JPS58173555A - Blood purifying apparatus - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a blood purification device, and more specifically, the present invention relates to a blood purification device, and more specifically, when separating plasma components from blood and removing high molecular weight proteins and proteins from the components, the present invention provides high throughput and separation performance during blood processing. The present invention relates to a blood purification device using a compact membrane that is easy to handle.

In recent years, he has been diagnosed with nephritis, 1% thrombocytopenic purpura with Gutsudbascher syndrome, myasthenia gravis, rheumatism, hypergammaglobulinemia, cancer, diabetes, hypergammaglobulinemia, hyperlipidemia, Raynaud's disease, drug addiction, Plasma exchange therapy is used to treat various diseases thought to be caused by abnormalities in the immune system such as liver failure, abnormal metabolites, and increases in toxic substances.

For example, in glomerulonephritis, immune complexes in the circulating blood deposit in the kidneys and cause damage, so antibodies in the blood, immune complexes, and fibrinogen associated with inflammatory reactions are It is considered effective to remove intermediate products such as In addition, in Gutsudbascher syndrome, it is desirable to reduce the blood level of anti-QA antibodies and remove plasma cisternae and coagulation factors, and in myasthenia gravis, it is desirable to reduce the blood level of anti-QA antibodies, and in myasthenia gravis, it is desirable to reduce the blood level of anti-QA antibodies, and to remove antibodies against acetylniline receptors in the nerve and nerve junctions. In other words, the removal of immunoglobulin, the removal of low-density riboprotein in the blood in high-lipid plasma, and the removal of fibrinogen and macroglobulin in Raynaud's syndrome have been shown to be effective in eliminating symptoms and treating symptoms.

The causative or harmful substances in the blood associated with these diseases are protein sources, play important functions in living organisms such as maintaining blood osmotic pressure and transporting ions and substances, and have molecular weights that account for 60 to 80% of plasma proteins. It is said that there are many substances with a larger molecular weight than albumin, which has a molecular size of 66.000 (molecular size 38 x 150 A)8, such as immunoglobulin, fibrinogen, and a! - It is desirable to remove macroglobulins, immunoglobulin-antigen substances, complement-binding substances, i.e., immune complexes, low-density riboproteins, and other substances with a molecular weight of at least 1,000,000 million or more, preferably α-globulin with a molecular weight of around 160,000. 〇In plasma exchange therapy, blood extracted from a patient is separated into blood cell components and plasma using a centrifuge or membrane plasma separator, and the plasma containing unnecessary components such as albumin and these disease-causing or harmful substances is removed. Everything and normal plasma
It exchanges the volume and returns the blood cell components to the patient. Such separation and exchange of plasma requires frequent exchange of a large amount of plasma in a short period of time, and usually 3 to 6 tons of plasma is exchanged in 5 to 3 hours. For plasma exchange therapy,
A large amount of fresh plasma, which mainly contains albumin, is required, but fresh plasma is extremely expensive and comes with risks such as limited supply and hepatitis infection. There are many problems that become obstacles.

Therefore, in order to solve these problems, only unnecessary components in autologous plasma separated from blood should be separated and removed, and useful components such as albumin should not be discarded. One possible method is to return the plasma to another person, thereby making it possible to further enhance the therapeutic effect without using expensive fresh blood plasma from another person and without the risk of hepatitis. Cascade filtration is the most economical, safe, and continuous treatment of large amounts of plasma, in which two or more substances of different sizes in plasma are separated and removed using a membrane, and TGI is collected. generally known.

However, the problem with the -J6 method is that the equipment and handling of rights are complicated. That is, first, plasma separation is performed using a plasma separator in a one-stage filter for separating blood into blood cell components and plasma components. The plasma separated through this process then undergoes a separation operation using a two-stage filter to separate and remove high-molecular proteins, and then the high-molecular proteins that have passed through the membrane are separated. A means is needed to combine the removed purified plasma with the blood cell components described above. It is preferable that the blood sensitive layer for therapeutic purposes be aseptically, continuously, and in a short period of time.For this purpose, a first-stage filter, a second-stage filter, and a blood cell and plasma mixing chamber are connected to a blood circuit and a plasma mixing chamber. The circuit requires complex connections via pumps.

