JP6584221B2 - Medical materials - Google Patents

Description

  The present invention relates to a medical member, and more particularly, to a medical member suitable for use in a body cavity fluid such as ascites, pleural effusion, and pericardial fluid, and other body fluid filtration systems and body fluid filtration methods.

  For example, as a treatment method for intractable ascites, ascites is collected from a patient, the ascites is filtered to remove pathogenic substances such as cancer cells and bacteria, and then a filtrate containing a useful substance of protein such as albumin Then, ascites filtration concentrated reinfusion therapy (CART) is used for reinjecting the concentrate into the body.

  For such treatment, an ascites treatment system is usually used. As a typical example, the ascites treatment system includes an ascites bag, a filter, a concentrator, and a concentrated ascites bag in this order in series. It has a connected liquid circuit.

  By the way, in the filter of the ascites treatment system, hollow fiber membrane bundles as filtration membranes are arranged inside the cylindrical container, and both ends of the hollow fiber membrane bundle are potted by potting material at both ends of the cylindrical container. Processed to form an open end face. Conventionally, this filter is generally used in an internal pressure system in which ascites is flowed from the inside to the outside of the hollow fiber membrane to perform filtration, but recently, the reverse method, that is, ascites is used in the hollow fiber membrane. It has been proposed to use an external pressure method in which filtration is performed by flowing from the outside to the inside (see Patent Documents 1 and 2).

Ascites contains a relatively large substance such as cancer cells and has a very high viscosity. Even when the filter is used for a short time, the hollow fiber membrane is easily clogged. Therefore, if filtration is performed by flowing ascites from the outside to the inside of the hollow fiber membrane having a relatively large surface area using the external pressure method, clogging of the hollow fiber membrane is alleviated and the lifetime of the filter is extended. It is reported that it can be done.
However, when filtered by the external pressure method, the hollow fiber membranes located on the center side (in the bundle) of the hollow fiber membrane bundle are densely packed together and covered with the hollow fiber membranes located on the outer peripheral side (outside the bundle) of the bundle. Therefore, when the viscosity is high like ascites, ascites does not reach the hollow fiber membrane at the center of the bundle, resulting in a decrease in filtration capacity.

  Furthermore, in order not to remove the cause of the clogging of the filtration membrane, it is not possible to treat as much as possible even if ascites is introduced from the inside of the hollow fiber or from the outside, causing clogging on the way. Absent.

  The cause of the clogging is thought to be cancer cells contained in ascites, one of which is known. As a cancer cell adsorbing material, a specific polymer hydrate is known. (Patent Document 3)

JP 2009-297242 A JP 2011-172797 A JP 2012-105579 A

  Thus, in the filtration method of body fluid containing cancer cells such as ascites filtration concentration therapy (CART), cancer cells are selectively removed while leaving useful protein in the protein solution (body fluid before treatment). Therefore, it is a problem to effectively prevent clogging of the filter for filtration.

  The present invention has been made in view of such points, and specifically, a medical member coated with a specific cancer cell selective adhesive polymer, specifically a bag for storing body fluid or a filter for filtering body fluid. For example, the surface (inner surface, surface in contact with body fluid) coated with a specific cancer cell selective adhesion polymer is used as a flow channel to be introduced into the cell, so that at least part of the cancer cells is excluded in advance before filtration. As a result, it was found that body fluid filtration can be performed to the end without clogging the filtration filter, and the present invention has been completed.

That is, the aspect of this invention contains the following.
[1] a main body containing polyvinyl chloride;
A medical member comprising: a coating containing a polymer material having a structure represented by the general formula (1) provided on at least a part of the surface thereof.
In the formula, R ¹ is a hydrogen atom or a methyl group, R ² is a methyl group or an ethyl group, m is 1 to 3, and n represents the number of repetitions.
[2] The medical member according to [1], which is a storage container for storing a body fluid containing a cancer cell component or a flow path for flowing a body fluid containing a cancer cell component.
[3] The medical member according to [2], wherein the storage container is a bag and has a coating film including a polymer material having a structure represented by the general formula (1) on an inner surface.
[4] The medical member according to [2], wherein the flow path is a tube and has a coating film containing a polymer material having a structure represented by the general formula (1) on an inner surface.
[5] The medical member according to any one of [1] to [4], which is used in a body fluid filtering device and is installed on an inlet side of a filtering filter.
[6] In the infrared absorption curve when the total reflection infrared absorption measurement (ATR-IR) is performed, the peak intensity (P1) of the infrared absorption peak near 1735 cm ⁻¹ is the same for polyvinyl chloride under the same conditions. (P1 / P2) is 1.15 or more with respect to the peak intensity (P2) of the infrared absorption peak near 1735 cm ⁻¹ in the infrared absorption curve when reflection infrared absorption measurement (ATR-IR) is performed. ,
The medical member according to any one of [1] to [5].
[7] The medical member according to any one of [1] to [6], wherein the polymer material having the structure represented by the general formula (1) has a number average molecular weight of 8,000 to 300,000. .
[8] The medical member according to any one of [1] to [7], wherein R ^{1 in} General Formula (1) is a hydrogen atom, R ² is a methyl group, and m is 1.
[9] The medical member according to any one of [1] to [8], wherein in general formula (1), R ¹ is a hydrogen atom, R ² is an ethyl group, and m is 2.
[10] The medical member according to any one of [1] to [9], wherein R ^{1 in} general formula (1) is a methyl group, R ² is a methyl group, and m is 2.
[11] The medical use according to any one of [1] to [9], wherein R ^{1 in} general formula (1) is a methyl group, R ² is an ethyl group, and m is 2. Element.
[12] A method for producing a medical member having a main body containing polyvinyl chloride and a coating containing a polymer material having a structure represented by the general formula (1) provided on at least a part of the surface of the main body. ,
A method for producing a medical member, comprising a step of bringing a coating liquid containing a polymer material having a structure represented by the general formula (1) into contact with at least a part of a surface of a main body containing the polyvinyl chloride.
In the formula, R ¹ is a hydrogen atom or a methyl group, R ² is a methyl group or an ethyl group, m is 1 to 3, and n represents the number of repetitions.
[13] The method for producing a medical member according to [12], wherein the coating liquid contains water and an organic solvent, and the organic solvent is ethanol, methanol, or a mixture thereof.
[14] A storage container for storing body fluid;
A filter for filtration capable of separating cancer cells present in the body fluid;
A first flow path having one end connected to the storage container and the other end connected to the inlet of the filtration filter;
A body fluid filtration device comprising: a collection container for collecting the solution filtered by the filtration filter,
The body fluid filtering device, wherein the storage container and / or the first flow path has a coating containing a polymer material having a structure represented by the following general formula (1) on at least a part of the inner surface. .
In the formula, R ¹ is a hydrogen atom or a methyl group, R ² is a methyl group or an ethyl group, m is 1 to 3, and n represents the number of repetitions.

