JP5856821B2 - Ascites filtration concentrator - Google Patents

Description

  The present invention relates to an apparatus for filtering and concentrating ascites and a method for producing a high concentration protein solution.

  Conventionally, for patients who have a tendency to collect ascites or pleural effusion (hereinafter collectively referred to as ascites) such as cirrhosis, the protein in the ascites is used to increase the patient's blood protein concentration. Ascites drained into the ascites is filtered and concentrated with two types of filters using hollow fiber membranes, etc. to obtain a concentrated protein solution, and this is instilled into the patient ascites filtered concentrated re-injection method (for example, Patent Document 1). The first of the two types of filters is a filter for removing cell components such as cancer cells and blood cell components contained in ascites, and does not allow cell components to pass through, but allows solute components such as moisture and protein to pass through. A membrane having such a pore size is used. On the other hand, the other filter is a concentration filter for dehydrating ascites, which is a dilute protein concentration, and concentrating the protein. A membrane that hardly passes protein components and allows moisture, electrolytes, etc. to pass through is used. In general, from the viewpoint of convenience, a method of concentrating ascites obtained by filtering cell components with a filter with a concentrator is used, and a device that performs these continuously is used.

JP 2009-297242 A

  The protein solution to be administered to a patient also has a purpose of increasing the blood protein concentration of the patient after administration, and therefore needs to be at a somewhat high concentration. For this purpose, it needs to be concentrated to a high concentration ratio. When the protein concentration of the ascites to be processed becomes high, the concentration filter is clogged with protein, the concentration rate is reduced, and there is a case where it cannot be concentrated to the target concentration ratio. In such a case, it is necessary to go through a very complicated process such as collecting the protein solution in an insufficiently concentrated state and then concentrating it additionally. In some cases, it is necessary to replace the concentration filter with a new one. Therefore, it is burdensome for the implementer in terms of work and time, and there is also an economic disadvantage. In addition, there is a disadvantage that the patient has a long restraint time until the protein solution is administered.

  On the other hand, patients with ascites can be broadly divided into patients with hepatic ascites that accumulates due to diseases such as cirrhosis and those with cancer ascites that retains cancers such as stomach cancer, ovarian cancer, and colon cancer. In the past, this treatment was mostly performed mainly for patients with hepatic ascites, but in recent years, the therapeutic effect of implementing this treatment for patients with cancerous ascites has been recognized. Opportunities for patients with ascites are increasing. However, since cancerous ascites generally tends to have a higher protein concentration than hepatic ascites, the additional concentration step as described above is frequently required.

  Further, Patent Document 1 discloses a method in which a negative pressure generator is installed downstream of a concentration filter to suppress accumulation of deposits in a method of concentration using a suction device provided on the waste liquid side of the concentration filter. However, even in this method, it is necessary to take action by the practitioner to open the pressure release line provided in the middle of the suction device and release the suction pressure applied to the concentrator.

  The present invention is a method for concentrating a dilute protein solution such as ascites to obtain a concentrated protein solution in response to the above-mentioned problems of the conventional method. It is an object of the present invention to provide an ascites filtration and concentration device for obtaining a concentrated protein solution having a high protein concentration without burden and a method for producing a high concentration protein solution.

  The inventors of the present invention have found that the ultrafiltration performance of the concentration filter used in the apparatus is related to the clogging of the concentrator, and a concentration filter having the optimum ultrafiltration performance for the concentration treatment of ascites. By using the apparatus used, it was found that the reduction in the concentration rate was suppressed, and that the protein could be concentrated to a high magnification without loss, and the present invention was completed. That is, the present invention relates to the following.

[1]
A storage container for storing a collected protein solution containing cellular components;
A hollow fiber membrane type ascites filtration filter capable of separating the cellular components present in the protein solution in the storage container;
A first flow path having one end connected to the storage container and the other end connected to the inlet of the ascites filter;
A polysulfone-based hollow fiber membrane type ascites concentration filter having an ultrafiltration performance of 85 mL to 150 mL / min / 200 mmHg and provided with a hydrophilic polymer;
A second flow path connected to the filtration-side outlet of the ascites filter and the other end connected to the inlet of the ascites filter;
A third flow path connected to the outlet of the ascites filter,
A collection container for collecting the protein solution concentrated by the ascites filter,
A fourth flow path having one end connected to the outlet of the ascites concentration filter and the other end connected to the collection container;
A fifth flow path connected to the filtration side outlet of the ascites concentration filter;
Ascites filtration and concentration device.