Therefore, although the healing method is an excellent treatment method that is economical and free of risks such as hepatitis, it is not generally used because it requires complicated equipment and operation skills. is the current situation.

In order to solve the problems of blood purification using conventional membrane separation methods, various studies have been conducted on methods and devices that can simplify them and obtain excellent separation effects. Method, namely 1.1-1j! j Filter uses a membrane with large pores to separate blood cells and plasma.
Next, the two-stage filter is a conventional method and device that uses a membrane with a small pore size to separate two or more types of proteins of different sizes in plasma, and then combines the purified plasma with the aforementioned blood cell components. In the end, at least 2
It became clear that the device would be complicated, requiring different types of filters, circuits and pumps to connect them. As a result of thorough research on membranes and how to use them, it was surprising to find that the molecular weight cutoff in both membranes WIK and filtration membranes with directional filtration, such as modules using jIIIv with different average pore diameters on both membrane surfaces KM, : In JIF, blood is separated into blood cell components and plasma components by flowing through the tube with a large pore diameter, and then the separated plasma is passed in reverse from the tube with a small average pore diameter of one membrane to the large tube. They discovered that scales can purify blood by separating high-molecular-weight proteins in plasma and allowing low-molecular-weight substances such as albumin, water, and electrolytes to pass through and combine with blood cell components. Plasma purification using an epoch-making membrane that is extremely compact by being housed inside the device, and solves the conventional problems of complex device combinations and complicated operations at once! ! I found that it causes wrinkles.

That is, in the present invention, a filtration membrane having a polarity of molecular weight cut-off is provided in a container having an inlet/outlet for blood, and the one outlet/outlet allows filtration of plasma components in the blood to be carried out in a direction of molecular weight cut-off. It is provided on one surface side of one membrane in the direction in which the blood becomes larger, and one membrane mKa is provided so that the blood to be processed flows 1 mKa.
A P liquid chamber is provided on the other side of the membrane, and a second filter membrane of the same type as the second filter membrane is provided in the filter chamber to refilter the separated plasma components. , and one side of the filtration membrane of spear 2 is in contact with the plasma component so that the refiltration direction is in the direction of the smaller molecular weight fraction.

#The other side of the filter membrane of spear 2 is communicated with the blood outlet.
The present invention relates to a blood purification device that measures the amount of blood present.

A detailed explanation will be given below with reference to the drawings. Figure 1 is an explanatory diagram showing an example of a conventional blood purification device using a membrane. Blood 1 collected from the human body passes through a blood circuit 2 and a pump 3 to a one-stage filter. :! Blood cells and plasma are separated by a plasma separator 4 (trade name: Plasma Flow, manufactured by Asahi Medical Co., Ltd.) using a cellulose acetate hollow fiber membrane with a pore size of 0.2μ, and then the separated plasma is passed through the plasma introduction circuit 5 and the pump 6. The plasma is sent to the membrane separator 7, which has a membrane with a smaller pore size than the plasma separator 4, and the high molecular proteins in the plasma that do not pass through the membrane are also discharged to the outside through the discharge circuit 8, where albumin, water, etc. , low molecular weight substances such as electrolytes are introduced from the recovery circuit 9 into the mixing chamber 10 through the membrane, mixed with the blood cell components 11, and led out from the extraction circuit 12. This conventional device requires two types of filters, a complicated circuit, and a plurality of pumps, making the compost handling operation cumbersome.

Figure 2 shows one way of using the invention and eyes! This is a clear diagram. The blood 1 passes through the blood circuit 2 and the pump 3, enters the grated iron*13VC of the present invention, and is led out from the #ized blood discharge 1 sweetfish 12. In Fig. 2, 14 is a pressure gauge, 15
8 is a pressure control amount, and 8 is a discharge circuit.

