingly being recognized. However, it is strongly required that the device not have any adverse effects on the living body, and for this purpose, there are many factors that the device must have. One of these is to avoid loss of protein components in the patient's blood, and in artificial kidney devices and the like, it has been avoided to contain plasma proteins in the waste fluid. However, in recent years, it has become clear that abnormal increases in high molecular weight solutes such as immune complexes, immunoglobulin aggregates, cold aggregates, and nucleic acids in the blood are deeply involved in the onset and pathology of autoimmune diseases. , plasma exchange therapy has come to be used for the purpose of removing these high molecular weight solutes. In addition, plasmapheresis is being applied to hepatitis, cancer, etc. However, in plasma exchange therapy, there is a problem in securing healthy plasma to be transfused to the patient, and due to the transfusion of healthy plasma,
There are side effects such as infection with new pathogens and serum sickness, and after further purification of one's own plasma,
It was considered desirable to perform transfusion, and there was a desire to develop a device for this purpose. Conventionally, centrifugation has been used for such therapeutic applications, but centrifugation is difficult to make continuous, and even when it is made continuous, damage to blood cells at the sliding parts is a problem, and more No technical means existed that could continuously and efficiently remove soluble high molecular weight solutes and apply them as a therapeutic method. Furthermore, even with separation means using membranes, it has been difficult to separate and remove high molecular weight solutes from blood without damaging or losing blood cells. The present inventors have conducted research for many years in order to solve the above-mentioned problems associated with conventional techniques related to blood purification treatment. In other words, all systems that efficiently remove unnecessary substances from the blood without damaging the blood and supply purified blood back to the circulatory system are safe.
Research was focused on developing a blood purification device that was easy to use and handle. As a result, by filtering blood under a low transmembrane pressure difference using a porous membrane with an appropriate average pore size, blood cells are not damaged and soluble solutes remain virtually unchanged. They discovered the fact that it was possible to obtain the desired amount of protein, and came up with the concept of a blood purification treatment in which high molecular weight solutes are removed by further membrane filtration of this plasma.After numerous experiments, they finally completed the present invention and achieved the desired results. I have reached my goal. The present invention provides a blood distribution system including a plasma separation device and a blood-plasma mixing device in this order between a blood introduction part and a purified blood delivery part, and a plasma separation system connected to the system. and a plasma reflux system path for causing the plasma separated by the device to flow into the mixing device via a plasma filtration device, and the plasma separation device has a blood inlet, a condensed blood outlet, and a plasma component through which the plasma components pass. A device having a structure including a porous membrane that does not allow blood cell components to pass through, a space in which separated plasma can be temporarily stored, and a plasma outlet separated from the blood inlet and blood outlet by the porous membrane. and the plasma filtration device has a plasma inlet;
It has a permselective filtration membrane that does not allow high-molecular-weight solutes in plasma to pass through, a disposal port for plasma filtration residue containing high-molecular-weight solutes in plasma, and a space in which filtered plasma can be temporarily stored. By constructing a device having an outlet for the plasma filtrate separated from the inlet and the disposal port for the residual plasma filtrate by the permselective membrane, the blood entering from the plasma inlet is separated by the plasma separator. Concentrated blood and plasma are separated, and the separated plasma is filtered to remove high molecular weight solutes using a plasma filter, then mixed with concentrated blood in a blood-plasma mixer and discharged from a blood outlet. The gist of the present invention is a blood purification device as described above. In the present invention, the blood introduction section generally refers to a device for introducing blood into the processing device using a blood sampler using a shunt, a syringe needle, other conduits, a pump, and a pump if necessary, and a purified blood outlet section. refers to a device that delivers blood purified by a blood processing device from a blood purification device using a conduit, a cot, and, if necessary, a blood pressure control valve, shunt, or drip. The blood purification device of the present invention includes a blood distribution system mainly comprising a blood-plasma mixing device and a plasma separation device, and a plasma filtration device for filtering and purifying plasma separated by the plasma separation device of this blood distribution system. The first feature is that the plasma reflux system is connected to the plasma reflux system, which has the main part of and is configured to allow blood and/or plasma to flow in a circulatory manner. The present invention will be explained in more detail below with reference to the accompanying drawings. FIG. 1 is an explanatory diagram showing an example of the basic configuration of the blood purification device of the present invention. Now, to explain the device of the present invention according to the flow of blood, blood A is introduced from the blood inlet 1 of the blood introduction part, and as necessary,
It is transported to a plasma separation device 3 by a pump 2, for example a roller pump. A shunt (not shown) is usually used when blood is introduced directly. Plasma B separated by the plasma separator 3 is sent to the plasma filtration device 4 by a pump 7 such as a roller pump as required, where high molecular weight harmful substances present in the plasma are discarded as a filtration residual liquid C. Ru. The purified filtered plasma is transferred to a blood-plasma mixing device 5.
There, it is mixed with concentrated blood drawn out from the plasma separator, and then drawn out from the blood drawing section 6. Plasma separation devices and plasma filtration devices, for example, have a structure in which a porous membrane or a permselective membrane is installed parallel to a flow path connecting an inlet and a filtration residual liquid disposal port, as shown in Figure 2. Preferably.