[2]
The protein solution stored in the storage container is fed to the ascites filter through the first flow path, and the filtered protein solution from which the cellular components have been removed is filtered to the ascites filter. And discharging the solution containing the cell component from the outlet of the ascites filter to the third channel, and
The filtered protein solution sent to the second flow path is sent to the ascites concentration filter, and the concentrated concentrated protein solution is sent from the outlet of the ascites concentration filter to the fourth flow path. Discharging the aqueous solution from the filtration side outlet of the ascites concentration filter to the fifth flow path;
Collecting the concentrated protein solution delivered to the fourth flow path in the collection container;
The ascites filtration concentrating device according to claim 1, further comprising control means for controlling a flow rate of at least one of the first to fifth channels.

[3]
The ascites filtration and concentration apparatus according to claim 2, wherein the control means includes a liquid feed pump provided in the first flow path.

[4]
The ascites filter is disposed at a position such that the drop pressure of the liquid at the inlet of the ascites filter is lower than the drop pressure of the liquid at the connection between the storage container and the first flow path. And,
The recovery container is disposed at a position such that a liquid drop pressure at a connection portion between the recovery container and the fourth flow path is lower than a liquid drop pressure at an outlet of the ascites concentration filter. Item 2. The ascites filtration concentration device according to Item 1.

[5]
5. The ascites concentration filter is disposed at a position such that a drop pressure of liquid at an inlet of the ascites filter is equal to a drop pressure of liquid at a filtration side outlet of the ascites filter. Ascites filtration concentrator.

[6]
The ascites concentration filter is disposed at a position such that a drop pressure of liquid at an inlet of the ascites filter is lower than a drop pressure of liquid at a filtration side outlet of the ascites filter. The ascites filtration and concentration apparatus described.

[7]
Since the ultrafiltration performance of the ascites concentration filter is optimal for ascites concentration treatment, ascites need only be concentrated once, and no additional concentration step is required. The ascites filtration concentrating device according to any one of 6.

[8]
The ascites filtration concentrating device according to any one of claims 1 to 7, wherein the concentration of the protein can be concentrated five times or more by one concentration by the ascites concentration filter.

[9]
The ascites filtration and concentration apparatus according to any one of claims 1 to 8, wherein a concentrated protein solution having a protein concentration of 7 g / dl or more can be obtained by one concentration by the ascites concentration filter.

[10]
A storage container for storing a collected protein solution containing cellular components;
A hollow fiber membrane type ascites filtration filter capable of separating the cellular components present in the protein solution in the storage container;
A first flow path having one end connected to the storage container and the other end connected to the inlet of the ascites filter;
A polysulfone-based hollow fiber membrane type ascites concentration filter to which a protein concentration rate per hour is 0.1 times / min or more and a hydrophilic polymer is added;
A second flow path connected to the filtration-side outlet of the ascites filter and the other end connected to the inlet of the ascites filter;
A third flow path connected to the outlet of the ascites filter,
A collection container for collecting the protein solution concentrated by the ascites filter,
A fourth flow path having one end connected to the outlet of the ascites concentration filter and the other end connected to the collection container;
A fifth flow path connected to the filtration side outlet of the ascites concentration filter;
Ascites filtration and concentration device.

[11]
Storing a low concentration protein solution having a protein concentration of 5 g / dL or less in a storage container;
The low-concentration protein solution stored in the storage container is passed through a polysulfone-based hollow fiber membrane filter having an ultrafiltration performance of 85 mL to 150 mL / min / 200 mmHg and provided with a hydrophilic polymer, and the filter A step of feeding a low concentration protein solution having a protein concentration of 100 mg / dL or less from the outlet of the filtration side, and a step of sending a high concentration protein solution having a protein concentration of 7 g / dL or more from the outlet of the filter;
Recovering the high-concentration protein solution delivered from the outlet of the filter in a recovery container.

  The ascites filtration concentrating device and the method for producing a high concentration protein solution of the present invention are characterized by using a filter having an optimum ultrafiltration performance so that it can be concentrated with high efficiency. . Therefore, the procedure of the enforcer can be facilitated and the processing is completed in a short time.

It is a figure which shows 1st Embodiment of the ascites filtration concentration apparatus of this invention. It is a figure which shows 2nd Embodiment of the ascites filtration concentration apparatus of this invention. It is a figure which shows 3rd Embodiment of the ascites filtration concentration apparatus of this invention. It is a figure which shows the test apparatus of the ascites concentration performance based on the filter for concentration.

  Hereinafter, the best mode for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described in detail. In addition, this invention is not limited to the following embodiment, It can implement by changing variously within the range of the summary.

(First embodiment)
As a first embodiment of the present invention, an example of the configuration of the ascites filtration concentration device 100 shown in FIG. 1 and a method for obtaining a concentrated protein solution (high concentration protein solution) by filtering and concentrating ascites (protein solution) using the device 100. Indicates.

