JP5420341B2 - Adsorbent for removing blood cells and method for producing the same - Google Patents

Description

  The present invention relates to an adsorbent for removing blood cells and a method for producing the same.

  Autoimmune diseases are diseases in which the immune system functions abnormally for some reason and attacks the normal cells and tissues of the self. Since drug therapy alone cannot be effective, extracorporeal circulation blood purification therapy that removes causative factors by circulating blood extracorporeally is effectively used.

  In recent years, for example, the occurrence of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease and autoimmune diseases represented by rheumatoid arthritis (RA) has increased. It is known that abnormally activated leukocytes are involved.

Recent research has revealed that not only leukocytes but also abnormally activated blood platelets are involved as inflammatory cells, especially in inflammatory diseases such as autoimmune diseases. (See Non-Patent Document 1). It is said that platelets not only have the ability to release cytokines and chemokines themselves, but also release active oxygen by forming leukocyte aggregates, and platelets are also considered to be involved in inflammatory reactions. Yes.

  Therefore, removal of activated blood cell components including not only leukocytes but also platelets is considered to be effective in the treatment of autoimmune diseases, and technology related to extracorporeal circulation blood purification therapy to remove activated blood cell components The demand is growing.

  At present, for example, as a leukocyte removal filter and a platelet separation filter, a nonwoven fabric made of polyethylene terephthalate (PET) or the like wound in a flat plate shape or a cylindrical shape has been proposed (see, for example, Patent Documents 1 and 2).

  However, in the case of the nonwoven fabric, there is a problem that the pressure loss of the filter portion is large, the blood flow path in the leukocyte adsorber is biased, and the blood processing capacity is lowered. In addition, the nonwoven fabric filter has a drawback that coagulation easily occurs in the adsorber during blood circulation.

  On the other hand, the adsorbent for blood cell components other than the nonwoven fabric includes beads. In the case of this bead-shaped adsorbent, the pressure loss in the leukocyte adsorber is less than that of the nonwoven fabric, so the blood flow in the adsorber is less biased and coagulation is suppressed. Becomes higher.

  Currently, beads made of cellulose acetate or the like have been devised as an adsorbent that effectively adsorbs granulocytes (see, for example, Patent Document 3). However, although cellulose acetate mainly adsorbs granulocytes, it is not effective for adsorption removal of activated platelets. Patent Document 3 describes that a material having a surface having a certain contact angle can selectively remove granulocytes. In addition, when only a hydrophobic resin is used as an adsorbent for blood cells, it is effective for adsorbing blood cells, but hydrophobic surfaces generally tend to cause protein adsorption and easily activate the coagulation system. Solidification may occur in the adsorber during extracorporeal circulation, which may cause an increase in pressure. In order to suppress blood coagulation and pressure increase in the adsorber, it is effective to make the surface of the adsorbent hydrophilic, but it is effective to have a hydrophobic surface in terms of blood cell adsorption and removal.

  Conventionally, however, the balance between hydrophilicity and hydrophobicity has been taken into consideration, and it has the ability to adsorb blood cell components (including platelets), reduces pressure loss during blood circulation, and suppresses coagulation in the adsorber. There was no adsorbent satisfying the function.

  On the other hand, for hollow fibers for hemodialysis, it has been proposed that it is effective to make the surface of the hollow fibers hydrophilic in order to suppress blood coagulation during hemodialysis and reduce residual blood in the hemodialyzer. (For example, see Patent Documents 4 and 5). For example, the hollow fiber of Patent Document 4 is produced by dry and wet spinning using a membrane forming stock solution composed of a polysulfone resin, a hydrophilic polymer resin, and a solvent that commonly dissolves them. Further, in Patent Document 5, a hydrophilic polymer resin substance is brought into contact with the inner surface of a cellulosic hollow fiber, and then hydrophilicity is formed on the inner surface of the hollow fiber by a radiation crosslinking method, an ultraviolet crosslinking method, a thermal crosslinking method, or the like. A method for producing a hollow fiber has been proposed in which a hydrophilic polymer resin material that is insoluble in water is physically held on the inner surface of the hollow fiber by crosslinking the functional polymer resin material.