Figure 3 is an explanatory diagram showing a simplified embodiment of the present invention apparatus 13d)-*jii. 16. 17 is the blood population, nozzle with purified blood outlet, 18 is case % 1 of device 1 body
9 is a cap, 20 is a plasma fraction l for separating plasma from blood.
In group Il, the filtration of plasma components in the blood is carried out in the direction of large molecular weight. 21 is a blood flow path, 22 is the plasma separator 20, and the membrane 11'' facing the plasma liquid chamber 23, which has a small fractional molecular weight; The pain forms a purified plasma flow path 25 closed with an adhesive 24 such as polyurethane. jI! 1120.22
Both ends thereof are adhesively fixed to the case 18 with an adhesive 26 such as &X polyurethane. In Figure 3, blood 1
flows through the blood flow path 21 from the blood inlet of the nozzle 16, and flows through the membrane 2.
Blood cell component 27 and plasma component 28K are separated by K. Blood cells flow down from upstream to downstream in the blood flow path, while plasma components 28 flow out and stay in the plasma p-liquid chamber 23 of the device, and a part of it is subsequently refiltered in the expansion 22 to become purified plasma. 2
9 enters the plasma flow path 25, mixes with blood cell components 27 inside the nozzle 17, and exits from the lower blood outlet as purified blood 3o (in a device with a plasma discharge port, A Pa line 3 consisting of a pressure transmitter 33 with a built-in bellows 32 in 31, a pressure adjustment piston 34, and a pressure gauge 35.
Connect 6, pressure Ii! ! ! By adjusting the movement of the regulating piston from side to side, intermittent positive pressure is applied to the plasma fluid chamber F (1-positive pressure), forcing the plasma through the membrane 2o and the plasma to be refiltered through the membrane 22. Cap 1 with purified blood outlet of the device shown in Fig. 3.
In the 70s, blood W=minute outlet 37, purification m1 plasma outlet 38
A plasma outlet 38 is provided with a nozzle 39 having separate
Plasma is discharged from the plasma by a discharge pump 4o and merged into a blood cell line 41 to become purified blood 30. Such a device makes it possible to reliably separate and purify plasma.

Figure 5 shows the membrane 20 and 22t of the device shown in Figure 3, which are placed in rung 2 in case 1B, with x-yt cutting @vcu and spear 6.
It has a membrane arrangement as shown in the figure. In such a device, it is possible to uniformly distribute the plasma across the membrane, which passes into the plasma p-fluid chamber and is re-needleled through the membrane 22. In the off-line view, the other end 24 of the membrane 22 of the device extends to the urethane adhesive 26 at the upper end, and the upper end of the plasma flow path 25 is closed. In this device, since the membrane 22 is fixed at both ends, it has excellent acupuncture impact properties and has the advantage of less damage to the membrane. Figure 8 shows the device shown in Figure 3, with a partition wall 42 installed in the center of the case, consisting of plasma chambers 43 and 44 separated by 22 feet from the membrane 2G, and Figure 19 is a Y-Y cross-sectional view of the device. Now, the separated plasma 28 and the blood 11 to be refiltered through the membrane 22
45 can be prevented from uneven mixing and refiltration in the plasma chamber 44 can be carried out smoothly.
An enlarged schematic diagram of part A of FIG. 1 is an enlarged schematic diagram of the membrane 22 of the 1iil device. As shown in figure 10 of the spear (, Emperor [
Blood flowing through allzx passes from the surface side 5 having a large molecular weight cutoff, for example, the side number 6 having a large pore diameter, to the small pore size 47 where plasma components in the blood are filtered. Also > 3 @ Ifi + 4th floor
) As shown in Figure 11, the plasma 28 in the plasma FffL chamber 23 flows back into the large pore 46 from the surface 1 where the fractional molecular weight is small, for example, from the small pore 47, and the blood It mixes with blood cells 27 in the flow path and becomes purified blood 30. At this time, the high molecular weight proteins in the separated plasma are separated, and the low molecular weight substances whose main components are albumin, water and electrolytes pass through the exchange again and become purified blood 30. mixed with ingredients.