  First, the patient's ascites is collected and stored in the storage container 1. In general, ascites is a low concentration protein solution with a protein concentration of 5 g / dL or less. The outlet 1 b of the storage container 1 is connected to the first flow path 31 and is connected to the inlet 3 a of the filter 3 for filtration via the first flow path 31. Ascites fluid in the storage container 1 is supplied to the filter 3 for filtration via the first flow path 31. In the filter 3 for filtration, since the cell component cannot pass through the filtration membrane, the ascites after filtration including the protein from which the cell component has been removed is discharged from the filtrate outlet 3c of the filter 3 for filtration. A third flow path 33 is connected to the outlet 3 b of the filter 3 for filtration, and a part of ascites containing cell components is discharged out of the device 100 through the third flow path 33. The filtrate outlet 3 c is connected to the ascites inlet 4 a of the concentration filter 4 via the second flow path 32, and the post-filtered ascites discharged from the filtrate outlet 3 c is concentrated via the second flow path 32. Introduced into the filter 4.

  In the concentration filter 4, the ascites water after filtration is separated and discharged from the apparatus 100 through the fifth flow path 35 connected to the filtrate outlet 4 c. Here, the liquid discharged from the filtrate outlet 4c is a low concentration protein solution having a protein concentration of 100 mg / dL or less. The pore diameter of the concentration filter 4 is smaller than the pore diameter of the filtration filter 3. Since the protein contained in the ascites after filtration does not pass through the filtration membrane and is retained in the concentration filter 4, the protein concentration in the ascites after filtration is increased by the drainage of the water, and the concentration filter 4 is concentrated as a concentrated protein solution. From the concentrated liquid outlet 4b. The concentrate outlet 4b of the concentration filter 4 is connected to the inlet 2a of the collection container 2 via the fourth channel 34, and the concentrated protein solution discharged from the concentrate outlet 4b passes through the fourth channel 34. Through the collection container 2. The concentrated protein solution recovered here is a high-concentration protein solution having a protein concentration higher than that of at least ascites in the storage container 1, for example, the protein concentration is 7 g / dL or more.

  The storage container 1 and the recovery container 2 may be anything as long as they can store a liquid, but usually a polyvinyl chloride bag is used from the viewpoint of handleability. The size of the container is determined by the amount of ascites collected.

  The filter 3 for filtration is not particularly limited as long as it can separate cell components and moisture, and solute components such as electrolytes and proteins. The structure, shape, and dimensions of the filter are not limited as long as it includes an ascites inflow port that can be connected to the flow path connected to the storage container 1 or the concentration filter 4 and a filtered ascites outlet. Further, the hollow fiber used in the filter 3 for filtration is not particularly limited, and for reasons of easy pore size control during film formation and excellent chemical stability, polyolefins such as polyethylene, polysulfones, regenerated celluloses, Polyvinyl alcohol is preferred. These exemplified hollow fiber materials may contain other materials or may be chemically modified. Usually, a hollow fiber membrane filter having a pore size of 0.2 μm or less and a protein permeability of 80% or more is used.

  In FIG. 1, the filtration filter 3 is used in an internal pressure filtration system to perform ascites filtration. However, if cell components can be separated, the external pressure filtration system can be used, and the third flow path 33 is sealed. It can be stopped and filtered by a dead end method, or the third flow path 33 can be opened to be a cross flow method.

  As long as each flow path 31-35 which comprises the apparatus of this invention can be connected with the storage container 1, the collection container 2, the filter 3 for filtration, and the filter 4 for concentration, there is no limitation in a material, a dimension, etc. Usually, a soft tube manufactured from polyvinyl chloride or the like is used as a tube forming the flow paths 31 to 35.

  Any means may be used for feeding ascites from the storage container 1 to the filter 3 for filtration. For example, as shown in FIG. 1, a pump 5 may be installed in the first flow path 31 to send liquid. As the pump 5, a roller pump or an infusion pump is generally used. In this case, a control device 41 that controls the driving of the pump 5 may be provided. The control device 41 controls the flow rate of ascites in the first flow path 31 (the amount of liquid delivered per unit time) by controlling the driving of the pump 5. The control device 41 is, for example, a computer, and may also serve as an input terminal that allows an enforcer to input information related to desired control. Further, a liquid feed pump may be added also on the second flow path 32 and the third flow path 33.

  The control unit 14 is installed in the middle of the fourth flow path 34, and the control unit 15 is installed in the middle of the fifth flow path 35. The control unit 14 adjusts the flow rate of the fourth flow path 34, and the control unit 15 adjusts the flow rate of the fifth flow path 35. The control units 14 and 15 can adjust the balance between the discharge amount of the filtrate of the concentration filter 4 and the amount of the concentrated protein solution, and can adjust the concentration ratio.