  According to the present invention, in a body fluid filtration method such as ascites filtration concentration therapy (CART), a cancer filter is selectively removed while leaving a useful protein in a protein solution (body fluid before treatment), and a filter for filtration. Can effectively prevent clogging.

It is explanatory drawing which shows the outline of a structure of an ascites processing system. It is explanatory drawing of the longitudinal cross-section of the filter for filtration. It is explanatory drawing which shows the cross section of a cylindrical container. It is explanatory drawing which shows the distance between hollow fiber membranes. It is explanatory drawing which shows the diameter of a hollow fiber membrane. It is explanatory drawing for demonstrating the crimp shape of a hollow fiber membrane. It is explanatory drawing which shows the ascites processing system of an Example. ATR analysis diagram of polyvinyl chloride surface and PVCA coated with PMEA It is a photograph which shows the adhesion state of a cancer cell.

Hereinafter, modes for carrying out the present invention (hereinafter referred to as “the present embodiment”) will be described.
Note that the positional relationship such as up, down, left, and right of the drawing is based on the positional relationship shown in the drawing unless otherwise specified. The dimensional ratios in the drawings are not limited to the illustrated ratios.
Further, the following embodiments are examples for explaining the present invention, and are not intended to limit the present invention only to the embodiments. The present invention can be variously modified without departing from the gist thereof.

The medical member of the present embodiment includes a main body containing polyvinyl chloride, and a polymer material having a structure represented by the following general formula (1) on at least a part of the surface thereof (hereinafter simply referred to as “general formula ( 1) a polymer material ").

In the formula, R ¹ is a hydrogen atom or a methyl group, R ² is a methyl group or an ethyl group, m is 1 to 3, and n represents the number of repetitions. When R ² is a methyl group, m is preferably 1 or 2. When R ² is an ethyl group, m is preferably 2.

Although the polymer material of the general formula (1) is known as a blood compatible material, according to the study by the present inventors, it has been found that the polymer material also has a property of adsorbing cancer cells. Moreover, it has also been found that the polymer material of the general formula (1) can be firmly fixed on a substrate containing polyvinyl chloride. Therefore, the film containing the polymer material of the general formula (1) can be stably provided on various medical members containing polyvinyl chloride.
The reason why the polymer material of the general formula (1) is firmly fixed on the base material containing polyvinyl chloride is not clear, but some interaction (for example, entanglement between molecules or This is presumably due to the anchor effect with the surface of the polyvinyl chloride.

Furthermore, according to the study by the present inventors, the polymer material of the general formula (1) selectively adsorbs cancer cells, and other proteins (for example, useful proteins such as albumin) and other components are hardly present. It was also found that it did not adsorb.
Therefore, if the medical member of this embodiment is used, only unnecessary cancer cells can be selectively adsorbed and removed without affecting useful proteins.
Polyvinyl chloride, which is a general medical material, also has some ability to adsorb cancer cells. However, since there is no selectivity for the adsorption target, not only cancer cells but also useful proteins and other components contained in body fluids are adsorbed. Therefore, even if it can adsorb | suck with respect to a cancer cell, it is thought that many cancer cells cannot be adsorbed.

  In the present embodiment, the number average molecular weight of the polymer material of the general formula (1) is preferably 8,000 to 300,000. When the number average molecular weight is less than 8,000, the interaction with the polyvinyl chloride surface is not sufficient, and the polymer material of the general formula (1) tends to be eluted from the substrate surface. When the average molecular weight is greater than 300,000, it tends to be easy to handle (adhesiveness, hardness, etc.) and poor solubility in a solvent when preparing a coating solution. The number average molecular weight is more preferably 10,000 to 250,000. The number average molecular weight of the polymer material of the general formula (1) can be measured by, for example, gel permeation chromatography (GPC).

