JP2011224142A - Bead-like adsorbent, and blood purifier using the same - Google Patents

Abstract

Even if adsorbents collide or rub against each other due to vibration during transportation or priming of a blood purification column, the generation of insoluble fine particles resulting from the collision and rub is greatly suppressed as compared with conventional beads. Providing materials.
A bead-like adsorbent has a concavo-convex surface with a ten-point average roughness Rz in the range of 200 nm or more and 900 nm or less, and a hydrophobic polymer resin having a breaking elongation of 50% or more as a main component. .
[Selection] Figure 1

Description

  The present invention relates to a bead-shaped adsorbent and a blood purifier using the same, and more particularly to a blood purifier that purifies blood by bringing blood into direct contact with the adsorbent.

  In recent years, blood purification technology called “apheresis” has progressed, and in particular, a method for purifying blood by directly contacting a patient's blood with an adsorbent, particularly called direct blood perfusion therapy (DHP), is rapid. Is popular. Direct blood perfusion therapy is a conventional apheresis technique, plasma adsorption method (PA: Plasma Adsorption) in which plasma separated using a plasma separation membrane is brought into contact with an adsorbent, or plasma is separated from blood using a plasma separation membrane Then, a substance with a large molecular weight including globulin and other pathogenic (related) substances is separated and removed from the separated plasma using a secondary membrane, and has a molecular weight equal to or lower than that of pathogenic (related) substances centering on albumin. Compared to a double membrane filtration plasma exchange (DFPP) method for recovering a substance, it can be used conveniently.

  Substances to be removed from blood by apheresis techniques vary depending on the disease. For example, in the case of an LDL adsorber used for the treatment of hypercholesterolemia, LDL (low density lipoprotein) is the substance to be removed, and ulcer In the case of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, inflammatory cells such as leukocytes and platelets are substances to be removed.

  Various forms of adsorbent used for direct blood perfusion therapy (DHP) have been devised, such as beads, non-wovens, and wovens. Among them, bead-shaped adsorbents are cloth-like adsorbents such as non-wovens and wovens. Compared to the above, the pressure loss when blood is allowed to pass is small, and the risk of coagulation of blood in the extracorporeal circulation circuit or blood purification column is low.

  On the other hand, the bead-shaped adsorbent is not fixed in the blood purification column as compared with the non-woven fabric and woven adsorbents. Depending on the strength of the adsorbent material and the surface properties, a part of the adsorbent peels off and becomes “insoluble fine particles,” and these insoluble fine particles are released into the filling liquid of the blood purification column or into the blood during blood purification. There is a risk of it. Here, “insoluble fine particles” refer to fine particles derived from an adsorbent that do not dissolve in water, blood, or the like.

  Usually, a blood purifier using a bead-shaped adsorbent is placed in the blood purifier to prevent the adsorbent from dropping out of the blood purifier and entering the patient's body through the extracorporeal circulation blood purification circuit. A mesh filter is provided. However, the insoluble fine particles generated due to the destruction of the surface due to the collision or rubbing of the adsorbents as described above easily pass through the mesh filter because the particle size is small and fine. For this reason, there is a high possibility of migration into the patient's body. If the amount of insoluble fine particles generated is large, there is a possibility that a problem such as occlusion of capillaries may occur.

  As a method for preventing the above-described problem, for example, Patent Document 1 discloses a method of densely filling an adsorbent material so as to be substantially immovable. Further, Patent Document 2 discloses a method in which collision between adsorbent particles is alleviated to some extent while ensuring blood cell passage by setting a filling rate and an occupation rate within a certain range.

JP-A-57-57552 Japanese Patent No. 4138488

  However, in Patent Document 1 described above, for example, when the adsorbent is packed densely so that it cannot be completely moved, the gap between the adsorbent particles is inevitably narrowed, and as a result, the blood cell permeability is reduced. There is concern about getting worse. Further, in the method described in Patent Document 2, it is difficult to fill and manage an appropriate amount of adsorbent, and depending on the material of the adsorbent, generation of insoluble fine particles cannot be sufficiently suppressed even if this method is used. There is.