  The control units 14 and 15 balance the amount of filtrate that is filtered from the concentration filter 4 and discharged from the concentrated solution outlet 4b in the ascites supplied to the concentration filter 4 and the amount of liquid that is directed to the collection container 2. Anything can be used as long as it can be controlled. For example, the control units 14 and 15 may control the flow path resistance by adjusting a flow path resistance such as a roller clamp, and applying a certain negative pressure or positive pressure to each of the flow paths 34 and 35. It may be a device that controls the flow rate, or may be a device that controls the flow rate, such as a roller pump or an infusion pump. Only one of the control units 14 and 15 may exist as long as the balance between the amount of liquid filtered and discharged from the concentration filter 4 and the amount of liquid directed to the collection container can be controlled. Further, the flow rate of the flow paths 34 and 35 may be controlled by the control device 41 by driving the control units 14 and 15 with a control signal from the control device 41.

  In the apparatus 100 shown in FIG. 1, the first flow path 31 is connected to the lower side of the filtration filter 3 and the third flow path 33 is connected to the upper side of the filtration filter 3. The effect is obtained. The second flow path 32 may be connected to any position as long as it communicates with the hollow fiber outer chamber portion of the filter 3 for filtration.

  The ultrafiltration performance of the concentration filter 4 used in the present invention is 85 mL to 150 mL / min / 200 mmHg. If the ultrafiltration performance is less than this range, the amount of filtrate discharged during concentration is reduced, and a sufficiently concentrated protein solution cannot be obtained. Moreover, if it is 95 mL / min / 200 mmHg or more, the possibility of clogging is lower, which is preferable. If it is 150 mL / min / 200 mmHg or more, the protein leaks into the filtrate, and a sufficient protein concentration cannot be obtained.

The ultrafiltration performance of the present invention is defined by the following test. Prepare bovine plasma with a protein concentration adjusted to 6 g / dL, and send it to the filter for concentration at a constant speed of 200 mL per minute with a roller pump. At this time, the filtrate outlet of the concentrator is open. Pressure is applied to the circuit connected to the recovery liquid outlet of the concentration filter, and the pressure difference applied to the inside and outside of the filter (hereinafter also referred to as TMP) is adjusted to 200 mmHg. At this time, the volume per hour of the filtrate discharged from the filtrate outlet is measured. TMP is calculated as follows.
TMP = (Filter inlet side pressure + Filter outlet side pressure) / 2− Filtrate side pressure

  In the present invention, a filter using a hollow fiber membrane is used from the viewpoint of concentration efficiency. The hollow fiber membrane here is not particularly limited in its shape and dimensions, and any hollow fiber membrane may be used as long as it has the above ultrafiltration performance. As the material, polysulfone is preferable because it is easy to control the pore diameter during film formation and is excellent in chemical stability. Since the polysulfone polymer is an aromatic compound, it is particularly excellent in radiation resistance, is extremely resistant to heat and chemical treatment, and is excellent in safety. Accordingly, various membrane forming conditions can be adopted and radiation sterilization can be performed, which is particularly preferable as a membrane material used in the ascites concentrator. In addition, “to system” means not only a homopolymer but also a copolymer with another monomer and a chemically modified analog.

  The polysulfone-based polymer (hereinafter sometimes referred to as PSf) as used herein is a general term for polymer compounds having a sulfone bond, and is not particularly defined. For example, the repeating unit is represented by the following formula (1 ), Formula (2), formula (3), formula (4), and polysulfone-based polymer represented by formula (5). It may be a modified polymer in which a substituent is introduced into a part of these aromatic rings. Aromatic polysulfone-based polymers represented by the formula (1), formula (2) and formula (3) are preferred from the viewpoint of industrial availability, and among them, polysulfone having a chemical structure represented by formula (1) is preferred. Particularly preferred. This bisphenol-type polysulfone resin is commercially available, for example, from Solvay Advanced Polymers under the trade name “Udel (registered trademark)”, and there are several types depending on the degree of polymerization, but there is no particular limitation.

  The polysulfone-based hollow fiber membrane in the present invention is preferably made hydrophilic by a hydrophilic polymer. This is because the surface of the hollow fiber membrane becomes hydrophobic only with the polysulfone-based polymer, and the protein is easily adsorbed on such a surface, which causes a decrease in the protein recovery performance. Examples of the hydrophilic polymer include polyvinyl pyrrolidone (hereinafter sometimes referred to as PVP), polyethylene glycol, polyvinyl alcohol, polypropylene glycol, and the like. Among them, PVP is preferable from the viewpoint of hydrophilization effect and safety. There are several types of PVP depending on the molecular weight and the like. Examples of commercially available products include PVP K-15, 30, 90 (all manufactured by ISP Corporation). The molecular weight (viscosity average molecular weight) of PVP used in the present invention is 10,000 to 2,000,000, preferably 50,000 to 1,500,000. The content of the hydrophilic polymer in the film is 3 to 20%, preferably 3 to 10% of the total amount of the polymer. When the content is 3% or less, the effect as a hydrophilizing agent is diminished, and when the content exceeds 20%, the viscosity of the film-forming stock solution is excessively increased, which is not preferable for production.