Japanese Patent Laid-Open No. 62-243561 Japanese Patent Laid-Open No. 1-121061 Japanese Patent Laid-Open No. 2-193069 JP-A-7-289863 Japanese Patent Laid-Open No. 6-228887

Novel uses for anti-platelet agents as anti-inflammatory drugs. Pitchford SC, Br J Pharmacol. 2007 Dec: 152 (7): 987-1002

  However, for example, the hollow fiber for hemodialysis treated with the hydrophilic polymer resin of Patent Document 4 described above is based on the production method, and covers the inner and outer surfaces of the produced hollow fiber and the entire thickness direction. Hydrophilicity is imparted, and the hydrophobic effect of the polysulfone resin is not exhibited. As a result, for example, the effect of removing blood cell components such as activated platelets cannot be expected as a function other than dialysis.

  Further, the hollow fiber for hemodialysis of Patent Document 5 is obtained by applying a hydrophilic polymer resin substance to the inner surface of the hollow fiber and then crosslinking the hydrophilic polymer resin substance by a radiation crosslinking method or a thermal crosslinking method. Since the insoluble hydrophilic polymer resin substance is held on the inner surface, the manufacturing process is complicated and the manufacturing cost increases. Further, as the cellulose-based hollow fiber of Patent Document 5, a cellulose acetate-based hollow fiber is exemplified, and as described above, cellulose acetate mainly adsorbs granulocytes, but is effective for adsorption removal of activated platelets. Therefore, it is difficult to divert the cellulosic hollow fiber of Patent Document 5 as a blood cell adsorbent for removing blood cells including platelets.

  The present invention appropriately imparts hydrophilicity to an adsorbing substrate while retaining a certain degree of hydrophobicity to an adsorbing substrate made of a hydrophobic polymer resin, reduces pressure loss in the blood cell adsorber, and reduces blood flow. An object of the present invention is to provide an adsorbent for removing blood cells and a method for producing the same, which can suppress the bias of the path and reduce problems such as coagulation in the adsorber during blood flow, and efficiently remove leukocytes and platelets.

  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 porous adsorption base material made of a hydrophobic polymer resin, and a hydrophilic polymer resin that is at least partially taken into the micro-sized surface pores of the adsorption base material and fixed by an anchor effect. The hydrophobic polymer resin is at least one selected from the group consisting of polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF), polystyrene resin, and polymethylmethacrylate resin. , the hydrophilic polymer resin, polyvinyl pyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, at least 1 Tanedea Ru blood cells removal adsorbent selected from the group consisting of polyacrylamide.

  (II) When the hydrophilic polymer resin is a hydrophilic polymer resin containing nitrogen, the nitrogen element derived from the hydrophilic polymer resin with respect to the carbon element on the surface of the blood cell adsorbent measured by X-ray photoelectron spectroscopy Spectral intensity N / C% is an adsorbent for blood cell removal as described in said (I) which is 0.3% or more and 1.5% or less.

( III ) A step of dropping a polymer stock solution containing a hydrophobic polymer resin into a coagulating solution made of a poor solvent with respect to the hydrophobic polymer resin to produce a porous adsorption substrate made of the hydrophobic polymer resin; A step of immersing the adsorption base material in a hydrophilic treatment liquid containing a hydrophilic polymer resin, and heating at a temperature lower than the glass transition temperature of the hydrophobic polymer resin; and a hydrophilic treatment-treated adsorption group And a step of cooling the material. A method for producing an adsorbent for removing blood cells.

( IV ) It is a manufacturing method of the adsorbent for blood cell removal as described in said ( III ) which has the process of wash | cleaning the surface of the adsorption base material in which the hydrophilic treatment was performed after the cooling process.

( V ) The washing step is the method for producing an adsorbent for removing blood cells according to (IV ) above, which comprises a preliminary water washing step and a main washing step with alcohols.

( VI ) The method for producing an adsorbent for removing blood cells according to any one of ( III ) to ( V ), wherein the heating temperature is 100 ° C. or higher and lower than the glass transition temperature of the hydrophobic polymer resin. It is.

( VII ) The concentration of the hydrophilic polymer resin in the hydrophilic treatment liquid is 0.1% by mass or more and 0.5% by mass or less according to any one of ( III ) to ( VI ) above. This is a method for producing an adsorbent for removing blood cells.