Membranes with different molecular weight cut-offs for plasma component filtration on both membrane surfaces mentioned here are not limited to membranes with different average pore diameters on both membrane surfaces, but also membranes with different charged properties or hydrophilic membranes. , hydrophobic material membranes, etc., have different protein adsorption properties or protein permeability on both IIL surfaces. The pore diameter is large enough to prevent blood cell components from leaking out, and the pore diameter of the duct sample on the membrane surface can be determined by observing it with an electron microscope such as a scanning electron microscope.
In other words, the average pore diameter 0 on the membrane surface side where the average pore diameter is smaller is preferably 0.05 to G-3s, or preferably 0.08. ~0.2
5μ, and the average pore diameter (■) on the membrane side, which has a larger average pore diameter, is 0.15 to 3.0μ, preferably 0.2 to 2.0μ, and the ratio is preferably 1.2 to 5.01. 1.4-3.0
belongs to. It is not clear why the molecular weight fraction differs depending on the direction of filtration of plasma components through membranes with different pore sizes, but one reason is that the pores that make up the membrane are inclined from the larger side to the smaller side. This may be because high molecular weight proteins in plasma easily pass through from the direction of larger pores to smaller pores, but are blocked by the pore walls from the direction of smaller pores. In many porous protein filtration membranes, the size of permeable substances is controlled by the pore size of the active layer on the surface of both layers, that is, the skin layer, but most of these porous filtration membranes are The membrane has a spongy structure, consisting of a large number of passages that pass through each other and are rough in the western part of the cross-sectional direction, and the membrane surface has a small pore size within the range of pore size variation. There are some large pores in the membrane, and the pores communicate with the large pores in the membrane through a number of channels in the internal sponge structure. In contrast, high molecular weight proteins probabilistically flow out from only a few pores through a small number of pores, whereas from the large pore side, they pass through the pores from a probabilistically large number of flow paths to the small pore surface @. As a result, the permeability of high-molecular weight proteins from the membrane side where the pores are maximum is increased due to outflow, or perhaps the permeability of high molecular weight proteins is increased from the membrane side where the pores are large!
! The surface is uneven (because it is a rich fox, the iL flow effect due to blood flow,
Or, for some reason, protein adhesion or adsorption, that is, the protein cake layer becomes relatively small, which improves high molecular weight protein permeability, whereas on the other hand, the surface of the small pore side is smooth and there is no turbulent flow effect. There are various possible reasons for this, such as a smaller amount of cake and a larger cake layer.

The membrane used in the 10,000-year-old unexploded unit* is broadly understood to include hollow fiber membranes, tubular membranes, and flat membranes, and is not limited to flat membranes. Also, is it possible to use a commercially available flat membrane having different average pore diameters in the membrane filtration region, such as Millibore and Amicon membranes, for example, with different average pore diameters on both membrane surfaces KX?

Since it is easy to obtain a large membrane area with a filtration device with a small priming volume, it is desirable to use a hollow fiber membrane.Membrane materials include cellulose membranes such as cellulose acetate, polyvinyl alcohol, and ethylene. Synthetic polymer porous membranes made of vinyl alcohol, polymethyl methacrylate, polyacrylonitrile, polycarbonate, polysulfone, polyvinylidene fluoride, polyethylene, polypropylene, polyamide, polyester, etc. These porous membranes can be obtained by already known techniques, for example, as a typical example.

Cellulose esters such as cellulose acetate can be obtained by applying the method disclosed in JP-A-52-84183.

In the method disclosed in JP-A-52-84183, a cationic metal hydrochloride having a valence of 25 to 35% by weight is used in its solvent, such as a cellulose ester. 20 to 100% by weight of at least one metal compound of nitrate, 8-bromide, and iodide based on the cellulose ester, and at least one type of saturated alcohol or cyclic hydrocarbons having 5 to 10 carbon atoms. A spinning dope containing a non-solvent of 50 to 80 weight JIk% relative to the solvent of the cellulose ester is discharged from an annular spinning hole, and an inner part that slowly coagulates the spinning dope from the center of the annular spinning hole. This method is characterized by quantitatively flowing out the coagulating liquid, allowing it to fall vertically under the spinning hole under its own weight, coagulating it in a coagulating bath, and washing away calcium chloride and non-solvent in a methanol solution. A hollow fiber separation membrane having different average pore diameters on both membrane surfaces depending on the method and having the pore diameter range of the present invention is preferable.

