JPS58173554A - 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] Does the present invention purify blood? For more information on & placement,
KIIIL, which removes high-molecular proteins from blood, and JILI, a blood purification device that maintains high blood processing power and separation performance during blood processing, and are easy to handle and compact.
related.

In recent years, he has been diagnosed with nephritis, Gutsudbascher syndrome, idiopathic thrombocytopenic purpura disease, 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 iron production, and an increase in toxic substances. In inflammatory diseases, such as glomerulonephritis,
Because immune complexes in the circulating blood deposit in the stomach and cause damage, it is considered effective to remove antibodies, immune complexes, and intermediate products such as fibrinogen associated with inflammatory reactions in the blood. In addition, in Gutdbuscher syndrome, anti-QB
Reduces blood levels of M antibodies and increases plasma complement, #-
Removal of intrinsic factor is desired, and in myasthenia gravis, it is necessary to remove antibodies against the acetylurin receptor at nerve junctions, that is, immunoglobulin, in hyperthermic plasma, removal of low-density riboproteins in the blood, and in Raynaud's syndrome, removal of fibrinogen, Columnar reform and therapeutic effects have been seen compared to K, such as removal of macroglobulin.

The pathogenic substances and H1-disturbing substances in the blood of these patients are protein sources and play important functions for the living body, such as maintaining blood osmotic pressure and transporting ions and substances, and have a molecular weight of 66 .000 (molecular size 38 x 15 ON), it is said that there are many substances with a larger molecular weight than albumin, such as immunoglobulin, fibrinogen, hemacroglobulin, immunoglobulin and antigen substances, and complement binding substances, that is, immune complexes. It is desired to remove at least 100 molecules of substances such as body and low-density riboprotein, preferably α-globulin with around 1,160,000 molecules.

In plasma exchange therapy, blood removed from the patient is centrifuged.
Blood cell components and plasma are separated using an IA device or a membrane plasma separator, and equal amounts of normal plasma are exchanged with plasma containing unnecessary components such as albumin and these disease-causing or harmful substances. It returns to blood cell components.

Separation and exchange of Kahetame plasma allows for frequent exchange of large amounts of plasma in a short period of time! I
It is necessary to exchange Fk, usually from 1.5 to 3 o'clock at 3 to @
Plasma exchange therapy, which involves exchanging as much plasma as possible, requires a large amount of 0＠Senko II, whose main component is albumin, but fresh plasma is extremely expensive and the supply is limited. There are a number of problems that will hinder the future development of such treatments, including limitations and risks such as hepatitis infection.

In order to solve these problems, a method has been considered to separate and remove only unnecessary components from autologous plasma, recover useful components such as albumin without discarding them, and return them to the body. This makes it possible to further promote the therapeutic effect without using someone else's fresh tetravalent plasma and without the risk of hepatitis. As one of the most economical, easy, safe, and continuous methods for processing large amounts of plasma, it is possible to treat more than 28 substances of different sizes in plasma.
[K separation/removal, - cascade, filtration/ is generally known.

However, problems with this method include the complexity of its equipment and handling.

That is, in order to separate blood into blood cell components and plasma components, a blood I[separator is used in the first stage filter and a bm plasma separation operation is required, and the plasma separated after the heating operation is Next, a separation operation using a second-stage filter is required to separate and remove high-molecular proteins, and after that, a means is required to combine the purified plasma from which high-molecular proteins have been removed after passing through the ruptured membrane with the above-mentioned blood cell components. . Blood processing for therapeutic purposes is preferably performed aseptically, continuously, and in a short period of time, and for this purpose, the first and second stage filters, blood cells, and plasma mixing chamber are pumped through a blood circuit and a plasma circuit. It is necessary to connect them in a complicated manner via . Therefore, although this method is economical and is an excellent treatment method with no risk of hepatitis, it is currently difficult to use in general because it requires complicated equipment and skill to operate. It is.