  In the present embodiment, the medical member includes various members used in a filtering device for filtering a body fluid containing cancer cells such as ascites, and particularly on the inlet side (upstream from the inlet) of the filtering filter. Suitable for the medical member used. Specifically, a storage container (bag) for storing body fluid before processing, a flow path (tube) for flowing body fluid to a filter for filtration, and the like can be given.

The body of the medical member includes polyvinyl chloride. Thereby, the film containing the polymer material of the general formula (1) is firmly fixed and a soft property is realized.
Here, polyvinyl chloride refers to a polymer containing units derived from vinyl chloride, may be a homopolymer of vinyl chloride, or a copolymer of vinyl chloride and other monomer components. There may be. The unit derived from vinyl chloride is preferably contained in an amount of 50% by mass or more, more preferably 60% by mass or more, and further preferably 70% by mass or more.

The amount of the polymer material of the general formula (1) to be present on the surface of the medical member is not limited, but the higher the amount, the higher the ability of the medical member to adsorb cancer cells. Therefore, in the infrared absorption curve when the total reflection infrared absorption measurement (ATR-IR) is performed, the peak intensity (P1) of the infrared absorption peak near 1735 cm ⁻¹ is the total reflection under the same conditions for polyvinyl chloride. It is 1.15 or more with respect to the peak intensity (P2) of the infrared absorption peak near 1735 cm ⁻¹ in the infrared absorption curve when infrared absorption measurement (ATR-IR) is performed. Is preferred.

  The coating containing the polymer material of the general formula (1) may be provided on at least a part of the surface of the medical member (specifically, the surface that comes into contact with the body fluid). The coating containing the polymer material of the general formula (1) is preferably provided on the entire surface in contact with the body fluid of the medical member, but on the other hand, it may be difficult to form as a continuous film. Therefore, the coating containing the polymer material of the general formula (1) is preferably provided over at least the entire surface of the medical member in contact with the body fluid (in the case of a storage container or a channel, the inner surface).

  In this embodiment, there is no limitation on the method of providing a film containing the polymer material of the general formula (1) on the surface of the medical member main body. For example, a coating solution containing the polymer material of the general formula (1) is used. A method of coating the medical member body is preferably used.

The solvent of the coating solution is not particularly limited as long as it is a solvent that does not dissolve polyvinyl chloride and can dissolve or disperse the polymer material of the general formula (1). From the viewpoint of process safety and good handling in the subsequent drying process, water or an aqueous alcohol solution is preferable. From the viewpoint of boiling point and toxicity, water, an aqueous ethanol solution, an aqueous methanol solution, an aqueous isopropyl alcohol solution, and the like can be suitably used, and an aqueous ethanol solution, an aqueous methanol solution, and an ethanol / methanol mixed aqueous solution are particularly preferable.
When the solvent of the coating solution is a mixed solvent of water and an organic solvent, the mixing ratio of the organic solvent depends on the type of the polymer material of the general formula (1), but the polymer material of the general formula (1) It is preferably 80% by mass or less, more preferably 60% by mass or less, and preferably 40% by mass or less as long as it dissolves.

  Although there is no limitation in the density | concentration of the polymeric material of General formula (1) of a coating liquid, For example, it can be set as 0.001 mass%-1 mass% of a coating liquid, and 0.005 mass%-0.3 mass. % Is more preferable.

Although there is no limitation on the method of coating the medical member main body with the coating liquid containing the polymer material of the general formula (1), for example, the coating liquid is applied to the main body (storage container (bag), flow path (tube), etc.). It can be coated by passing the liquid (holding as necessary) and bringing the coating liquid into contact with the surface (inner surface).
Drying is preferably performed after coating, and the drying method is not limited. However, drying may be performed under reduced pressure until a constant weight is reached, or heat drying may be performed. The heat drying temperature may be set as appropriate in consideration of the process time as long as the temperature does not deteriorate the module members.

  Next, a bodily fluid filtration device provided with the medical member of the present embodiment will be described using an ascites treatment system 1 shown in FIG. 1 as an example.

  As shown in FIG. 1, the ascites treatment system 1 includes an ascites treatment circuit 10. The ascites treatment circuit 10 connects the ascites bag 20 as a body fluid reservoir, a filter 21 for filtration, a concentrator 22, a concentrated ascites bag 23 as a concentrate reservoir, the ascites bag 20 and the filter 21 for filtration. It has the 1st flow path 24, the 2nd flow path 25 which connects the filter 21 for filtration, and the concentrator 22, and the 3rd flow path 26 which connects the concentrator 22 and the concentrated ascites bag 23. .

  The ascites bag 20 is a container made of a soft resin such as polyvinyl chloride, and can store ascites collected from a patient.

  The first flow path 24 is a soft tube such as polyvinyl chloride, for example, and is connected from the outlet of the ascites bag 20 to a port 45 on the side surface portion to be described later of the filter 21 for filtration. For example, a tube pump 30 is provided in the first flow path 24, and the ascites in the ascites bag 20 can be sent to the filter 21 for filtration. In addition, you may make it supply the ascites of the ascites bag 20 to the filter 21 for filtration by gravity dropping, without providing the tube pump 30. FIG.