( VIII ) The method for producing an adsorbent for removing blood cells according to any one of ( III ) to ( VII ), wherein the cooling temperature is 10 ° C. or higher and 30 ° C. or lower.

  According to the adsorbent for removing blood cells of the present invention, hydrophilicity is imparted to suppress coagulation and pressure increase in the adsorber during treatment while leaving a hydrophobic portion necessary for adsorption of blood cell components. The pressure loss in the adsorber is small, the bias of the blood flow path is suppressed, there are few problems such as coagulation in the adsorber when blood is passed, and blood cell components such as leukocytes and platelets are efficiently removed.

  According to the method for producing an adsorbent for removing blood cells of the present invention, a porous adsorption base material made of a hydrophobic polymer resin is heated at a temperature lower than the glass transition temperature of the hydrophobic polymer resin, whereby the hydrophobic adsorbent is made hydrophobic. Looseness occurs in the structure of the polymer resin, a micro-sized surface hole of the adsorbing substrate is opened, and at least a part of the hydrophilic polymer resin is taken into the surface hole and then cooled, so that the surface hole is formed. Shrink and close, and at least part of the hydrophilic polymer resin is firmly fixed to the surface pores by the so-called anchor effect, so the hydrophilic polymer resin may elute into the blood over time from the adsorbent during treatment There is no. In addition, even when the adsorbing substrate subjected to the hydrophilic treatment is washed after cooling, the hydrophilic polymer resin fixed to the surface hole of the adsorbing substrate by the anchor effect causes the polymer chain to adhere to the surface of the blood cell adsorbent. On the other hand, since the hydrophilic polymer resin that is excessively attached to the surface of the blood cell adsorbent is removed, it has the ability to adsorb blood cell components (including platelets), and pressure loss during blood circulation A blood cell adsorbent having a suitable balance between hydrophobicity and hydrophilicity that can suppress coagulation in the adsorber can be obtained.

  The adsorbent for removing blood cells and the production method thereof according to the embodiment of the present invention will be described below.

  The adsorbent for removing blood cells according to the embodiment of the present invention includes a porous adsorbent base material made of a hydrophobic polymer resin, and at least a part of the adsorbent base material is incorporated into a micro-sized surface hole and fixed by an anchor effect. And a hydrophilic polymer resin.

  Since the adsorbent for removing blood cells contains a hydrophobic polymer resin and the surface of the adsorbent for removing blood cells is hydrophobic, adsorption of blood cell components such as leukocytes and platelets in blood is likely to occur. On the other hand, at least a part of the hydrophilic polymer resin is taken into the surface pores of the porous adsorption base material made of the hydrophobic polymer resin and fixed by the anchor effect, so that the coagulation in the adsorber during treatment and The pressure rise is suppressed.

  The hydrophobic polymer resin is not particularly limited as long as it is a hydrophobic polymer. For example, polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF), polystyrene resin, polymethyl At least one selected from the group consisting of methacrylate resins is used.

  Furthermore, the hydrophobic polymer resin has a glass transition temperature (Tg) of 100 ° C. or higher. When the glass transition temperature of the hydrophobic polymer resin is less than 100 ° C., it is difficult to fix a predetermined amount of the hydrophilic polymer resin to the micro-sized surface holes of the porous adsorption base material by the anchor effect.

  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 less than 20,000, the strength of the adsorbent for removing blood cells is lowered, and the production yield of the adsorbent for removing blood cells 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 less than 15,000, the strength of the adsorbent for removing blood cells is lowered, and the production yield of the adsorbent for removing blood cells 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 hydrophilic polymer resin is not particularly limited as long as it is a polymer having hydrophilicity. For example, the hydrophilic polymer resin is selected from the group consisting of polyvinylpyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymer, and polyacrylamide. At least one selected from the above is used. The hydrophilic polymer resin is preferably polyvinyl pyrrolidone (hereinafter sometimes abbreviated as “PVP”), and the weight average molecular weight of PVP is preferably 1,000,000 to 1,200,000.