Next, to describe the effects of the present invention, albumin*i in the currently supplied blood and in the purified blood is adjusted to CPA and CFA, respectively.
, CPHMN, CFkmM,
If the processing time is increased, the recovery rate (integral recovery rate) of each component protein in plasma, namely albumin and molecular protein, to the purified blood within a certain processing time is RA, H
MW %), and the total supplied blood volume and total purified blood volume are Q.
When PT and QFT, it is shown as.

In this case, the conditions required for blood purification treatment are that KA is large, M is small, and the value IRA-RH that indicates separation property is
It is desirable that the MWI is large.

Particularly in processing for the purpose of blood purification, as mentioned above, it is essential that a large amount of blood can be processed in a short time and with a filtration device with a small membrane area, and that the kLA is large. The amount of blood processed in time is 2 to 41. It is preferable to use an apparatus in which the angle A is 60 to 90%, or more than 1 degree.
The first membrane, which separates plasma from blood by flowing blood in the direction of F1 of plasma components in blood or the direction in which the molecular weight cutoff is large, of the F1a membrane having force tropism, and then the reverse KBi! By storing two membranes of the same type in the same plasma purification device, which have a smaller molecular weight, it is extremely compact, easy to handle, and has excellent purification properties. It turned out to be a blood purification device.

The present invention will be described below with reference to examples.

Example 1 Cellulose acetate (eA manufactured by Eastman)
-394-45J16f% Acetone 329% as solvent
A mixed solvent of 402 and 8 f of methanol, 99.1 calcium chloride dihydrate as a metal compound, and 342 cyclohexanol as a heating medium were stirred to form a completely uniform bath to obtain a defoamed stock solution. This spinning dope was discharged from the annular spinning hole, and from the internal coagulation liquid outflow hole in the center, the methanol water bath solution was flowed out in a regular manner, and passed through the 801III air to the lower blade. A coagulation bath of 50 volumes of methanol aqueous solution was used, and the coagulated hollow fibers were treated in the methanol bath. As a result, the neglected hollow fiber has an inner diameter of 360μ, a membrane thickness of 150μ, and an inner and outer surface of t! 0 was observed with an electron microscope at a magnification of 10,000 times, the average pore diameter on the inner surface was 0.33 μ in the direction of the yarn axis and 0.25 μ in the direction perpendicular to the axis, and the average pore diameter on the outer surface was 0.33 μ in the direction of the yarn axis. The hollow fiber had an oval hole of 0.19μ in the axial direction and 0.13μ in the direction perpendicular to the axis, and the outer surface had a smaller hole diameter than the inner surface. An apparatus of the present invention as shown in Figures 2' and 3 was prepared using a flexible hollow fiber. In other words, to the device? In this case, 3,600 hollow fibers, an effective length of 1 gon, and an effective membrane area of 0.7 mm were bundled to form a plasma II membrane 20 with both ends bonded with urethane. Force, η The hollow opening at one end of the hollow fiber was closed with urethane resin, and 400
A plasma fractionation membrane 22 is formed by bundling 0 membranes, 4r effective length 163, and effective membrane area 0.7, and the other ends are glued with urethane. Such a modular device was assembled into the device shown in Figure 2. Next, the hematocrit is 4516.
The original I! 5 tons of fresh bovine blood adjusted to 5% protein plasma and added with 10,000 units/lt of heparin! jI! It was fed into the apparatus at 150 d1 min and was continuously fed with recirculation at an ultrafiltration pressure of 80 III Hg. At this time, the yield of albumin in plasma, a high-molecular protein component with a molecular weight of 100 or more, is calculated using a liquid chromatography HLC-801A (column swa-a
oo.