  The filter 21 for filtration has a cylindrical container 40, and inside the cylindrical container 40, a hollow fiber membrane bundle (a bundle of hollow fiber membranes 41) 42 is disposed along the longitudinal direction thereof. The hollow fiber membrane 41 can remove predetermined pathogenic substances such as cancer cells and bacteria from the ascites, and allow other components containing useful substances such as albumin to pass therethrough. Ports 43 and 44 leading to the inner side (space) of the hollow fiber membrane 41 are provided in the upper and lower portions of the cylindrical container 40, and the outer side (space) of the hollow fiber membrane 41 is provided on the side surface of the cylindrical container 40. Two ports 45 and 46 are provided. A port 45 on the side surface of the filtration filter 21 communicates with the ascites bag 20. The port 46 on the side surface of the filtration filter 21 communicates with a drainage unit (not shown) from which components that do not pass through the hollow fiber membrane 41 are drained. An upper port 43 of the filtration filter 21 communicates with a concentrator 22 described later, and a lower port 44 of the filtration filter 21 is closed, for example. Details of the content configuration of the cylindrical container 40 of the filter 21 for filtration will be described later.

  The second flow path 25 is a soft tube such as polyvinyl chloride, and is connected to the port 63 of the concentrator 22 from the port 43 at the top of the filter 21 for filtration. For example, a tube pump 50 is provided in the second flow path 25, and the filtrate filtered by the filter 21 for filtration can be sent to the concentrator 22.

  The concentrator 22 has a cylindrical container 60, similar to the filtration filter 21, and a hollow fiber membrane bundle (hollow fiber membrane 61) as a concentrated membrane along the longitudinal direction inside the cylindrical container 60. 62) is arranged. The hollow fiber membrane 61 can remove moisture by allowing moisture in the filtrate to pass therethrough and concentrate the filtrate. Ports 63 and 64 that communicate with the inner space of the hollow fiber membrane 61 are provided at the upper and lower portions of the cylindrical container 60, and two ports that communicate with the outer space of the hollow fiber membrane 61 are provided on the side surface of the cylindrical container 60. 65 and 66 are provided. The upper port 63 of the concentrator 22 communicates with the port 43 of the filtration filter 21, and the lower port 64 of the concentrator 22 communicates with the concentrated ascites bag 23. One port 65 on the side surface of the concentrator 22 communicates with a drainage part from which water discharged from the filtrate is drained, and the port 66 is closed. The concentrator 22 uses an internal pressure method in the system of FIG. 1, but may use an external pressure method.

  The third flow path 26 is a flexible tube such as polyvinyl chloride, for example, and is connected to the concentrated ascites bag 23 from the port 64 at the lower part of the concentrator 22.

  The concentrated ascites bag 23 is a container made of a soft resin such as polyvinyl chloride, and can contain a concentrated liquid containing useful substances concentrated by the concentrator 22.

  Next, the internal configuration of the cylindrical container 40 of the filter 21 for filtration will be described. FIG. 2 is an explanatory view of a longitudinal section showing an outline of the configuration of the filter 21 for filtration.

  The filter 21 for filtration has the cylindrical container 40 as mentioned above, and the hollow fiber membrane bundle 42 is arrange | positioned along the longitudinal direction inside the cylindrical container 40. As shown in FIG. The cylindrical container 40 includes a cylindrical container body 40a and a header 40b that closes both end openings of the container body 40a. The ports 43 and 44 are formed in the header 40b, and the ports 45 and 46 are formed in the container body 40a.

Both ends of the hollow fiber membrane bundle 42 are potted with a potting material 70 of a curable resin at both ends of the cylindrical container 40. Thereby, the both ends of the hollow fiber membrane bundle 42 are fixed to the cylindrical container 40, and the open end surfaces 71 in which the inner sides of the hollow fiber membranes 41 of the hollow fiber membrane bundle 42 are opened at both ends of the cylindrical container 40. Is formed. The outer space of the hollow fiber membrane 41 inside the cylindrical container 40 communicates with the port 45 on the side surface of the cylindrical container 40. The inner space of the hollow fiber membrane 41 communicates with the port 43 through the open end surface 71. With this configuration, ascites flows into the outer space of the hollow fiber membrane 41 from the port 45, flows into the inner space of the hollow fiber membrane 41 through the hollow fiber membrane 41, and the pathogenic substance can be filtered and removed from the ascites. The filtrate flowing into the inner space of the hollow fiber membrane 41 can be discharged from the port 43 through the open end surface 71.

It is desirable that the hollow fiber membranes 41 are dispersed and arranged so that the filling rate J of the hollow fiber membrane bundle 42 is preferably 10% or more and 68% or less in the inner cross section of the cylindrical container 40. As shown in FIG. 3, the filling rate J of the hollow fiber membrane bundle 42 is S (when the inner cross-sectional area of the container body 40a is the inner diameter K of the container body 40a, S = (K / 2) ² × π) When the cross-sectional area s of one hollow fiber membrane 41 and the total number of hollow fiber membrane bundles 42 are N, the following equation (1) is obtained.
Filling ratio of hollow fiber membrane bundle 42 J = s × N / S × 100 (%) (Equation 1)
In addition, the cross-sectional area S of the container trunk | drum 40a is taken as the area of the minimum part, when changing along the longitudinal direction of the container trunk | drum 40a.