  Further, the adsorbent for removing blood cells in the present embodiment is such that when the hydrophilic polymer resin is a hydrophilic polymer resin containing nitrogen, carbon on the surface of the blood cell adsorbent measured by X-ray photoelectron spectroscopy is used. The nitrogen element spectral intensity N / C% derived from the hydrophilic polymer resin with respect to the element is 0.3% or more and 1.5% or less, preferably 0.7% or more and 1.1% or less. As the hydrophilic polymer resin containing nitrogen, for example, the above-mentioned polyvinyl pyrrolidone (hereinafter sometimes abbreviated as “PVP”) is used, and the preferred weight average molecular weight of PVP is 1 million to 1.2 million.

  Adsorption performance of blood cell components is high when the nitrogen element spectral intensity N / C% derived from the hydrophilic polymer resin with respect to the carbon element on the surface of the blood cell adsorbent measured by X-ray photoelectron spectroscopy is less than 0.3% However, it can cause clotting and pressure buildup in the adsorber during treatment. On the other hand, when N / C% exceeds 1.5%, coagulation and pressure increase in the adsorber during treatment are suppressed, but the blood cell adsorption performance deteriorates.

  N / C% of nitrogen element spectrum intensity derived from hydrophilic polymer resin with respect to carbon element on the surface of blood cell adsorbent by X-ray photoelectron spectroscopy (XPS) method in this embodiment and examples described later Was measured using “Sigma Probe” (manufactured by Thermo VG Scientific).

  By setting the Ra on the surface of the adsorbent for removing blood cells to 5 to 100 nm, the adsorptivity of leukocytes and platelets can be further improved. In addition, it is difficult in manufacturing to make the Ra of the surface of the adsorbent for removing blood cells smaller than 5 nm. On the other hand, if Ra on the surface of the adsorbent for removing blood cells is larger than 100 nm, contribution to the adsorption of platelets (size 2 to 4 μm) decreases. Ra of the surface of the adsorbent for removing blood cells can be measured by an AFM (atomic force microscope). In the present embodiment, Ra on the surface of the adsorbent for removing blood cells is measured by AFM using “SPA400” manufactured by Seiko Instruments Inc. as an AFM and “DMF SZDF20AL” (manufactured by Seiko Instruments Inc.) as a probe. The area is 10 μm × 10 μm.

  The shape of the adsorbent for removing blood cells in this embodiment may be either beaded or fibrous, and the fibrous cross section may be either hollow or solid. The length of the fiber may be cut to several mm to several cm. In consideration of reducing pressure loss in the adsorber, the shape of the adsorbent for removing blood cells is preferably a bead.

  Next, the manufacturing method of the adsorbent for removing blood cells in the embodiment of the present invention will be described below.

  In the method for producing an adsorbent for removing blood cells in the present embodiment, a polymer stock solution containing a hydrophobic polymer resin is dropped into a coagulating liquid composed of a poor solvent with respect to the hydrophobic polymer resin, and the hydrophobic polymer resin is used. Forming a porous adsorption base material, and immersing the adsorption base material in a hydrophilic treatment liquid containing a hydrophilic polymer resin, and heating at a temperature lower than the glass transition temperature of the hydrophobic polymer resin. And a step of cooling the adsorption base material that has been subjected to the hydrophilic treatment.

  Each step of the method for producing a blood cell removing adsorbent in the present embodiment will be described below.

  First, in the step of producing a porous adsorption substrate made of a hydrophobic polymer resin, a phase change method (also referred to as “coagulation method”) is used, and the hydrophobic polymer resin described above is used as the hydrophobic polymer resin. A polymer stock solution prepared by dissolving in an organic solvent that is a compatible good solvent is prepared, dropped into a coagulating liquid consisting of a poor solvent with respect to the hydrophobic polymer resin, and made of a hydrophobic polymer resin. A porous adsorption substrate is produced.

  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.

  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. In this application, when two types of hydrophobic polymer resins are dissolved in an organic solvent, the clear state of the solution is expressed as compatible, and when the solution becomes cloudy or separated, it is expressed as incompatible. .

  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.

  As described above, the porous adsorption base material made of the hydrophobic polymer resin in the present embodiment may be in the form of beads, hollow fibers, or solid threads, and is preferably in the form of beads. An example of a manufacturing method of these shapes will be described below using the polymer stock solution and the coagulating solution described above.