In order to solve the problems of blood purification using conventional membrane separation methods, extensive research has been carried out on methods and devices to simplify them and obtain superior separation effects. Target Ki! The conventional method, that is, the 111-stage filter, uses a membrane with a large pore size to separate blood cells and plasma from blood.
Next, the second stage filter uses a membrane with a small pore size (a conventional method and device in which purified plasma obtained by separating two or more proteins of different sizes in plasma is combined with the aforementioned blood cell components). In the end, at least 2
It turned out to be a complex device requiring woodcutter filters, a circuit to connect them, and a pump.

Therefore, as a result of a thorough study of membranes with different structures and their usage, by changing the conventional ideas and ways of thinking, we found that the fractionated molecules tK in both membranes, the filtration direction, In a single module using a filtration membrane with different characteristics, for example, a membrane with different average pore sizes on both membrane surfaces, blood stains are separated into blood cell components and plasma components by flowing from the side with the larger pore size, and then the separated plasma is On the other hand, by increasing the average pore size of the ruptured membrane from the smaller one to the larger one, the high-molecular proteins in the plasma are separated, and the
The researchers discovered that scales purify blood by allowing low-molecular-weight substances such as electrolytes to pass through it, allowing them to merge with blood cell components. By using a membrane separation device incorporating a heating membrane, we hope to create a temporary membrane-based plasma purification device that is extremely compact and can solve the conventional problems of complicated device combinations and complicated operations. I found it.

That is, in the present invention, a transient membrane having a filtration direction according to a molecular weight cut-off is provided in a container having an inlet and an inlet for blood, and a mosquito inlet and an outlet allows plasma components in the blood to pass through with a high molecular weight cut-off. A liquid chamber is provided on one side of the membrane in the direction of KIl* so as to allow blood to flow therethrough, and a P liquid chamber is provided on the other side of the ruptured membrane. In addition, the blood purification device K11l is characterized in that the part of the ruptured membrane that is at least close to the blood outlet is separated into the P liquid chamber, which serves as a refiltration area for plasma components to the blood side.

Details will be explained below with reference to FIG. IIK. FIG. 1 is an explanatory diagram showing an example of a conventional blood purification device using a membrane. Via the pump 3, the blood cells and plasma are separated by a first stage filter and a plasma separator 4 (trade name, Plasma Flow, manufactured by Asahi Medical Co., Ltd.) using a cellulose acetate hollow fiber membrane with an f4Lkl pore size of 0.2μ, and then the separation is performed. Plasma is sent from the plasma introduction circuit via a pump 6 to a membrane separator 7 having a membrane with a smaller pore size than the plasma separator 4, where high molecular proteins in the plasma that do not pass through the membrane are sent from a discharge circuit 8. Discharged to the outside, low molecular weight substances such as albumin, water, and electrolytes pass through the membrane and are introduced into the mixing group 10 from the recovery circuit 9, where they are mixed with blood cell components 11 and led out from the extraction circuit 12. Such a conventional device requires two types of filters 4, 7, a complicated circuit 2, 5°9.12, and a plurality of pumps 3, 6, and is cumbersome to handle.

gzaa is an explanatory diagram showing one way of using the device of the present invention. Blood 1 enters the purification device 13vC of the present invention via the blood circuit 2 and pump 3, and is led out from the purified blood outlet path 12. 21st! In II, 14 is a pressure needle, 1
5 is a pressure 1 liter Jl device, and 8 is a discharge circuit.

FIG. 3 is an explanatory diagram showing a simplified embodiment of the device 13 of the present invention. 16. 17 is a nozzle having a blood inlet and a purified blood outlet; 18 is a case of the main body of the device; 19 is a cap; 20 is an adhesive such as urethane for fixing the membrane 21 and the case; 22 is a nozzle in the middle of the device; Upstream plasma P
This is a partition wall that separates the liquid chamber 23 from the plasma P liquid chamber 24 on the downstream side.
In FIG. 3, blood l flows through a blood flow path 25 from the blood inlet of the nozzle 16, and is separated from blood cell components 26 and blood by filtration a[21 having a molecular weight cut-off F-1m directionality It is separated into 27 parts. Blood cell component is blood #LR
While flowing through the IC from upstream to downstream IC, plasma 27 is transferred to the plasma plasma compartment 23 of the equipment. The plasma is transferred from the upper plasma outlet 29 to the plasma circuit 3 by the pump 28.
0, enters the plasma PK chamber 24 from the plasma lower introduction port 31, is refiltered by the membrane 21, enters the blood flow channel 25 as a purification surface #I32, is mixed with blood cell components 26, and becomes F
The purified blood 33 exits from the other blood outlet. On the other hand, to prevent clogging of the sliding door, the valve 34 is opened and plasma is intermittently drained from the F liquid chamber 23, or the bypass circuit 35
Close the valve 36, open the valve 37, and reversely from the pH chamber 2+.
Bypass circuit 35, pump 28, plasma circuit 30, square 34
It is also possible to intermittent icW& of plasma via .