  The hollow fiber membranes 41 are distributed and arranged so as not to be dense with each other. Here, “dispersed and arranged” means that the hollow fiber membranes are treated so that the hollow fiber membranes are arranged substantially uniformly in a certain range, for example, by blowing air so that the hollow fiber membranes do not adhere to each other. That means. Specifically, in the hollow fiber membrane bundle 42, the distances from the nearest four hollow fiber membranes to any hollow fiber membrane 41 are D1, D2, D3, and D4 (shown in FIG. 4). The maximum value when measured with respect to five hollow fiber membranes is defined as the maximum distance between the hollow fiber membranes. In this embodiment of the present invention, the maximum distance between the hollow fiber membranes is 300 μm or more. preferable. Similarly, when the average of all the hollow fiber membranes D1 to D4 is defined as the average distance between the hollow fiber membranes, in this embodiment of the present invention, the average distance between the hollow fiber membranes is 150 μm or more. Thus, the hollow fiber membrane 41 is preferably dispersed. The preferable values of “maximum hollow fiber membrane distance” and “average hollow fiber membrane distance” described here are regions indicated by a circle having a radius of 5 mm centered on at least the center point of the inner cross section of the container. It is preferable to hold for hollow fiber membranes existing inside, and it is preferable to hold for all hollow fiber membranes when the radius of the inner cross section of the container is 5 mm or less.

  Furthermore, the distance L between the two open end faces 71 of the hollow fiber membrane bundle 42 shown in FIG. 2 is preferably set to 50 mm or more and 240 mm or less, more preferably 100 mm or more and 240 mm or less, and further preferably 150 mm or more and 240 mm or less. If the distance L is smaller than 50 mm, the number N of the hollow fiber membranes 41 is increased when the membrane area is designed to be equal, and ascites does not reach the bundle, which is not preferable. If the distance L is larger than 240 mm, the flow path of the entire module is narrowed, so that when the ascites entering from the port 45 is clogged somewhere until it exits from the port 43, the pressure easily rises. Therefore, it is not preferable.

The effective membrane area of the hollow fiber membrane bundle 42 (inner circumference of the hollow fiber membrane 41 (inner diameter d of the hollow fiber membrane 41 (shown in FIG. 4) × π) × distance L between opening end faces × number N of hollow fiber membranes) is: preferably 0.7 m ² or more 3.0 m ² or less, and more preferably is set to 1.0 m ² or more 2.5 m ^2. In addition, when the effective membrane area of the hollow fiber membrane bundle 42 is smaller than 0.7 m ² , the filtration ability of the entire filter is lowered, which is not preferable. When the effective membrane area of the hollow fiber membrane bundle 42 is larger than 3.0 m ² , the loss increases when treating a small amount of ascites, which is not preferable.

  The inner diameter d of the hollow fiber membrane 41 is set to, for example, 50 μm or more and 500 μm or less, preferably 100 μm or more and 450 μm or less. In addition, it is not preferable that the inner diameter d is smaller than 50 μm because clogging easily occurs when proteins or the like are deposited inside the hollow fiber membrane. On the other hand, when the inner diameter d is larger than 500 μm, the yield at the time of producing the hollow fiber is remarkably lowered.

  The number N of the hollow fiber membranes 41 is, for example, 2000 or more and 10,000 or less, preferably 3000 or more and 9000 or less. The diameter of the hole of the hollow fiber membrane 41 is, for example, 0.010 μm or more and 10 μm or less, preferably 0.05 μm or more and 5 μm or less. The outer diameter of the hollow fiber membrane 41 is, for example, 200 μm or more and 600 μm or less, preferably 300 μm or more and 500 μm or less. In addition, when the number N of the hollow fiber membranes 41 is less than 2000, it is not preferable because the filtering ability of the entire module is lowered. If the number N is larger than 10,000, the filling rate increases and clogging is likely to occur. Moreover, since it becomes easy to clog when the diameter of the hole of the hollow fiber membrane 41 is smaller than 0.010 micrometer, it is unpreferable. If the diameter of the hole of the hollow fiber membrane 41 is larger than 10 μm, it is not preferable because most of the cancer cells and bacteria cannot be filtered.

  Next, ascites treatment performed in the ascites treatment system 1 will be described.

  First, an ascites bag 20 containing ascites collected from a patient is connected to the first flow path 24. Next, the tube pumps 30 and 50 are driven, and the ascites in the ascites bag 20 is supplied to the outer space of the hollow fiber membrane 41 of the cylindrical container 40 from the port 45 of the filtration filter 21 through the first flow path 24. Is done. Ascites flows into the inner space from the outer space of the hollow fiber membrane 41 through the hole of the hollow fiber membrane 41, and at this time, predetermined pathogenic substances such as cancer cells and bacteria are removed and filtered. The filtrate that has passed through the hollow fiber membrane 41 flows out from the port 43 to the second flow path 25, passes through the second flow path 25, and flows into the inner space of the hollow fiber membrane 61 from the port 63 of the concentrator 22. . In the concentrator 22, the filtrate passes through the inner space of the hollow fiber membrane 61, moisture in the filtrate is discharged to the outer space of the hollow fiber membrane 61 through the hollow fiber membrane 61 of the concentrate membrane, and the filtrate is concentrated. . The concentrated liquid containing a useful substance such as albumin concentrated by the concentrator 22 is discharged from the port 64 to the third flow path 26, and sent to the concentrated ascites bag 23 through the third flow path 26 to be stored. Thus, when all the ascites in the ascites bag 20 is filtered and concentrated, the ascites treatment is completed. Thereafter, the concentrated solution in the concentrated ascites bag 23 is reinjected into the patient.