(Method for producing an adsorbent substrate made of a bead-like hydrophobic polymer)
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 phase separation or the like is less likely to occur.

(Method for producing an adsorbent base material comprising a hollow fiber-like hydrophobic polymer)
Using a double nozzle, the polymer stock solution (hereinafter also referred to as “spinning stock solution” for hollow fibers and solid yarn) is extruded together with the internal coagulation liquid (organic solvent containing water), and the external coagulation liquid (organic containing water) The hollow fiber for removing blood cells can be produced by dropping into the solvent. The temperature when spinning the blood cell removing hollow fiber is preferably about 5 to 15 ° C. By setting the spinning temperature within this range, the stability of the polymer stock solution is improved, and phase separation or the like hardly occurs. The ratio of the concentration difference between the internal coagulating liquid (core liquid) and the external coagulating liquid is preferably 0.6 to 1.6.

(Manufacturing method of adsorbing substrate made of solid yarn hydrophobic polymer)
By using a single nozzle (orifice) and dropping the polymer stock solution into a coagulation solution (an organic solvent containing water), a solid yarn for removing blood cells can be produced. The temperature for spinning the blood cell removing solid yarn is preferably about 5 to 15 ° C. By setting the spinning temperature within this range, the stability of the polymer stock solution is improved, and phase separation or the like hardly occurs.

  Further, the diameter of the bead-shaped adsorption substrate made of the hydrophobic polymer in the present embodiment is 0.5 mm to 5 mm, and the outer diameter of the fibrous adsorption substrate (hollow fiber or solid yarn) is 0.1 mm to 1 mm. is there.

  Next, the heating process which performs a hydrophilic process is demonstrated. The above-mentioned heating temperature is 100 ° C. or higher and lower than the glass transition temperature (Tg) of the hydrophobic polymer resin. When a polyarylate resin (Tg: 193 ° C.) is used as the hydrophobic polymer resin, the temperature is 100 ° C. More than 190 degreeC is preferable. If the heating temperature is less than 100 ° C., the desired hydrophilic polymer resin cannot be fixed to the adsorption base material made of the hydrophobic polymer resin by the anchor effect, while the heating temperature is lower than that of the hydrophobic polymer resin. If the temperature is higher than the glass transition temperature, the structure of the adsorbing substrate made of the hydrophobic polymer resin may change.

  When a porous adsorption substrate made of a hydrophobic polymer resin is heated below the glass transition temperature of the hydrophobic polymer resin, the structure of the hydrophobic polymer resin is loosened, and the adsorption substrate micro- A size surface hole is opened, and at least a part of the hydrophilic polymer resin is taken into the surface hole. Then, by cooling, the surface hole contracts and closes, and at least a part of the hydrophilic polymer resin is firmly fixed to the surface hole by a so-called anchor effect. Therefore, there is no possibility that the hydrophilic polymer resin elutes into the blood over time from the adsorbent during treatment. In addition, as will be described later, even when the adsorbing substrate subjected to hydrophilic treatment is washed after cooling, the hydrophilic polymer resin fixed to the surface pores of the adsorbing substrate by the anchor effect does not have its polymer chain. Adsorption of blood cell components (including platelets) remains on the surface of the blood cell adsorbent, while the hydrophilic polymer resin that does not adhere to the surface of the blood cell adsorbent and is excessively attached to the surface is removed. A blood cell adsorbent having a balance between hydrophobicity and hydrophilicity which has performance and can reduce coagulation in the adsorber by reducing the pressure loss during blood circulation is obtained.

  Although the heating time depends on the heating temperature, it is, for example, 30 minutes to 1 hour. When the heating time is less than 30 minutes, the hydrophilic polymer resin is not taken into the surface pores of the adsorption base material. On the other hand, when the heating time exceeds 1 hour, the production efficiency is lowered.

  Further, in the heating step, the hydrophilic treatment liquid containing the hydrophilic polymer in which the adsorption substrate is immersed is obtained by dissolving the hydrophilic polymer resin in a good solvent compatible with the hydrophilic polymer resin. Prepared. In addition, since hydrophilic polymer resin is the same as that of the above-mentioned, description here is abbreviate | omitted. On the other hand, as a good solvent having compatibility with the hydrophilic polymer resin, for example, purified water is preferable.