In order to perform filtration efficiently and stably over time, the narrower the channel is, the better, and it is preferable to use a membrane shaped like a hollow fiber and use the hollow portion as the channel. FIG. 2 is a sectional view showing an example of a plasma separation or filtration device, which has a blood or plasma inlet 8, a blood or plasma outlet 9, a plasma outlet 10, and a large number of hollow fibers 11 filled inside. The ends of the hollow fibers 11 form a bonded and solidified portion with an adhesive 12, and near the solidified portion, nozzles 14 and 15 having a blood or plasma inlet 8 and a blood or plasma disposal port 9 connect to the threaded portion of the body 13. It is tightened with a screw-fitting cap 16. The space surrounded by the outer wall of the hollow cell and the main body 13 is a space in which separated plasma is temporarily stored. This is a structure for flowing blood or plasma into the hollow part of the hollow fiber, and the plasma moves outward from the hollow part of the hollow fiber. vice versa,
A plasma separator having a structure in which blood or plasma flows outside the hollow fiber and the plasma moves into the hollow part can also be used in the present invention. The porous membrane for plasma separation used in this device is a membrane that allows substantially all soluble components in plasma to pass through while not allowing blood cell components to pass through. 1.2μ
It has a structure in which pores penetrating the front and back sides of the membrane are distributed almost uniformly on the membrane surface, with an average pore diameter of 3.
A material having a water permeability of /m ² ·hr · mmHg or higher is preferably used. In order to stably obtain plasma without damaging blood cells using the plasma separator using the above-mentioned membrane, it is necessary to
In the separator shown in the figure, the filtration pressure (blood inlet 1
0 and plasma outlet 12) from 10 to 60 mm.
It is necessary to control Hg. As the permselective membrane for plasma filtration, a membrane having a pore size in the range of so-called microfiltration membranes can be used. It is preferable that the membrane has a structure in which penetrating pores are distributed almost uniformly on the membrane surface, and has a pure water permeability of 2/m ² ·hr · mmHg or more. Materials for the selectively permeable membrane that can be used in the present invention include ethylene, propylene, vinyl chloride, vinylidene chloride, ethylene fluoride, and 4-methyl-1
-Pentene, 1,3-butadiene, isoprene,
Isobutylene, chloroprene, styrene, chlorostyrene, dichlorostyrene, carbomethoxystyrene, vinyltoluene, vinylbenzoic acid, vinylnaphthalene, vinylcarbazole, vinylpyrrolidone, methyl methacrylate, ethyl methacrylate, 2-hydroxyethyl methacrylate,
Dimethylaminoethyl methacrylate, 2-ethylhexyl methacrylate, benzyl methacrylate, methyl acrylate, ethyl acrylate, acrylonitrile, methacrylonitrile,
Homopolymers such as vinyl acetate, vinyl alcohol, vinyl formal, vinyl butyral, ethylene carbonate, methyl vinyl ether, maleic anhydride or copolymers consisting of a combination of two or more, and polyamides such as nylon-6, nylon-66, nylon-12, Polyesters such as polyethylene terephthalate and polybutylene terephthalate, polycarbonates, polyurethanes, silicone resins, cellulose derivatives such as nitrocellulose, ethylcellulose, and cellulose acetate are used. The mixing device used in the present invention is for mixing filtered plasma and concentrated blood, or freshly filtered plasma and filtration residual liquid in which high molecular weight solutes are condensed. Although it is desirable that the mixing be carried out completely by stirring or the like, a device such as a Y-shaped connector for merging two fluids can also satisfactorily achieve the purpose. In carrying out the present invention, a buffer tank may be further provided in the circuit shown in FIG. 1, or a plasma separation device or a plasma filtration device may be separately inserted to form a multi-stage system. Next, the present invention will be described in more detail with reference to Examples. Example 1 The blood purification device shown in FIG. 1 was assembled using a plasma separation device and a plasma filtration device having the structure shown in FIG. 2. A polycarbonate membrane (average pore diameter: 0.8 μm, effective membrane area: 60 cm ² ) was used as the membrane for plasma separation, and a plasma separation device was prepared by pressing both sides of the membrane with flat plates having grooves of 0.4 mm in depth.
A plasma filtration device was created using 60 cellulose acetate hollow fibers (outer diameter 500μ, inner diameter 300μ, effective length 115mm, average pore diameter 0.09μ).
With this device, 100 mg of systemic lupus erythematosus patient model blood containing 5 mg of deoxyribonucleic acid was used.
As a result of blood processing for 2 hours using 1.5 ml of blood, the amount of plasma that does not contain blood cell components such as red blood cells and platelets was 0.8 at a blood flow rate of 3 ml/min and a filtration pressure of 50 mmHg.
The blood was obtained at an almost constant rate of ml/min, no hemolysis was observed, and purified blood was obtained. The results of changes in solutes and blood cells before and after using this device are shown in Table 1 along with the results of the following examples. Example 2 The same plasma separation device and plasma filtration device as in Example 1 were used, and the same treatment as in Example 1 was performed except that the blood purification device was operated at a filtration pressure of 20 mmHg. 0.4ml/free plasma
It was obtained almost constantly in minutes. The results are also listed in Table 1. Comparative Example 1 Blood treatment was carried out in the same manner as in Example 1 except that a polycarbonate membrane with an average pore size of 3 μm was used as the plasma separation membrane, and platelets and red blood cells were found to be mixed in the plasma. Comparative Example 2 Cellulose acetate hollow fibers with an average pore size of 0.3μ (outer diameter 500μ, inner diameter 300μ,
Example 1 except that 60 pieces (effective length 115 mm) were used.
Blood was processed in the same manner. The results are also listed in Table 1. Comparative Example 3 Cellulose acetate hollow fibers with an average pore size of 0.03μ (outer diameter 500μ, inner diameter 300μ,
Example 1 except that 60 pieces (effective length 115 mm) were used.
Blood was processed in the same manner. The results are also listed in Table 1. Comparative Example 4 Blood was treated in the same manner as in Example 1, except that a polycarbonate membrane with an average pore size of 0.45 μm was used as the plasma separation membrane. The plasma obtained was 0.7 ml/min. The results are also listed in Table 1. Comparative Example 5 Example 1 except that the transmembrane pressure was 100 mmHg
When blood was processed in the same manner as above, damage to the red blood cells was observed, and the plasma was colored red.