Analysis was performed using a chromatograph using a phosphate buffer (using a phosphate buffer as the eluent). @ Figure 12 The dotted line is bovine blood plasma 5 before processing.
This is a liquid chromatography pattern of a 100-fold dilution of the S protein solution (mother liquor), and the solid line is a pattern of a 100-fold dilution of purified blood plasma.

Now, in the plasma of purified blood by pre-processed blood, albumin,
The peak areas of high molecular weight proteins, AA and AA, respectively, were determined from the following formula. In this case, these values were measured using a pool of purified blood from before and up to 3 hours after the start. In addition, blood II total protein concentration was measured by the biuret method. The results are shown in Table 1. 8 in Table 1, P is the ultimate pressure (-1 mongo) of this device.

From these results, it was found that the apparatus of the present invention had good albumin recovery rate and separation performance, was easy to handle, and had sufficient processing capacity.

Table 1

[Brief explanation of the drawing]

Figure 1 is an explanatory diagram showing an example of a conventional blood purification device using a membrane, and Figure 2 is an explanatory diagram showing one mode of use of the device of the present invention.
Figure 3 is a simplified explanatory diagram of one embodiment of the device of the present invention;
,! Figures 4% and 5 are explanatory diagrams showing other embodiments of the Figure 3 device, Figure 6 is a sectional view taken along line X-X@ of the Figure 5 device, and the off view is another actual ms+ of the Figure 5 device. A simple explanatory diagram of , 1
Figure -8 is an explanatory diagram showing another example of J11i]1 of the 3-figure device, Figure 9 is a cross-sectional view of Y-Ym of the 8-dimensional figure, and Figures 10 and 11 are used for the 3-figure device. Enlarged schematic diagram of membrane, spear 1
FIG. 2 is a graph explaining the recovery rate of Examples. l・−・・−・・−・Blood 2・・・・・・・
・・Blood circuit 3・−・・・Pump 4・
...Plasma separator 5 --- Plasma introduction circuit 6 ... Pump 7 ...
Membrane separator 8...beating/discharge circuit 9...
...Recovery circuit 1o...Mixing chamber 11...
...Blood cell component 12 ...Derivation circuit 13
... Device of the present invention, 14 ... Pressure needle 1
5... Pressure regulator 16.17... Tuzzle 18... Case 19...
Cap 20...Plasma separation lA21...
・Blood flow path 22...Plasma separation membrane 23...
...Plasma F liquid chamber 24...Adhesive 25
...Purified plasma flow path 26...Adhesive
27...Blood cell component 28...Plasma component 29...Purified plasma 30...Purified blood 31...Plasma outlet 32-...・
・Bellows 33...Pressure transmitter 34...
...Pressure car adjustment piston 35...Pressure gauge 36
...F fluid line 37... Blood cell component outlet 38... Purified plasma outlet 39... Tuzzle 40... Discharge pump 41...・・・
Blood cell line 42... Interval @ 43.
44... Plasma chamber 45... Plasma to be refiltered 46... Side with larger pore size 47...
・Thickness with small pore diameter Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 7 Fig. 8 Fig. 10 Fig. 11 Fig. 12 m

Claims (1)

[Claims] A filtration membrane having a p-direction of the molecular weight cut-off is provided in a container having an inlet and an inlet for blood, and the inlet and outlet are arranged so that the plasma components in the blood are filtered in the direction in which the molecular weight is larger. It is provided on the 10,000 side and along the membrane v7iK so that the blood to be processed flows, and on the other side of the layer there is a P[chamber, and in the #F fluid chamber. In order to NF-treat the separated plasma components, 20 filtration membranes of the same type as the 1f) P filtration membranes are provided, and the 12 V filtration membranes are separated in the refiltration direction.
A blood purification device characterized in that one side of the K is in contact with the plasma component so as to be in the direction of decreasing molecular weight, and the other force of the 20V voltage is communicated with the blood outlet.