  The present invention has been made in view of the above situation, and relates to a blood purifier using a bead-shaped adsorbent, regardless of the filling rate at which the bead-shaped adsorbent is filled. An object of the present invention is to provide a blood purifier in which the generation of insoluble fine particles resulting from collision or rubbing is suppressed compared to conventional cases even if adsorbents collide or rub due to vibration during column transportation or priming. To do.

  As a result of intensive studies to solve the above problems, the present inventors have completed the present invention shown below. The present invention has the following features.

  (I) A bead-shaped adsorbent having a concavo-convex surface with a ten-point average roughness Rz in the range of 200 nm or more and 900 nm or less and a hydrophobic polymer resin having a breaking elongation of 50% or more as a main component.

  (II) The bead-shaped adsorbent according to (I), wherein the bead-shaped adsorbent has a particle size of 0.2 mm or more and less than 2.0 mm.

(III) The bead-shaped adsorbent is composed of a polyarylate resin having a repeating unit represented by the following chemical formula (1) and a polysulfone-based resin having a repeating unit represented by the chemical formula (2) or chemical formula (3). The bead-shaped adsorbent according to the above (I) or (II), which contains a hydrophobic polymer resin selected from the group consisting of:
In the chemical formula (1), R1 and R2 are lower alkyl groups having 1 to 5 carbon atoms, and R1 and R2 may be the same or different.
In the chemical formula (2), R3 and R4 are lower alkyl groups having 1 to 5 carbon atoms, and R3 and R4 may be the same or different.

  (IV) An inlet for introducing blood and an outlet for discharging the purified blood are provided at both ends, respectively, and a filter is provided on each of the downstream side of the inlet and the upstream side of the outlet. To a blood purifier filled with the bead-shaped adsorbent according to any one of (III).

  According to the blood purifier of the present invention, even if a bead-like adsorbent collides or rubs due to vibration during transportation or priming of the blood purification column, partial separation of the bead-like adsorbent due to impact or the like The amount of insoluble fine particles generated due to the above can be greatly suppressed as compared with the conventional case.

  Further, according to the blood purifier of the present invention, since the generation of insoluble fine particles is not easily affected by the filling rate of the bead-like adsorbent, the bead-like adsorbent filling rate can be freely set in order to ensure the passage of blood. Can be changed. In addition, since the generation of insoluble fine particles is small, the safety is high, and the amount of cleaning liquid during priming can be reduced.

It is a figure explaining how to obtain the ten-point average roughness Rz. It is a general | schematic disassembled perspective view of an example of the blood purifier in this Embodiment.

  The bead-shaped adsorbent and the blood purifier using the same in the embodiment of the present invention will be described below.

  The adsorbent used for the blood purifier in the present embodiment is a bead-shaped adsorbent, and is a bead-shaped adsorbent having an uneven surface with a ten-point average roughness Rz in the range of 200 nm to 900 nm. By setting the ten-point average roughness Rz of the surface of the bead-shaped adsorbent to 200 nm or more and 900 nm or less, even if a collision or rubbing between the bead-shaped adsorbents occurs during transportation or priming of the blood purification column, The amount of insoluble fine particles derived from the like is greatly suppressed as compared with the conventional case. In addition, it is technically difficult to produce a bead-shaped adsorbent having a ten-point average roughness Rz of less than 200 nm, and if the surface roughness is too small, the amount of adsorption of the target pathogenic substance is reduced. On the other hand, when the 10-point average roughness Rz on the surface of the bead-shaped adsorbent exceeds 900 nm, the amount of insoluble fine particles generated is determined by the Japanese Pharmacopoeia 15th edition, which will be described later. Exceeds the standard (10 μm or more: 12 / mL or less, 25 μm or more: 2 / mL or less) based on the particle counting method.