  As a method for producing a hydrophilic polysulfone hollow fiber membrane, a known dry / wet film-forming technique can be used. First, a polysulphone polymer and a hydrophilic polymer such as polovinylpyrrolidone are dissolved in a common solvent to prepare a uniform spinning solution. As such a common solvent, when the hydrophilic polymer is polyvinylpyrrolidone, for example, dimethylacetamide (hereinafter referred to as DMAC), dimethylsulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane, dioxane, etc. Or a solvent composed of a mixture of two or more of the above solvents. In order to control the pore size, additives such as water may be added to the spinning dope.

  When forming the hollow fiber membrane, a tube-in-orifice type spinneret is used, and the spinning solution from the orifice of the spinneret and the hollow internal solution from the tube are simultaneously discharged into the air. The hollow inner liquid is for coagulating the spinning dope, and water or a coagulating liquid mainly composed of water can be used. The composition of the hollow inner liquid should be determined according to the performance of the intended hollow fiber membrane, such as the ultrafiltration performance, and cannot be determined in general, but generally the solvent used for the spinning dope A mixed solution of water and water is preferably used. For example, a 0-65 wt% DMAC aqueous solution or the like is used as the hollow inner liquid. The spinning stock solution discharged from the spinneret together with the hollow inner liquid travels through the idle running portion, and is introduced and immersed in a coagulation bath mainly composed of water installed at the lower part of the spinneret to complete the coagulation. Thereafter, the solidified hollow fiber is subjected to a washing step and the like, and then wound with a wet hollow fiber membrane winder to obtain a bundle of hollow fiber membranes, and then dried. Alternatively, a hollow fiber bundle may be obtained through a washing process and then drying in a dryer, and the production method is not specified.

  A known method may be used for a method for producing a filter using a hollow fiber. For example, a hollow fiber membrane bundle is inserted into a cylindrical container having a fluid inlet / outlet port, a potting agent such as polyurethane is injected into both ends of the bundle to form a potting layer, and both ends are sealed. It can be produced by cutting and removing the potting agent, opening the end face of the hollow fiber, and attaching a header having a fluid inlet / outlet. By this method, the hollow fiber membrane bundle is filled in the container, a hollow fiber membrane inner chamber and a hollow fiber membrane outer chamber are formed, and has a fluid inlet / outlet leading to the hollow fiber membrane inner chamber and a fluid inlet / outlet leading to the hollow fiber membrane outer chamber. A hollow fiber membrane type concentration filter can be manufactured.

  The protein concentration of the concentrated protein solution obtained by the apparatus and method of the present invention is 7 g / dL or more. If the concentration is lower than this concentration, even if it is administered to a patient, the effect of increasing the blood protein concentration of the patient is low, and the patient tends to accumulate ascites again. The protein concentration is preferably 10 g / dL or more from the above effect.

  The apparatus and method of the present invention can concentrate the protein concentration up to about 5 times in a short time without an additional concentration step. The value obtained by dividing the concentrated protein concentration by the initial protein concentration is defined as the protein concentration ratio. The protein concentration ratio after the concentration reaches one fifth or less of the initial protein solution volume. When the value divided by the time (minutes) required for the above is defined as the protein concentration rate per hour, the protein concentration rate per hour is preferably 0.10 times / minute or more, preferably 0.15 times / minute. More preferably.

(Second Embodiment)
The ascites filtration and concentration apparatus 200 shown in FIG. 2 is configured to send ascites by the drop pressure of the liquid at each component. In order to perform liquid feeding using the drop pressure, in the ascites filtration and concentration apparatus 200, the drop pressure of the liquid at the inlet 3 a of the filter 3 for filtration is lower than the drop pressure of the liquid at the outlet 1 b of the storage container 1. The liquid drop pressure at the inlet 2 a of the recovery container 2 is lower than the liquid drop pressure at the concentrate outlet 4 b of the concentration filter 4. The liquid drop pressure at the ascites inlet 4 a of the concentration filter 4 is arranged to be lower than the liquid drop pressure at the filtrate outlet 3 c of the filter 3 for filtration.