FIG. 4 is an enlarged view of the blood flow section of the device of the present invention,
Figures 2 and 5 are enlarged views of downstream section B. As shown in FIG. 4, blood flowing through the blood flow path 25 is filtered to remove plasma components in the blood! ] If the J molecule is large, then the pore diameter is large (114113B) or small [39]. In addition, in Figure 3-〇 Shimotaki, plasma FflL chamber 2
The blood of No. 4 @27 has plasma component 'tFi as shown in Figure 5.
If the pore size is small, the fractionated molecules flow into the large side 38 again from the small pore diameter 114!139,
It mixes with blood cells 26 in the blood flow path and becomes purified blood 33.

At this time, high-molecular proteins in the separated plasma are separated, and albumin, water, etc. ! The low-molecular finished product, which is mainly composed of 4 molecules, passes through PiI again and is mixed with blood cell components.

FIG. 6 shows a blood purification device without the PVh wall 22 of the device in FIG. 3, and consists of a single blood #IP fluid chamber 40. A one-way valve 41 is provided in a plasma circuit 30 provided between an upper plasma outlet 29 and a lower plasma inlet 31, and a part of the plasma circuit is provided with an in/out circuit 43 in which a pump 28 and a storage tank 42 are combined. It is being In the recharging device, the plasma collected in the blood IF liquid chamber 40 is transferred from the upper plasma outlet 29 to the storage tank 4 via the plasma outlet 30 by the pump 28-C.
2, then by intermittently operating the pump 28 in forward and reverse directions, the removal of plasma from the upper plasma outlet and the forced injection of plasma into the lower plasma inlet 31 are repeated, and the plasma is collected in the vicinity of the plasma removal port. Noll! Plasma separation at the membrane and refiltration at the membrane near the lower plasma inlet can be forcibly performed.

Maki 711iii is a device similar to that shown in Fig. 6, but a pressure car adjustment hole 44 is provided in the plasma F liquid chamber 40 instead of the plasma extraction volume 29.31, and the pressure 111! It consists of a pressure circuit 45, a pressure transmitter 47 with a built-in bellows 46, a pressure adjustment piston 48, and a pressure gauge 49. Also,
50 and 51 are device inlet and outlet pressure gauges on the blood side. In this device, the blood 1 is passed through the blood inlet 16 at the top of the device.
The blood flows through the blood flow path 25 of the membrane 21 from the blood outlet 1 to the lower blood outlet 1.
At this time, the blood flows down the blood flow path 25 while creating a pressure gradient, and is separated into plasma. That is, the pressure in the lower blood flow path near the outlet 17 is lower than the pressure in the upper flow path near the inlet 16 due to the pressure gradient due to the pressure loss of the blood fluid. At this time Fm
The pressure in the chamber 40 is defined as the pressure P1 on the blood inlet side and the pressure P1 on the outlet side,
+7) intermediate ofiP, i.e. Pt < Ps
By adjusting <P by the action of the piston 48 and the pressure transmitter 470, the blood'/plasma F is separated once on the upstream side of the membrane.
The plasma 27 accumulated in the liquid chamber 40 is recycled to the blood F on the downstream side of the membrane.
Blood #L 25 in the membrane 21 from the liquid chamber 40 can be used again as purified plasma 32.

The plasma purification ability of such a device, ie.