Here, as shown in FIG. 1, the value of the ten-point average roughness Rz is obtained by extracting only the reference length from the roughness curve in the direction of the average line, and from the average line of the extracted portion, from the highest peak. This is the sum of the absolute value of the altitude (Yp) at the top of the fifth mountain and the average value of the absolute values of the altitude (Yv) at the bottom of the bottom from the lowest valley.

  Usually Ra (centerline average roughness) often used as surface roughness is the average value of all deviations from the average line, and deep valleys and high peaks that deviate from the average tend to be averaged. Since Rz is the sum of the average value of the fifth deviation from the deepest valley and the average value of the fifth deviation from the highest peak, it is expressed as a value that particularly emphasizes deep valleys and high peaks. In the present invention, the reason why the generation of insoluble fine particles from the surface having a large Rz increases is considered to be because the peak portion higher than the average is peeled off mainly by a force such as contact with another surface.

  The ten-point average roughness Rz of the blood contact surface of the bead-shaped adsorbent can be measured by an AFM (Atomic Force Microscope). As the AFM, “SPA400” manufactured by Seiko Instruments Inc. is used, and “DMF SZDF20AL” is used as a probe. ”(Manufactured by Seiko Instruments Inc.), the measurement area by AFM is 10 μm × 10 μm.

  Moreover, the bead-shaped adsorbent used for the blood purifier in the present embodiment contains a hydrophobic polymer resin having a breaking elongation of 50% or more according to ASTM D-638. When the elongation at break is less than 50%, the generation of insoluble fine particles cannot be sufficiently suppressed. Here, the hydrophobic polymer resin having the elongation at break is not particularly limited as long as it is a polymer having hydrophobicity. For example, polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin At least one selected from the group consisting of (PSF) is used.

  The polyarylate resin is a resin having a repeating unit represented by the following chemical formula (1). The number average molecular weight of the polyarylate resin is preferably 20,000 to 30,000. When the number average molecular weight of the polyarylate resin is larger than 30,000, the surface unevenness becomes too large, and it becomes difficult to form appropriate surface unevenness. On the other hand, when the number average molecular weight of the polyarylate resin is smaller than 20,000, the strength of the bead-shaped adsorbent is lowered, and the production yield of the bead-shaped adsorbent is deteriorated.

  In the chemical formula (1), R1 and R2 are lower alkyl groups having 1 to 5 carbon atoms, and R1 and R2 may be the same or different. Examples of R1 and R2 include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Preferred R1 and R2 are methyl groups.

  The polyarylate resin is not particularly limited as long as the repeating unit represented by the chemical formula (1) is a main repeating unit, and may contain other repeating units as long as the object of the present invention is not impaired.

  The polyethersulfone resin is a resin having a repeating unit represented by the following chemical formula (2) or chemical formula (3). The number average molecular weight of the polyethersulfone resin is preferably 15,000 to 30,000. If the number average molecular weight of the polyethersulfone resin is larger than 30,000, the surface unevenness becomes too large, and it becomes difficult to form appropriate surface unevenness. On the other hand, when the number average molecular weight of the polyethersulfone resin is smaller than 15,000, the strength of the bead-shaped adsorbent is lowered, and the production yield of the bead-shaped adsorbent is deteriorated.

  In the chemical formula (2), R3 and R4 are lower alkyl groups having 1 to 5 carbon atoms, and R3 and R4 may be the same or different. Examples of R3 and R4 include a methyl group, an ethyl group, a propyl group, a butyl group, and a pentyl group. Preferred R1 and R2 are methyl groups.

  The diameter of the bead-shaped adsorbent used for the blood purifier in the present embodiment is 0.2 mm or more and less than 2.0 mm. Here, if the particle size is less than 0.2 mm, the particle size is too small, and even if the blood purifier is filled, the blood flow will deteriorate, which may cause an increase in the circuit pressure during treatment. There is. On the other hand, when the particle size of the bead-shaped adsorbent is 2.0 mm or more, there is a problem that the surface area for removing blood cell components (particularly, white blood cells and platelets) in the blood is reduced. Further, when the production by the phase change method which is one form of the production method in the present embodiment is selected, there is a problem that it is difficult to remove the solvent used in the production method from the adsorbent.