  As a specific example of the above arrangement, as shown in FIG. 2, the filter 3 for filtration and the storage container 1 are arranged in a positional relationship such that the vertical position of the inlet 3a is lower than the vertical position of the outlet 1b. The The collection container 2 and the concentration filter 4 are arranged in a positional relationship such that the vertical position of the inlet 2a is lower than the vertical position of the concentrate outlet 4b. Further, the concentration filter 4 and the filtration filter 3 are arranged in such a positional relationship that the vertical position of the ascites inlet 4a is lower than the vertical position of the filtrate outlet 3c. With the arrangement as described above, liquid feeding using a drop pressure is performed in each of the flow paths 31 to 35, so that the pump 5 and the control device 41 (see FIG. 1) can be omitted. Note that the vertical position relationship of each part shown in FIG. 2 corresponds to the vertical position relation of each part of the actual ascites filtration concentrator 200 as it is. Further, in the ascites filtration and concentration apparatus 200, the same or equivalent components as those of the ascites filtration and concentration apparatus 100 described above are denoted by the same reference numerals and redundant description is omitted.

(Third embodiment)
In the ascites filtration concentrator 300 shown in FIG. 3, the liquid drop pressure at the ascites inlet 4 a of the concentration filter 4 is arranged to be equal to the liquid drop pressure at the filtrate outlet 3 c of the filter 3. Specifically, the concentration filter 4 and the filtration filter 3 are arranged in a positional relationship such that the vertical position of the ascites inlet 4a is the same height as the vertical position of the filtrate outlet 3c. The positional relationship of other parts is the same as that of the ascites filtration and concentration apparatus 200 described above. Note that the vertical position relationship of each part shown in FIG. 3 corresponds to the vertical position relation of each part of the actual ascites filtration concentrator 300 as it is. In the ascites filtration and concentration apparatus 300, the same or equivalent components as those of the ascites filtration and concentration apparatus 200 described above are denoted by the same reference numerals, and redundant description is omitted.

  According to the ascites filtration concentration apparatus 100, 200, 300 and the method for producing a high-concentration protein solution described above, the concentration filter 4 has an ultrafiltration performance that is optimal for concentrating ascites. The decrease is suppressed, and the protein can be concentrated to a high magnification without loss. Further, due to the optimum ultrafiltration performance of the concentration filter 4, the concentration rate hardly decreases. Therefore, the procedure of the practitioner can be facilitated, and the treatment can be completed in a short time, so that the patient can receive the protein solution quickly and the restraint time is short.

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

  The test method for ascites concentration performance is shown below. Bovine plasma adjusted to a total protein concentration of 3 g / dL was used as simulated ascites, and 3 L was prepared. Since bovine plasma with no cellular components is used as simulated ascites, this simulated ascites can be regarded as having passed through a filter. And the filter 3 for filtration was implemented by the method which abbreviate | omitted. That is, the performance test of each concentration filter 54 according to the example and the comparative example was performed by the test apparatus 400 shown in FIG. The test apparatus 400 has a structure in which the first flow path 31 and the second flow path 32 are directly connected to each other in the apparatus 100 shown in FIG. Polyvinyl chloride bags were used for the storage container 1 and the collection container 2, polyvinyl chloride tubes were used for the respective flow paths, roller pumps were used for the pump 5, and roller clamps were used as the control unit 15. The pump 5 was adjusted to a flow rate of 100 mL per minute, and simulated ascites was introduced into the concentration filter 54.

  Regarding the concentration target, in order to obtain a protein concentration of about 15 g / dL as a concentrated protein solution, it was aimed to concentrate until the protein concentration of the concentrated protein solution was about 5 times the protein concentration of the liquid to be treated. In order to concentrate the protein concentration to about 5 times, the amount of the concentrated protein solution was adjusted to be 1/5 or less of the amount of the liquid to be treated. Specifically, the flow rate of the waste liquid discharged from the filtrate outlet 4 c of the concentration filter 54 and the amount of inflow into the collection container 2 installed above the concentration filter 54 are compressed by the flow path 35 of the roller clamp 15. While adjusting according to the degree, the simulated ascites was concentrated. When all the 3 L of simulated ascites were introduced into the concentration filter 54, that is, after 30 minutes, the roller pump was stopped and the amount of liquid collected in the collection container 2 was measured by gravimetric method. If it has reached 1 or less, the process is terminated. If not, the circuit and the roller pump are reassembled, and the recovery liquid in the recovery container 2 is additionally concentrated. The additional concentrated amount was calculated based on the amount of remaining waste liquid required for the amount of the concentrated protein solution to reach 1/5 or less of the liquid to be treated. The evaluation of each filter was based on whether or not additional concentration was necessary, the time required for the concentration process up to the target, and the protein concentration of the collected concentrated protein solution.