  In the present embodiment, the hollow fiber membranes 41 of the filtration filter 21 are dispersed and arranged so that the filling rate J of the hollow fiber membrane bundles 42 is 10% or more and 68% or less in the inner cross section of the cylindrical container 40. ing.

  In this embodiment, the hollow fiber membrane 41 of the filter for filtration 21 may have a crimp shape. That is, the hollow fiber membrane 41 may be curved in a wave shape as shown in FIG. The amplitude of the crimp is preferably 0.2 mm to 1.2 mm and the wavelength is 3.0 mm to 16 mm. In such a case, a gap is easily formed between the hollow fiber membranes 41, and ascites easily enters the center of the hollow fiber membrane bundle 42. In addition, it is preferable that the crimp amplitude and wavelength are irregular in the filter for filtration 21 because ascites easily enters the center of the hollow fiber membrane bundle.

  As mentioned above, although an example of the bodily fluid filtration apparatus of this embodiment was demonstrated referring an accompanying drawing, this invention is not limited to this example. It is obvious for those skilled in the art that various modifications or modifications can be conceived within the scope of the idea described in the claims, and these naturally belong to the technical scope of the present invention. It is understood.

  For example, the configuration of the cylindrical container 40 is not limited to this and may have other configurations. The configurations of the ascites treatment system 1 and the ascites treatment circuit 10 are not limited to this, and may have other configurations. The filtration device of the present invention can also be applied to a pleural effusion treatment system that treats body cavity fluid other than ascites, such as pleural effusion. In addition, this pleural effusion processing system may have the same structure as the above ascites processing system, and may have a different structure.

  In the following examples, experimental results are shown in which the filtering device using the medical member of the present embodiment has been verified for clogging relief and filtration capacity maintenance.

[Preparation of polymer material of general formula (1)]
(1) Preparation of PMEA (Polymethoxyethyl Acrylate) 75 g of 2-methoxyethyl acrylate in 60 g of 1,4-dioxane with azobisisobutyronitrile (0.1 wt%) as an initiator while bubbling nitrogen Polymerization was carried out at 10 ° C. for 10 hours. After completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and to be isolated. The obtained product was dissolved in tetrahydrofuran and further purified twice using n-hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent syrupy polymer was obtained. The yield (yield) was 12.3 g (82.0%).
It was confirmed by 1H-NMR that the obtained polymer structure was PMEA.
From the results of GPC molecular weight analysis, the number average molecular weight (Mn) was 20,000, and the molecular weight distribution (Mw / Mn) was 2.4.

(2) Preparation of PEt2A (poly [2- (2-ethoxyethoxy) ethyl acrylate]) 15 g of 2- (2-ethoxyethoxy) ethyl acrylate was added in 60 g of 1,4-dioxane (azobisisobutyronitrile (0. The polymerization was carried out at 75 ° C. for 10 hours with nitrogen bubbling using 1 wt%) as an initiator. After completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and to be isolated. The obtained product was dissolved in tetrahydrofuran and further purified twice using n-hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent syrupy polymer was obtained. The yield (yield) was 12.0 g (80.0%).
It was confirmed by 1H-NMR that the obtained polymer structure was PEt2A.
From the results of GPC molecular weight analysis, the number average molecular weight (Mn) was 11,600, and the molecular weight distribution (Mw / Mn) was 3.9.

(3) Preparation of PMe2MA (poly [2- (2-methoxyethoxy) ethyl methacrylate]) 10 g of 2- (2-methoxyethoxy) ethyl methacrylate was added in 50 g of 1,4-dioxane with azobisisobutyronitrile (0. Polymerization was carried out at 80 ° C. for 8 hours with nitrogen bubbling using 1 wt%) as an initiator. After completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and to be isolated. The obtained product was dissolved in tetrahydrofuran and further purified twice using n-hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent syrupy polymer was obtained. The yield (yield) was 8.2 g (82.0%).
It was confirmed by 1H-NMR that the obtained polymer structure was PMe2MA.
From the results of GPC molecular weight analysis, the number average molecular weight (Mn) was 104,300, and the molecular weight distribution (Mw / Mn) was 4.6.

(4) Preparation of PEt2MA (poly [2- (2-ethoxyethoxy) ethyl methacrylate]) 15 g of 2- (2-ethoxyethoxy) ethyl methacrylate was added to azobisisobutyronitrile (0. 1% by weight) was used as an initiator, and polymerization was carried out at 75 ° C. for 2 hours with nitrogen bubbling. After completion of the polymerization reaction, the obtained polymerization solution was added dropwise to n-hexane to precipitate the product and to be isolated. The obtained product was dissolved in tetrahydrofuran and further purified twice using n-hexane. The purified product was dried under reduced pressure overnight. A colorless and transparent syrupy polymer was obtained. The yield (yield) was 5.2 g (34.7%).
It was confirmed by 1H-NMR that the obtained polymer structure was PEt2MA.
From the results of GPC molecular weight analysis, the number average molecular weight (Mn) was 142,500, and the molecular weight distribution (Mw / Mn) was 6.1.