【table】

[Table] As described in detail above, when using the device of the present invention to remove and purify high molecular weight harmful substances from blood, it is possible to efficiently remove and purify the blood without damaging or losing red blood cells or platelets. It can be used as a treatment device for autoimmune diseases such as SLE and rheumatoid arthritis, and as a virus removal system for hepatitis viruses.

[Brief explanation of drawings]

FIG. 1 is an explanatory diagram illustrating the configuration of the apparatus of the present invention. FIG. 2 is a sectional view showing an example of a plasma separation device or a plasma filtration device of the device of the present invention. 1...Blood inlet, 2...Pump, 3...Plasma separation device, 4...Plasma filtration device, 5...Blood/plasma mixing device, 6...Blood outlet, 7...Pump,
8... Blood or plasma inlet, 9... Blood outlet or plasma disposal port, 10... Plasma outlet, 11... Porous membrane or permselective membrane, 12... Adhesive, 13... Main body, 14, 15 ... Nozzle, 16 ... Cap,
A...Blood, B...Plasma, C...Filtration residual liquid.

Claims (1)

[Scope of Claims] 1. A blood distribution system path including a plasma separation device and a blood-plasma mixing device in this order between the blood introduction section and the purified blood output section, and a blood distribution system path connected to the system path, a plasma reflux system path for causing the plasma separated by the plasma separator to flow into the mixing device via a plasma filtration device, and the plasma separator has a blood inlet, a condensed blood outlet, and a plasma component It has a porous membrane that allows blood cell components to pass through but does not allow blood cell components to pass through, a space that can temporarily store separated plasma, and a plasma outlet that is separated from the blood inlet and blood outlet by the porous membrane. The plasma filtration device has a plasma inlet, a permselective filtration membrane that does not allow high molecular weight solutes in the plasma to pass through, and
It has a disposal port for the plasma filtration residue containing high molecular weight solutes in plasma and a space where the filtered plasma can be temporarily stored, and the plasma inlet and the plasma filtration residue disposal port are connected to the selective permeation. By using a device with a structure that has a plasma filtrate outlet separated by a membrane, the blood that enters from the plasma inlet is separated into concentrated blood and plasma by the plasma separator, and the separated plasma is A blood purification device in which high molecular weight solutes are filtered and discarded using a plasma filter, and then mixed with concentrated blood in a blood-plasma mixer and discharged from a blood outlet. 2. The blood purification device according to claim 1, which is a plasma separation device using a porous membrane in which pores having an average pore diameter of 0.5 to 2.0 μ are uniformly distributed on the membrane surface. 3. The blood purification device according to claim 1, which is a plasma filtration device using a selectively permeable membrane in which cells having an average pore diameter of 0.05 to 0.20 μ are uniformly distributed on the membrane surface.