[Example 1]
18 parts by weight of a polysulfone resin (Solvay, P-1700), 5 parts by weight of polyvinylpyrrolidone (hereinafter also referred to as PVP) (N-catalyst, K-85N), N, N-dimethylacetamide (hereinafter also referred to as DMAC) A uniform film-forming stock solution consisting of 77 parts by weight was prepared. A 40% by weight aqueous solution of N, N-dimethylacetamide was extruded from the double nozzle simultaneously with the hollow inner solution, passed through a hood attached to block it from the outside, and coagulated with 50 ° C. water provided 30 cm below. It was immersed in a bath and wound up at a speed of 50 m / min. The resulting hollow fiber membrane was treated with a 20% by weight aqueous glycerin solution and then dried at 75 ° C. The hollow fiber membrane bundle was adjusted so as to have a membrane area of 1.5 m 2, loaded into a cylindrical container, and both ends were potted with a polyurethane resin to produce a polysulfone hollow fiber membrane filter. The ultrafiltration performance of this filter was 107 mL / min / 200 mmHg. When this filter was subjected to the ascites concentration performance test as the above-described concentration filter 54, it was possible to process all the simulated ascites until the liquid volume became 1/5 or less of the liquid to be treated without additional concentration. An additional concentration step was not necessary. Therefore, the concentration time is 30 minutes. The protein concentration rate per hour was 0.17 times / min. Table 1 shows the concentration of the obtained protein solution.

[Example 2]
A polysulfone hollow fiber membrane filter was produced in the same manner as in Example 1 except that the membrane area was 1.1 m2. The ultrafiltration performance of this filter was 88 mL / min / 200 mmHg. When this filter was subjected to the ascites concentration performance test as the above-described concentration filter 54, all simulated ascites were processed and the amount of recovered liquid was measured, and the liquid volume was treated without additional concentration of all simulated ascites. It was possible to process until the liquid became 1/5 or less, and an additional concentration step was unnecessary. Therefore, the concentration time is 30 minutes. The protein concentration rate per hour was 0.17 times / min. Table 1 shows the concentration of the obtained protein solution.

[Example 3]
A polysulfone hollow fiber membrane filter was produced in the same manner as in Example 1 except that the membrane area was 2.1 m 2. The ultrafiltration performance of this filter was 134 mL / min / 200 mmHg. When this filter was subjected to the ascites concentration performance test as the above-described concentration filter 54, all the simulated ascites were processed and the amount of the recovered liquid was measured. It was possible to treat the solution until it was 1/5 or less of the liquid, and an additional concentration step was unnecessary. Therefore, the concentration time is 30 minutes. The protein concentration rate per hour was 0.16 times / min. Table 1 shows the concentration of the obtained protein solution.

[Comparative Example 1]
Using an ascites concentrator manufactured by Asahi Kasei Kuraray Medical Co., Ltd. with an ultrafiltration performance of 77 mL / min / 200 mmHg, AHF-UNH (polyacrylonitrile hollow fiber, 1.1 m2), and applying the filter to the aforementioned concentration filter 54 Ascites fluid concentration performance test was conducted. When all the simulated ascites were processed and the amount of the collected liquid was measured, the amount of liquid did not reach 1/5 or less of the liquid to be treated, and an additional concentration step was necessary. The additional concentration step required 30 minutes for the liquid volume to reach 1/5 or less of the liquid to be treated, so the concentration time was 1 hour. The protein concentration rate per hour was 0.09 times / min. Table 1 shows the concentration of the obtained protein solution.

[Comparative Example 2]
A uniform spinning dope comprising 18 parts by weight of PSf (manufactured by Solvay, P-1700), 4.5 parts by weight of PVP (manufactured by Nippon Shokubai Co., Ltd., K-85N) and 77.5 parts by weight of dimethylacetamide was prepared. Simultaneously with a hollow inner solution of DMAC 57% aqueous solution, it was extruded from a double nozzle and passed through a hood attached to be cut off from the outside, immersed in a 75 ° C. coagulation bath composed of water provided 90 cm below, and 40 m / min. Winded up at speed. The obtained hollow fiber membrane was treated with a 40% by weight glycerin aqueous solution and then dried at 80 ° C.

  A hollow fiber membrane bundle was adjusted so as to have a membrane area of 2.0 m 2, loaded into a cylindrical container, and potted at both ends with a polyurethane resin to prepare a polysulfone hollow fiber membrane filter. The ultrafiltration performance of this filter was 170 mL / min / 200 mmHg. When this filter was subjected to the ascites concentration performance test as the above-described concentration filter 54, a protein solution having a volume of 1/5 of the liquid to be treated was obtained in about 30 minutes. However, the protein was not concentrated, and the protein concentration of the obtained protein solution was almost the same as that before the treatment. The protein concentration rate per hour was 0.03 times / min. Table 1 shows the concentration of the obtained protein solution.