[Measurement of surface abundance ratio of polymer material of general formula (1) by infrared ATR (total reflection method)]
The sample measurement procedure was as follows.
Prepare a polyvinyl chloride base material (circuit for ascites filtration concentration reinjection type Model AF-CART release source Asahi Kasei Medical) alone and a sample coated with the polymer material of general formula (1) on the polyvinyl chloride base material. The surface was washed with distilled water, vacuum-dried at 37 ° C. for 2 hours, and left at room temperature, and the measurement surface was faced upward, and prisms were pressed at any of the five locations to perform infrared ATR measurement ( 1690cm ^-1 ~1770cm ^-1). The prism used was ATR-30-Z (ZnSe, refractive index 2.4) manufactured by JASCO Corporation, and the incident angle was 60 degrees.
Since both the ester group —O—C═O of the polymer material having the structure represented by the general formula (1) and polyvinyl chloride as the base material have an infrared absorption peak near 1735 cm ⁻¹ , formula vinyl substrate (1) samples and poly vinyl chloride base single 1735 cm ^-1 infrared peak intensity area of the absorption peak (both 1690 cm ^-1 and 1770 cm ^-1 baseline where the polymeric material is applied in The peak areas were defined as P1 and P2, respectively, and the abundance of the polymer material of the general formula (1) on the surface of the separation membrane was measured from the average value of the ratios of P1 / P2.

[Preparation of filter for filtration]
Pellets of high-density polyethylene (trade name Suntec HDJ240, manufactured by Asahi Kasei Chemicals Corporation) are heated at 147 ° C. and extruded with a pump. Nitrogen is ventilated at a flow rate of 22 mL / min, and then cooled. A raw yarn was obtained. Then, the hollow fiber membrane bundle intermediate product which has micropores was obtained by winding after extending | stretching at the temperature of 70 to 120 degreeC, and the roll speed of 5-30 m / min, and cut | disconnecting to 330 mm. Further, this hollow fiber membrane bundle intermediate product is immersed in an EVAL coating solution (trade name: Soreserin Nippon Synthetic Chemical Co., Ltd.) dissolved in 58% 1-propanol aqueous solution for 1 hour and then dried at 60 ° C. Thus, a hollow fiber membrane bundle was obtained. The hollow fiber membrane had an inner diameter of 280 μm, a film thickness of 50 μm, an outer diameter of 380 μm, and a hole diameter of 0.2 μm. The obtained hollow fiber membrane bundle is loaded into a cylindrical container made of polycarbonate (inner diameter of container body 50.5 mm), both ends are potted with polyurethane resin, and then sterilized with a dose of 25 kGy for filtration. A filter was obtained.

[Cancer cell adhesion test]
(1) Cancer cell culture cells: Resource No. JCRB9113HT1080 cells obtained from the Human Science Research Resource Bank.
Medium: DMEM / F12 (1: 1) (GIBCO) + 10% fetal bovine serum (FBS) (Equitech-Bio, Inc.) + 1% Penicillin-Streptomycin (GIBCO) incubator (SANYO, MYO) 19AIC (UV)) [37 ° C, CO2 concentration 5%, humidity 100%]
The culture was performed under the conditions described above, and the medium was changed every two days.
(2) Preparation of sample ・ Polyvinyl chloride base material: Polyvinyl chloride base material (circuit for ascites filtration concentration re-injection circuit Model AF-CART release source Asahi Kasei Medical) was washed with distilled water and vacuum-dried at 37 ° C for 2 hours Then, what was left at room temperature was prepared.
A sample in which a polymer material of the general formula (1) is applied to a polyvinyl chloride base material: The base material is placed in a solution in which 2000 ppm of PMEA is dissolved in an ethanol / water 40/60 (Wt%) solution for 1 minute. It was immersed, pulled up, immediately washed with distilled water, vacuum dried at 37 ° C. for 2 hours, and then allowed to stand at room temperature.
An infrared ATR (total reflection method) analysis was performed on each of the substrates to obtain an area ratio P1 / P2.
(3) Cancer cell adhesion test HT1080 cells that became sub-confluent were seeded on the surface of each sample. The seeding density was 1 × 10 ⁴ / cm ² , the cells were fixed with 1% glutaraldehyde (PBS) for 1 hour in culture, fixed at 37 ° C. for 2 hours, and then PBS for 10 minutes, DW: PBS = 1: Replacement was performed at 18 minutes and DW 8 minutes × 2 times. After drying, sputtering with platinum palladium was performed, and SEM (Scanning Electron Microscope) was observed to visually count the number of cancer cell adhesion on the surface (each n = 3).
The results are shown in the table below.

  It was confirmed that the sample in which the polymer material of the general formula (1) was applied to the polyvinyl chloride base material had a larger number of cancer cells attached than the base material alone. Thereby, it has confirmed that the polymeric material of General formula (1) had cancer cell adhesion ability.