In order to improve the separation ability between blood cells and plasma and the repurification ability of the plasma membrane, it is desirable to increase the blood lateral velocity and increase the pressure drop within a range that does not cause destruction of blood cells. It is preferable to increase the thickness of the plate flow path, or to increase the distance between the blood inlet and outlet in the module, as a practical blood fIL thickness that is less likely to cause hemolysis and coagulation. In the case of a hollow fiber with an inner diameter of 360μ, it is preferable to use a practical #11 module with a diameter of at least 301 to 100a*.Furthermore, the apparatus of the present invention is not limited to the above-mentioned examples, and can also be used, for example. Contrary to the device shown in Fig. aI6, two portions of plasma components are placed in the plasma F liquid chamber @, one side having a larger molecular weight, and the blood is transferred from the plasma S* outlet to the blood lIP liquid chamber 40.
KjlL, while the lower sO plasma flows out from the lower 84 population 31, the blood flow path 2s is used as a blood INF liquid chamber, and the blood inlet/outlet 16.17 is used as a plasma outlet and an inlet.
It may also be a device connected to the path 30.

Membranes with different p distributions and molecular weights of plasma components 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 charge properties, or hydrophilic and hydrophobic membranes. The material membranes have different protein adsorption properties or protein permeability on both sides, but for example, the membranes with different pore sizes on the membrane surface described here are: It is a membrane with a pore diameter that is large enough to exceed the force of blood cell components in the blood, and it can be estimated with a scanning electronic J141i1i etc. that the pore diameter of a random sample on the membrane surface, that is, the diameter of the pores. This is a method of averaging a large number of short diameter Jl average waxes, and the semi-uniform pore diameter of a membrane with a small average pore diameter (q is 0.05 to 0.3 μ, preferably 0.08
~0.25μ, and the average pore diameter on the larger gg side (Di is 0.15-40 mm, preferably 0.2-2.
0μ, and the ratio D/C is 1.2~! 1LO1 is preferably 1.4 to 3.0. The reason why the molecular weight fraction differs depending on the direction of plasma components passing through membranes with different pore sizes is unclear, but one reason is that the pores that make up the membrane slope from the larger side to the smaller side. This may be due to the fact that high molecular weight proteins in plasma easily pass through from the direction of large pore size to the direction of small pore size, whereas they are blocked by the pore wall from the direction of minimum pore size, or because of a second reason. is Kayoru Protein F
In most porous F membranes, the size of the permeable substance is regulated by the pore size K of the active layer on the surface of both membranes, that is, the skin layer. It consists of a large number of mutually communicating channels with rough interiors in the wRIjir direction, that is, a sponge structure, and the surface of such a membrane is within the range of variation in pore size, and there are a small number of channels on the membrane side with small pore sizes. There are some pores with large pore diameters, and the pores that are hidden communicate with the pores on the 11th side of the larger pore diameter through a large number of channels in the internal sponge structure, so that from the side with smaller pore diameters, High-molecular-weight proteins only stochastically flow out from very small pores with a small number of probabilistic V-intervals, whereas from the large pore side, they pass through the pores stochastically from a large number of flow paths. Image side K
ll, as a result, the permeability of high molecular weight proteins from the membrane side where the pores are maximum increases, or thirdly, the membrane side where the pores are large is rough and uneven. However, due to the current effect caused by blood flow or for some reason, protein adhesion or adsorption, that is, the protein cake layer becomes relatively small, improves the permeability of polymer chain proteins, whereas There are various possible reasons for this, including the smooth surface, less turbulent flow, and large cake layer.

On the other hand, the membrane used in the apparatus of the present invention has a broad concept such as a hollow fiber membrane, a tubular membrane, and a flat membrane, and is not limited to flat membranes.

In addition, membranes with different average pore diameters in both membranes 1 can be used, for example, commercially available flat membranes having pore diameters in the filtration region, such as Millibore Co., Ltd. and Amicon Co., Ltd. In order to easily obtain a large membrane area with the device, it is desirable to use a hollow fiber membrane.
a-silt, myohyyl libinyl alcohol, ethylene vinyl alcohol, boq methyl methacrylate, polyacrylonitrile, polycarbonate, polysulfone,
Polyvinylidene fluoride, polyethylene, polypropylene,
It is a synthetic polymer porous membrane made of boria 2, polyester, etc.