  Moreover, the density | concentration of hydrophilic polymer resin in the hydrophilic processing liquid mentioned above is 0.1 to 0.5 mass%. When the concentration of the hydrophilic polymer resin in the hydrophilic treatment liquid is less than 0.1% by mass, a predetermined amount of the hydrophilic polymer resin is sufficiently fixed to the porous adsorption substrate made of the hydrophobic polymer resin. However, although the adsorption performance of blood cell components is high, the hydrophilicity is low, which may cause coagulation and pressure increase in the adsorber during treatment. On the other hand, when the concentration of the hydrophilic polymer resin in the hydrophilic treatment liquid exceeds 0.5% by mass, coagulation and pressure increase in the adsorber during treatment are suppressed, but the hydrophobicity is low. Blood cell adsorption performance is reduced.

  Next, in the cooling step, the cooling temperature is 10 ° C. or higher and 30 ° C. or lower. Even if it is cooled below 10 ° C, further shrinkage of the surface pores of the porous adsorption substrate made of a hydrophobic polymer resin cannot be expected, and a large-scale cooling device is required for cooling to below 10 ° C. , Manufacturing costs increase. On the other hand, in cooling at a temperature exceeding 30 ° C., even if at least a part of the hydrophilic polymer resin is taken into the surface pores in the heating step, the surface pores of the porous adsorption base material made of the hydrophobic polymer resin Since the hydrophilic polymer resin does not adhere to the surface hole due to the anchor effect and is detached by washing in the next step, as a result of insufficient hydrophilic treatment, adsorption during treatment May cause solidification and pressure increase in the vessel.

  In addition, the method for producing an adsorbent for removing blood cells according to the present embodiment further includes a step of washing the surface of the adsorption base material that has been subjected to the hydrophilic treatment after the cooling step described above. As described above, the washing step can remove the hydrophilic polymer resin that is not adhered to the surface of the blood cell adsorbent and is excessively attached to the surface.

  Furthermore, the above-described washing step preferably includes a preliminary water washing step and a main washing step with alcohols. In the preliminary water washing step, for example, purified water is used, and alcohols used in the main washing step include, for example, Methanol or ethanol is used. By washing with alcohol, the hydrophilic polymer resin that has adhered to the surface of the blood cell adsorbent can be washed away more reliably, and hydrophilicity in the filling water and blood during the treatment of blood cell removal Elution of the polymer resin is prevented. In the present embodiment, a blood cell adsorbent can also be produced by irradiating the adsorbent substrate after ethanol washing with radiation. By irradiation with radiation, the hydrophilic polymer resin fixed to the adsorption substrate can be more firmly fixed, and the elution of the hydrophilic polymer resin into the blood can be further prevented.

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

Example 1:
15 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 dissolving, stirring, and mixing 85 parts by mass of 2-pyrrolidone. This polymer stock solution was discharged and dropped from a single nozzle (orifice) into a coagulating liquid bath containing N-methyl-2-pyrrolidone as an organic solvent and water in a proportion of 40% by volume. A 0 mm hydrophobic porous PAR bead-shaped adsorption substrate was produced.

  A hydrophobic porous PAR bead-like adsorption base material was packed in a column made of polycarbonate having a diameter of 55 mm and a length of 150 mm in a sedimentation volume of 270 mL. In this column, 170 mL of 0.1 mass% aqueous solution of polyvinylpyrrolidone (hereinafter also referred to as “PVP”, manufactured by BASF, trade name “Collidon K-90”) was packed. Next, the column was heated at 121 ° C. for 1 hour to perform a hydrophilic treatment.

  Thereafter, the hydrophilic treatment-treated bead-like adsorption base material was washed by passing 1 L of water at 100 mL / min. Next, using “Sigma Probe” (manufactured by Thermo VG Scientific Co., Ltd.), nitrogen element spectral intensity N / C derived from PVP with respect to carbon elements on the surface of the blood cell adsorbent by X-ray photoelectron spectroscopy (XPS) method % Was measured. The results are shown in Table 1.