  In Examples 1 and 2, a thick protein solution of 7 g / dL or more could be obtained without additional concentration step. On the other hand, in Comparative Example 1 using a filter with low ultrafiltration performance, an additional concentration step is required, and it takes time to concentrate. Moreover, in the comparative example 2 using the filter with very high ultrafiltration performance, protein is not concentrated and only a protein solution with a low protein concentration can be obtained.

  As described above, when the apparatus and method of the present invention are implemented, a protein solution with a high concentration can be obtained in a short time.

  DESCRIPTION OF SYMBOLS 1 ... Storage container, 1b ... Outlet (connection part of a storage container and a 1st flow path), 2 ... Recovery container, 2a ... Inlet (connection part of a collection container and a 4th flow path), 3 ... Filter for filtration, 3a: Filtration filter inlet, 3b: Filtration filter outlet, 3c: Filtrate outlet (filtration side outlet of ascites filter), 4: Concentration filter, 4a: Ascites flow inlet (ascites concentration filter inlet) 4b ... Concentrate outlet (exit of ascites concentration filter), 4c ... Filtrate outlet (filter side outlet of ascites concentration filter), 5 ... Pump (control means), 14, 15 ... Control section (control means), DESCRIPTION OF SYMBOLS 31 ... 1st flow path, 32 ... 2nd flow path, 33 ... 3rd flow path, 34 ... 4th flow path, 35 ... 5th flow path, 41 ... Control apparatus (control means), 100, 200, 300 ... Ascites filtration concentrator.

Claims (9)

A storage container for storing a collected protein solution containing cellular components;
A hollow fiber membrane type ascites filtration filter capable of separating the cellular components present in the protein solution in the storage container;
A first flow path having one end connected to the storage container and the other end connected to the inlet of the ascites filter;
A polysulfone-based hollow fiber membrane type ascites concentration filter having an ultrafiltration performance of 85 mL to 150 mL / min / 200 mmHg and provided with a hydrophilic polymer;
A second flow path connected to the filtration-side outlet of the ascites filter and the other end connected to the inlet of the ascites filter;
A third flow path connected to the outlet of the ascites filter,
A collection container for collecting the protein solution concentrated by the ascites filter,
A fourth flow path having one end connected to the outlet of the ascites concentration filter and the other end connected to the collection container;
A fifth flow path connected to the filtration side outlet of the ascites concentration filter;
Ascites filtration and concentration device. The protein solution stored in the storage container is fed to the ascites filter through the first flow path, and the filtered protein solution from which the cellular components have been removed is filtered to the ascites filter. And discharging the solution containing the cell component from the outlet of the ascites filter to the third channel, and
The filtered protein solution sent to the second flow path is sent to the ascites concentration filter, and the concentrated concentrated protein solution is sent from the outlet of the ascites concentration filter to the fourth flow path. Discharging the aqueous solution from the filtration side outlet of the ascites concentration filter to the fifth flow path;
Collecting the concentrated protein solution delivered to the fourth flow path in the collection container;
The ascites filtration concentrating device according to claim 1, further comprising control means for controlling a flow rate of at least one of the first to fifth channels.   The ascites filtration and concentration apparatus according to claim 2, wherein the control means includes a liquid feed pump provided in the first flow path. The ascites filter is disposed at a position such that the drop pressure of the liquid at the inlet of the ascites filter is lower than the drop pressure of the liquid at the connection between the storage container and the first flow path. And,
The recovery container is disposed at a position such that a liquid drop pressure at a connection portion between the recovery container and the fourth flow path is lower than a liquid drop pressure at an outlet of the ascites concentration filter. Item 2. The ascites filtration concentration device according to Item 1.   5. The ascites concentration filter is disposed at a position such that a drop pressure of liquid at an inlet of the ascites filter is equal to a drop pressure of liquid at a filtration side outlet of the ascites filter. Ascites filtration concentrator.   The ascites concentration filter is disposed at a position such that a drop pressure of liquid at an inlet of the ascites filter is lower than a drop pressure of liquid at a filtration side outlet of the ascites filter. The ascites filtration and concentration apparatus described.   Since the ultrafiltration performance of the ascites concentration filter is optimal for ascites concentration treatment, ascites need only be concentrated once, and no additional concentration step is required. The ascites filtration concentrating device according to any one of 6.   The ascites filtration concentrating device according to any one of claims 1 to 7, wherein the concentration of the protein can be concentrated five times or more by one concentration by the ascites concentration filter.   The ascites filtration and concentration apparatus according to any one of claims 1 to 8, wherein a concentrated protein solution having a protein concentration of 7 g / dl or more can be obtained by one concentration by the ascites concentration filter.

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