  Next, the manufacturing method of the bead-shaped adsorbent used in the embodiment of the present invention will be described below. However, the present invention is not limited to the manufacturing method described above.

  In this embodiment, as one form of the method for producing a bead-shaped adsorbent, a phase change method (also referred to as “coagulation method”) is used, and the above-described hydrophobic polymer resin is dissolved in the hydrophobic polymer resin. A polymer stock solution prepared by dissolving in an organic solvent, which is a good solvent, has a bead-like adsorbent made of a hydrophobic polymer resin. Generate.

  Since the hydrophobic polymer resin is the same as described above, description thereof is omitted here. On the other hand, the organic solvent is not particularly limited as long as it is a good solvent for the hydrophobic polymer resin. For example, N-methyl-2-pyrrolidone (NMP), dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, Tetrahydrofuran and the like can be mentioned. Among these, NMP is preferable as the organic solvent.

  In addition, when using 2 or more types of substances as hydrophobic polymer resin, it is necessary to select what has compatibility mutually. Here, the term “compatible” refers to the property that two or more substances have an affinity for each other and form a solution or a mixture, that is, ease of mixing of the substances.

  The coagulating liquid is an organic solvent containing water, and is preferably a solution in which the organic solvent used in the polymer stock solution and water are mixed at a predetermined ratio.

  Below, an example of the manufacturing method of a bead-shaped adsorption material is demonstrated below using the polymer stock solution and coagulation liquid which were mentioned above.

(Method for producing adsorbent made of hydrophobic polymer in bead form)
Drops of a polymer stock solution from a single nozzle (orifice) drop into a coagulation liquid (an organic solvent containing water), coagulates a polymer made of a hydrophobic polymer resin in the coagulation liquid, and adsorbs porous beads. A substrate is formed. The temperature for producing beads is preferably about 5 to 15 ° C. By setting the bead generation temperature within this range, the stability of the polymer stock solution is improved, and abnormal phase separation that hinders proper structure formation of the beads is less likely to occur.

  The production method of the bead-shaped (spherical) adsorbent in the present invention is not limited to the phase change method for obtaining a spherical adsorbent by dropping a solution obtained by dissolving a polymer resin material in a predetermined solvent into a coagulation bath. Can be selected. For example, a method of obtaining a spherical adsorbent by cutting and polishing a round bar made of a polymer resin, a method of obtaining a spherical adsorbent by pouring a polymer resin material dissolved in a mold, and an emulsion method can be selected.

  Next, an example of the blood purifier of the present embodiment will be described with reference to FIG. The blood purifier includes a case and a bead-shaped adsorbent 190.

  The case has a case main body 210, a pair of meshes 220, and a pair of headers 230. The case main body 210 is a cylindrical member made of polycarbonate, for example. The material of case body 210 is not limited to polycarbonate, and a known resin material, metal material, or composite material may be used.

  A pair of meshes 220 each having a function of a polyester filter is attached to both ends of the case body 210. The mesh 220 has an eye smaller than the diameter of the bead-shaped adsorbent 190 described above, and the bead-shaped adsorbent 190 is held in the case by this mesh. The material of the mesh 220 is not limited to polyester, and a known resin material, metal material, or composite material may be used.

  A header 230 is attached to both openings of the case body 210 with the mesh 220 described above interposed therebetween. Each header 230 is provided with an inlet portion serving as a blood introduction passage and an outlet portion serving as a blood discharge passage after blood purification. Then, both end openings of the case main body 210 are sealed by the header 230. In order to ensure sealing, a sealing member such as an O-ring may be provided between the header 230 and the case body 210.