  Next, 3 g of the beaded adsorption base material subjected to hydrophilization treatment after water washing was immersed in 30 mL of an ethanol stock solution for washing, and X-ray photoelectron spectroscopic analysis (XPS) was performed as described above. The results are shown in Table 1.

  Both adsorbents for blood cell removal after water washing and after water washing and ethanol washing detected a peak of the nitrogen element spectral intensity and confirmed that PVP, a hydrophilic polymer resin, was applied to the surface of the adsorbent. It was done. Since the surface of the adsorbent subjected to water washing and ethanol washing has a lower detection peak in the nitrogen element spectrum intensity derived from PVP than water washing, the surface of the adsorbent is further fixed by performing ethanol washing. It is considered that the excess PVP that did not adhere and adhered was removed.

Example 2:
As an aqueous polyvinyl pyrrolidone solution to be hydrophilized, an adsorbent substrate was prepared under the same conditions as in Example 1 except that a 0.3% by mass aqueous solution of polyvinyl pyrrolidone (trade name “Collidon K-90” manufactured by BASF Corporation) was used. Hydrophilic treatment and washing treatment were performed, and X-ray photoelectron spectroscopy (XPS) was performed in the same manner as in Example 1. The results are shown in Table 1. From the XPS measurement results, the adsorbent for blood cell removal after water washing and after water washing and ethanol washing both detected a peak of the nitrogen element spectrum intensity, and the hydrophilic polymer resin PVP was found on the surface of the adsorbent. It was confirmed that it was granted. In addition, it is thought that the excess PVP which adhered without adhering to the surface of an adsorbent was removed by performing ethanol washing further.

Example 3:
As an aqueous polyvinyl pyrrolidone solution to be hydrophilized, an adsorbent substrate was prepared under the same conditions as in Example 1 except that a 0.5% by mass aqueous solution of polyvinyl pyrrolidone (trade name “Collidon K-90” manufactured by BASF Corporation) was used. Hydrophilic treatment was performed, and X-ray photoelectron spectroscopy (XPS) was performed. The results are shown in Table 1. From the XPS measurement results, the adsorbent for blood cell removal after water washing and after water washing and ethanol washing both detected a peak of the nitrogen element spectrum intensity, and the hydrophilic polymer resin PVP was found on the surface of the adsorbent. It was confirmed that it was granted. In addition, it is thought that the excess PVP which adhered without adhering to the surface of an adsorbent was removed by performing ethanol washing | cleaning further similarly to Example 1. FIG.

Example 4:
When performing the hydrophilization treatment, the column was heated at 180 ° C. for 0.5 hours, and the hydrophilization treatment was performed under the same conditions as in Example 1 except that the hydrophilization treatment was performed. In the same manner as in Example 1, X-ray photoelectron spectroscopy (XPS) was performed. The results are shown in Table 1. From the XPS measurement results, the adsorbent for blood cell removal after water washing and after water washing and ethanol washing both detected a peak of the nitrogen element spectrum intensity, and the hydrophilic polymer resin PVP was found on the surface of the adsorbent. It was confirmed that it was granted. In addition, it is thought that the excess PVP which adhered without adhering to the surface of an adsorbent was removed by performing ethanol washing further.

Comparative Example 1:
When performing the hydrophilization treatment, the adsorbing substrate was hydrophilized under the same conditions as in Example 3 except that the heating step of raising the column to 121 ° C was not performed and the column was kept at room temperature (25 ° C). Cleaning treatment was performed, and X-ray photoelectron spectroscopy (XPS) was performed in the same manner as in Example 1. The results are shown in Table 1. According to the XPS measurement results, the adsorbents for removing blood cells after washing with water and after washing with water and ethanol were both obtained with less peak of nitrogen element spectrum intensity than those of Examples 1 to 4, although the peak of nitrogen element spectrum intensity was detected. The amount of PVP that is a hydrophilic polymer resin imparted to the adsorbent for removing blood cells was considered to be small. In addition, the decrease in detection peak due to ethanol washing was remarkable.