[Time required for clogging]
(Preparation of pseudocancerous ascites)
Pseudocancerous ascites was prepared by adding cancer cells cultured in the same manner as described above to 3.0 L of bovine plasma (pseudoascites) adjusted to an albumin concentration of 3 g / dL. Specifically, it was prepared by the following procedure.
1. The dish in which HT1080 cells are cultured is taken out from the 37 ° C. incubator, and the medium is sucked up with an aspirator.
2. Add PBS to the dish, and then suck with an aspirator.
3. Add trypsin / EDTA solution, cover the dish and tap from the side to detach the cells.
4. Under a microscope, confirm that the cells have peeled off, add a medium to stop the action of trypsin, and pipet the cells peeled off in clumps into single cells.
5. Put the liquid in a centrifuge tube and centrifuge.
6. After centrifugation, the supernatant of the centrifuge tube is discarded and separated from the outside of the centrifuge tube so as to loosen the cell mass.
7. Add 5 mL of simulated ascites and pipette with pipette to make a uniform cell suspension.
In order to measure the number of cells in the cell suspension prepared in Steps 8 and 7 and adjust the number of cells, the total amount or the necessary amount is suspended in a suitable amount of simulated ascites, and approximately 2 million cells are present. Create 3 L of cancerous ascites.
(Evaluation criteria)
When the pressure of the pressure gauge C reached 500 mmHg during the filtration and concentration treatment, it was judged as “clogged”, and the time from the start of treatment to clogging was judged as follows.
Time to clogging is 15 minutes or more: ○ Time to clogging is less than 15 minutes: ×

(Measurement of maximum distance between hollow fiber membranes and average distance between hollow fiber membranes)
The potting surface is visually observed with an optical microscope (trade name: IX70, manufactured by Olympus Co., Ltd.), and the images taken so that the field of view is 10 mm × 10 mm are used, and between the maximum hollow fiber membranes of any five hollow fiber membranes The distance and the average distance between the hollow fiber membranes were measured.

(Clogging test)
Example 1
Ascites filtration concentration reinjection circuit (model AF-CART release source Asahi Kasei Medical) consisting of ascites bag and flow path (tube), 2000ppm PMEA is dissolved in it (ascites bag and flow path) as pretreatment 3 L of a solution (coating solution) of 35 Wt% ethanol and 65 Wt% distilled water was added. The circuit was left for 1 hour while immersed in the coating solution. Thereafter, the coating solution was discharged, distilled water was added, and the circuit was washed with distilled water. The washing was repeated three times, followed by vacuum drying at 37 ° C. for 24 hours and then standing at room temperature. P1 (sample) / P2 (Blank) of the ascites bag after the pretreatment was 1.605. Thereafter, 3 L of pseudocancerous ascites was placed in the ascites bag and stored for 1 hour. During storage, the bag was stored sideways so that cancer cells adhered to the inside of the bag, and the bag was turned over so that the front and back sides would be reversed after 30 minutes. Thereafter, as shown in FIG. 7, the ascites bag 20, the filter 21 for filtration, the concentrator 22, and the concentrated ascites bag 23 are connected to the ascites treatment circuit so as to be an external pressure filtration system, and the pump A Set the flow rate of 50 mL, pump B to a flow rate of 5 mL per minute,
Filtration concentration treatment (clogging test) was performed under the conditions that the filtration rate of the filter for filtration was 65%, the distance between the hollow fiber membranes was 250 mm, there was no crimp, and the effective area was 2.3 m ^2. The time was 41 minutes. Further, the number of cancer cells adhering to the ascites bag was measured in the same manner as the cancer cell adhesion test described above. The results are shown in Table-1.

(Examples 2 to 11)
Other than changing the kind of polymer (polymer material of general formula (1)), polymer concentration, solvent ratio at the time of polymer dissolution, filling rate of filter for filtration, presence of crimp, effective area as shown in Table-1 The clogging test was conducted in the same manner as in Example 1.
The results are shown in Table-1. All the time required for clogging was 15 minutes or more.

(Comparative Examples 1-2)
A clogging test was performed in the same manner as in Example 1 or 4 except that no pretreatment was performed.
The time required for clogging was 6 minutes and 10 minutes, respectively, both of which were unacceptable results.

  The medical member of the present invention can be suitably used in a body fluid filtration device used in ascites filtration concentration therapy (CART) or the like, and selectively retain cancer cells while leaving useful proteins in the body fluid before treatment. It is possible to effectively remove clogging of the filter for filtration, and is useful for suppressing a decrease in the filtration capacity of the filter for filtration.

DESCRIPTION OF SYMBOLS 1 Ascites treatment system 10 Ascites treatment circuit 20 Ascites bag 21 Filter for filtration 22 Concentrator 23 Concentrated ascites bag 40 Cylindrical container 41 Hollow fiber membrane 42 Hollow fiber membrane bundle

Claims (1)

A storage container for storing bodily fluids;
A filter for filtration capable of separating cancer cells present in the body fluid;
A first flow path having one end connected to the storage container and the other end connected to the inlet of the filtration filter;
A body fluid filtration device comprising: a collection container for collecting the solution filtered by the filtration filter,
The body fluid filtering device, wherein the storage container and / or the first flow path has a coating containing a polymer material having a structure represented by the following general formula (1) on at least a part of the inner surface. .
In the formula, R ¹ is a hydrogen atom or a methyl group, R ² is a methyl group or an ethyl group, m is 1 to 3, and n represents the number of repetitions.