  A bead-shaped adsorbent 190 is accommodated inside the case main body 210 sandwiched between the pair of meshes 220. The bead-shaped adsorbent 190 is arranged inside the case body 210 at random, in other words, in an irregular and unfixed state. The filling rate of the bead-shaped adsorbent 190 with respect to the volume of the case body 210 is preferably 70 to 100%. By setting the filling rate of the bead-shaped adsorbent 190 to 70% or more, the amount of blood necessary for blood purification is reduced, so that the burden on the patient can be reduced. On the other hand, when the filling rate of the bead-shaped adsorbent 190 is greater than 100%, it is difficult to fill the beads, and the work efficiency is reduced.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these Examples.

Example 1:
13 parts by mass of polyarylate resin (hereinafter also referred to as “PAR”, number average molecular weight: 25,000, manufactured by Unitika Ltd., trade name “U polymer”, glass transition temperature: 193 ° C.) and N-methyl- as an organic solvent A polymer stock solution was prepared by heating and dissolving, stirring and mixing with 87 parts by mass of 2-pyrrolidone. Further, N-methyl-2-pyrrolidone (hereinafter also referred to as “NMP”) was used as the organic solvent, and a coagulation liquid containing NMP at a ratio of 55 vol% with respect to water was used. Then, the polymer solution was dropped from a single nozzle (orifice) having an inner diameter of 0.25 mm from the liquid surface of the coagulating liquid tank at a height of about 10 cm. After sufficiently coagulating in the coagulating liquid, it was washed with distilled water to obtain a bead-shaped adsorbent having a diameter of 1.0 mm.

  The bead-shaped adsorbent of Example 1 is almost a perfect circle, “SPA400” manufactured by Seiko Instruments Inc. is used as the AFM, “DMF SZDF20AL” (manufactured by Seiko Instruments Inc.) is used as the probe, and the measurement area by AFM is When the 10-point average roughness Rz of the surface of the bead-shaped adsorbent was measured as 10 μm × 10 μm, it was 580 nm.

Example 2:
A bead-shaped adsorbent having a diameter of 1.0 mm was obtained in accordance with Example 1 except that the concentration of NMP with respect to the water of the coagulation liquid was 40% by volume. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and found to be 300 nm.

Example 3:
A bead-shaped adsorbent having a diameter of 1.0 mm was obtained in accordance with Example 1 except that the concentration of NMP with respect to the water of the coagulation liquid was 60% by volume. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and found to be 880 nm.

Comparative Example 1:
A bead-shaped adsorbent having a diameter of 1.0 mm was obtained in accordance with Example 1 except that the concentration of NMP with respect to the water of the coagulation liquid was set to 70% by volume. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and found to be 910 nm.

Example 4:
Example 1 except that a polysulfone resin (hereinafter referred to as “PSF” manufactured by Solvay Advanced Polymers Co., Ltd., trade name: “Udel P-1700”, number average molecular weight 27,000) was used instead of the polyarylate resin. Based on the above, a bead-shaped adsorbent having a diameter of 1.0 mm was obtained. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and it was 470 nm.

Comparative Example 2:
Instead of the polyarylate resin, a polysulfone resin (hereinafter referred to as “PSF”, manufactured by Solvay Advanced Polymers, Inc., trade name: “Udel P-1700”, number average molecular weight 27,000) is used, and NMP for water of the coagulation liquid A bead-shaped adsorbent having a diameter of 1.0 mm was obtained in accordance with Example 1 except that the concentration of was changed to 70% by volume. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and it was 950 nm.

Example 5:
A polyethersulfone resin (hereinafter referred to as “PES” manufactured by Sumitomo Chemical Co., Ltd., trade name: “Sumika Excel 4800P”, coagulation value: 8.4 mL, number average molecular weight 21,000) was used in place of the polyarylate resin. In accordance with Example 1, a bead-shaped adsorbent having a diameter of 1.0 mm was obtained. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and it was 400 nm.