  From the results after the ethanol washing in Examples 1 to 4 and Comparative Example 1, by heating in the hydrophilization treatment, a larger amount of the hydrophilic polymer resin becomes a porous adsorption substrate made of a hydrophobic polymer resin. It has been found that the extra hydrophilic polymer resin that adheres more firmly and adheres to the surface of the adsorbing substrate without being adhered to the surface of the adsorbing substrate can be more reliably removed by washing with ethanol.

Example 5:
The adsorbent for removing blood cells after washing with ethanol obtained in Example 3 was packed in a column made of polycarbonate having a diameter of 27 mm and a length of 70 mm with an outer surface area of about 0.14 mm ² to conduct a leukocyte and platelet adsorption test.

[Leukocyte and platelet adsorption test] 250 mL of blood was collected from a healthy subject in a blood bag, heparinized, and after circulating blood at 7 mL / min for 30 minutes using the above column, granulocytes before and after circulation (preferably The changes in the number of neutrophils, platelets, and lymphocytes were observed, and the adsorption rate of each blood cell component was calculated.

  The results of the above test are shown in Table 2. In Example 5, no residual blood was observed in the blood cell removing adsorbent after the blood circulation.

Comparative Example 2:
A test was conducted and evaluated in the same manner as in Example 5 except that the hydrophobic porous PAR bead-shaped adsorption base material before hydrophilic treatment of Example 1 was used as an adsorbent for removing blood cells. The results are shown in Table 2. Adhesive capacity for granulocytes (neutrophils) and platelets was shown, and the ability of lymphocytes to remain in the body as memory cells was kept low, but it was used as an adsorbent for removing blood cells after blood circulation. Residual blood was observed on the PAR bead-shaped adsorption substrate.

  The present invention is suitable for blood cell removal applications.

Claims (8)

A porous adsorption substrate made of a hydrophobic polymer resin;
Have a, a fixed hydrophilic polymer resin at least partially incorporated anchoring effect on the surface pores of microscopic size of the adsorbent substrate,
The hydrophobic polymer resin is at least one selected from the group consisting of polyarylate resin (PAR), polyethersulfone resin (PES), polysulfone resin (PSF), polystyrene resin, and polymethylmethacrylate resin.
The hydrophilic polymer resin, polyvinyl pyrrolidone, polyethylene glycol, polyglycol monoester, polypropylene glycol copolymers, blood cells removal adsorbent for at least 1 Tanedea characterized Rukoto selected from the group consisting of polyacrylamide .   When the hydrophilic polymer resin is a hydrophilic polymer resin containing nitrogen, the nitrogen element spectrum intensity N derived from the hydrophilic polymer resin with respect to the carbon element on the surface of the blood cell adsorbent measured by X-ray photoelectron spectroscopy The adsorbent for removing blood cells according to claim 1, wherein / C% is 0.3% or more and 1.5% or less. Dropping a polymer stock solution containing a hydrophobic polymer resin into a coagulation solution made of a poor solvent with respect to the hydrophobic polymer resin to produce a porous adsorption substrate made of the hydrophobic polymer resin;
Immersing the adsorption substrate in a hydrophilic treatment liquid containing a hydrophilic polymer resin, and heating at a temperature lower than the glass transition temperature of the hydrophobic polymer resin;
And a step of cooling the adsorbent substrate that has been subjected to hydrophilic treatment. 4. The method for producing an adsorbent for removing blood cells according to claim 3 , further comprising a step of washing the surface of the adsorption base material that has been subjected to the hydrophilic treatment after the cooling step. The method for producing an adsorbent for removing blood cells according to claim 4, wherein the washing step comprises a preliminary water washing step and a main washing step with alcohols. The temperature for heating is 100 ° C or higher and lower than the glass transition temperature of the hydrophobic polymer resin, The production of the adsorbent for removing blood cells according to any one of claims 3 to 5 , Method. The density | concentration of hydrophilic polymer resin in the said hydrophilic treatment liquid is 0.1 mass% or more and 0.5 mass% or less, The any one of Claim 3 to 6 characterized by the above-mentioned. Of manufacturing an adsorbent for removing blood cells. The method for producing an adsorbent for removing blood cells according to any one of claims 3 to 7 , wherein the cooling temperature is 10 ° C or higher and 30 ° C or lower.