These porous membranes can be obtained by already known techniques, but for example, as a typical example, cellulose x 7 *
The cellulose ester of f-)rx can be obtained by applying the method disclosed in JP-A-52-84183Kil.

%! l@52-84183Kl! In the method shown, 25 to 35% by weight of cellulose ester, based on its solvent, and at least one metal compound of -valent, divalent cationic metal hydrochloride, nitrate, bromide, and iodide are added to the cellulose ester. The cellulose ester contains at least one non-solvent selected from 20 to 100% by weight of a saturated alcohol or a cyclic hydrocarbon having 5 to 10 carbon atoms, and 50 to 80% by weight of the solvent for the cellulose ester. The spinning stock solution is discharged from the annular spinning hole, and the inner g# solid liquid having a slow coagulating effect on the spinning material ltK is quantitatively flowed out from the center of the annular spinning hole, and after falling under its own weight vertically under the spinning hole, This method is characterized by coagulating in a coagulation bath, and washing and removing calcium chloride and non-solvent in a methanol solution. A hollow A separation membrane having a pore size range of .

Next, to describe the effects of the present invention, the albumin concentrations in the currently supplied blood and in the purified blood are measured by CPA and CFA, respectively.
, CPHMV, CFHMW% of macromolecular proteins around 100
If the Asahi cycle time is increased, the recovery rate of each component protein in plasma, that is, albumin and high molecular protein, to the purified blood side within a certain sensitive layer 1liIrka (collection rate)
) LA, R) IMW~, and the total amount of blood supplied and the total amount of purified blood are QPT and QFT.

In this case, the blood purification #&salt K1K condition is large and RHMW is small, so the value I
It is desirable that RA-RHMWI is large m'tltK
For the purpose of blood purification in Kusho-dori, it is essential that a large amount of blood can be collected in a short time and with a small-area f'A device, as described above, and that the Rm is large, but in this case, In 1.5 to 3 hours, the amount of blood lost was 2 to 41. It would be desirable to have a device that achieves a R rate of 90%.

By the way, the blood plasma component in the blood flowing through the filtration membrane, which has IFi directionality in molecular weight on both sides, flows in the direction of increasing molecular weight to separate blood cells and plasma, and then vice versa. It consists of passing the separated plasma into blood from the direction of the ruptured membrane with a lower molecular weight cutoff, and mixing the membrane-passed plasma, which consists of low-molecular-weight substances whose main components are albumin, water, and '11 solute, with blood cells. It has been found that when the device of the present invention is used, it becomes a blood purification device that is excellent in albumin recovery vehicles and is easy to handle.

Hereinafter, the present invention will be explained by giving examples.

Example 1 Cellulose acetate (Eastman CA-39
4-45) 16F, a mixed solvent of 32f acetone and 8t methanol as a solvent, 40t1, calcium chloride dihydrate 91% as a metal compound, and cyclohexanol 34% as an added heating medium are stirred to form a completely uniform #1 slurry, and defoamed. A stock solution was obtained. This spinning stock solution is discharged from the annular spinning hole, and from the outflow hole of the internal coagulated liquid in the center, 50% methanol aqueous solution is discharged at a constant violet KH, and 80% methanol is discharged downward.
After the fibers were completely evaporated into air, the fibers were introduced into a coagulation bath containing a 50% by volume methanol aqueous solution, and the coagulated hollow fibers were treated in the methanol bath. As a result, the obtained hollow fiber had an inner diameter of 360μ and a membrane thickness of 150μ, and when both the inner and outer surfaces were observed with an electron microscope at a magnification of 10,000 times, the average pore diameter on the inner surface was 0.33μ in the fiber axis direction. The hollow fiber has a diameter of 0.25μ in the direction perpendicular to the axis, a diameter of 0.19μ in the direction of the fiber axis, and a diameter of 0.13μ in the direction perpendicular to the axis. there were. Bundle 3,600 of these hollow fibers, fix both ends and the center with urethane, and have an effective length of 36 om.
, total effective surface 4511.5 m'+7) The module 13 shown in Fig. 3 was created and the device shown in Fig. 2 was assembled.