Comparative Example 3:
Instead of the polyarylate resin, a polyethersulfone resin (hereinafter referred to as “PES” manufactured by Sumitomo Chemical Co., Ltd., trade name: “Sumika Excel 4800P”, coagulation value: 8.4 mL, number average molecular weight 21,000) was used for coagulation. A bead-shaped adsorbent having a diameter of 1.0 mm was obtained in accordance with Example 1 except that the concentration of NMP with respect to the liquid water was 70% by volume. When the ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM measurement, it was 1100 nm.

Comparative Example 4:
Except that polystyrene resin (hereinafter referred to as “PSt” manufactured by Asahi Kasei Co., Ltd., trade name: “GP Stylon”) was used instead of polyarylate resin, and the concentration of NMP with respect to the water of the coagulation liquid was set to 70% by volume. 1, a bead-shaped adsorbent having a diameter of 1.0 mm was obtained. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM, and it was 490 nm.

Comparative Example 5:
A polymethyl methacrylate resin (hereinafter referred to as “PMMA” manufactured by Sumitomo Chemical Co., Ltd., trade name: “LG”) was used instead of the polyarylate resin, and the concentration of NMP with respect to the water of the coagulation liquid was set to 70% by volume. In accordance with Example 1, a bead-shaped adsorbent having a diameter of 1.0 mm was obtained. The ten-point average roughness Rz of the surface of the bead-shaped adsorbent was measured by AFM measurement and found to be 450 nm.

[Evaluation methods]
The bead-shaped adsorbents obtained in Examples 1 to 5 and Comparative Examples 1 to 5 are packed in a case made of about 300 mL polycarbonate with a filling rate of about 95% (the definition of the filling rate is the same as that of Japanese Patent No. 4138488) with purified water. After filling, a vibration drop test (conforming to JIS Z 0200: 1999, JIS Z 0232: 2004, JIS Z 0202: 1994) was performed, and the number of insoluble fine particles ( Japanese Pharmacopoeia 15th edition 6.07 Insoluble fine particle test method for injections 2nd method Conforms to microscopic particle counting method: Standard 10 μm or more: 12 / mL or less, 25 μm or more: 2 / mL or less) Counted. The results are shown in Table 1. From the results of Examples 1 to 5, the number of insoluble fine particles was within the specifications in the bead-shaped adsorbent of the present invention.

Example 6:
The bead-shaped adsorbent obtained in Example 1 was filled with about 300 mL of a polycarbonate case together with purified water at a filling rate of about 75%, and then a vibration drop test was performed to count the number of insoluble fine particles. The results are shown in Table 1. From the result of Example 6, in the bead-shaped adsorbent of the present invention, the number of insoluble fine particles was within the specification.

  The present invention is suitable for blood purification applications.

Claims (4)

  A bead-like adsorbent comprising a hydrophobic polymer resin having a ten-point average roughness Rz in a range of 200 nm or more and 900 nm or less and a breaking elongation of 50% or more as a main component.   The bead-shaped adsorbent according to claim 1, wherein the bead-shaped adsorbent has a particle size of 0.2 mm or more and less than 2.0 mm. The bead-shaped adsorbent is selected from the group consisting of a polyarylate resin having a repeating unit represented by the following chemical formula (1) and a polysulfone resin having a repeating unit represented by the chemical formula (2) or chemical formula (3). The bead-shaped adsorbent according to claim 1 or 2, comprising a selected hydrophobic polymer resin.
In the chemical formula (1), R1 and R2 are lower alkyl groups having 1 to 5 carbon atoms, and R1 and R2 may be the same or different.
In the chemical formula (2), R3 and R4 are lower alkyl groups having 1 to 5 carbon atoms, and R3 and R4 may be the same or different.
  4. An inlet for introducing blood and an outlet for discharging blood after purification are provided at both ends, respectively, and filters are provided on the downstream side of the inlet and the upstream side of the outlet, respectively, and between the filters. A blood purifier filled with the bead-shaped adsorbent according to any one of the above.