Next, the hematocrit was adjusted to 45 N, the plasma was adjusted to 5% protein, and 5 tons of Ushikomisaki blood to which heparin was added at 10,000 units/1 was supplied to Honkomeiso at a rate of tSO-/min.
aliquot the plasma in the upper m@F liquid chamber at
In the flow of 0atg/'+, operate y continuously, blood #t
F' flow u+ tSS delivery room entry, 3 o'clock IMIII [
I disposed of it after using the late Zenpo Merchant Ring. At this time, the recovery rate of albumin in plasma, a disease molecular protein component of more than 1 million molecules, was determined by Toyo Chodatsusha = A-body chromatography HL C,
-801A (column 5vV-3000x1, using phosphate buffer as dissociation solution) was analyzed using chromatography.

The point in Figure 8 is a cross pattern of a 100-fold dilution of pre-processed bovine blood plasma with 5% protein (11), and in reality it is Butter 7, a 100-fold dilution of plasma comparable to purification.

Now, in the plasma of unprocessed blood and purified blood, albumin,
The peak area of each high molecular weight protein is AA.

AfLviW, AA', A') (where MW is the integral recovery rate of each component, ΣQ l) was calculated using the following formula. In this case, these values were measured using the pooled blood samples from before and up to 3 hours after the start. Table 1 shows the 0M plasma protein concentration measured by the biuret method.

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

Shoes L Clothes

[Brief explanation of drawings]

Fig. 5g1 is an explanatory diagram showing an example of a surface number purification device y'+ 1 using a conventional membrane, and Fig. 2 is an explanatory diagram showing an example of the device of the present invention for one use. ! i
Fig. 3 is an explanatory diagram showing the body of the present invention.
Figure 4 is an enlarged schematic diagram of the upstream portion of the blood flow of the Hongen Meiso, Figure 5 is an enlarged schematic diagram of the same lower part, and Figure 6 is another diagram of the device shown in Figure 3. An explanatory diagram showing the implementation 11A, Figure 7 is an explanatory diagram showing yet another example of the equipment shown in Figure 3, and Figure 8 is a graph explaining the collection vehicle of Central Office H. 1...Blood 2...Plasma circulation 3...Pump 4...Plasma 45...Plasma sage L
GL complex 6...Bonga...Membrane spectrometer 8
...Concurrent circulation 9...Collection times m 10...
Mixing group 11... Blood cell component 12... Derivation circuit 13... Device of the present invention 14... Pressure needle 15...
・Pressure A amount 16, 17... Nozzle 18... Case 19... Cap 20... Adhesive
21... Membrane 22... Partition wall 23...
・Upstream side F liquid chamber 24...Downstream @Full room 25...
Blood flow path 26... Blood cell component 27... Plasma 28... Pump 29... Upper plasma outlet 30... Plasma circuit 31... Lower plasma inlet 32... Purification surface end 33 ...Number of purifications: 34.
... Valve 35 ... Bypass circuit 36. 37 ... Measure 38 ... Large pore size -39 ... Pore size O" @ size @ 40 ... Plasma v'i
Liquid chamber 41... One-way valve 42... Storage tank 43
...Derived person times @44...Pressure adjustment hole 45...Pressure III circulation M 46...Bellows 47...Pressure transmission 48...Pressure car princess piston 4 to 5 5
1...Pressure needle Figure 1 Figure 2 Figure 4 Figure 6 Figure 7 Figure 8

Claims (1)

[Claims] Minutes - molecular weight P) 1! in a container with a blood inlet and outlet.
A directional p-filtration membrane is provided, and the inlet/outlet is located in one direction of the Km membrane in which the filtration of plasma components in the blood increases in molecular weight. The pressure on the other side of the ruptured membrane is v
A blood vessel characterized in that an i-liquid chamber is provided, and at least a portion of the ruptured membrane near the blood outlet is used as an area where plasma components separated in the v-liquid chamber are recirculated into the blood stream. Ika equipment.