US20180326136A1 - Phosphate adsorbing agent for blood processing, blood processing system and blood processing method - Google Patents

Phosphate adsorbing agent for blood processing, blood processing system and blood processing method Download PDF

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US20180326136A1
US20180326136A1 US15/774,858 US201615774858A US2018326136A1 US 20180326136 A1 US20180326136 A1 US 20180326136A1 US 201615774858 A US201615774858 A US 201615774858A US 2018326136 A1 US2018326136 A1 US 2018326136A1
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blood
phosphate
blood processing
formed article
adsorbing agent
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Naoki Morita
Hiroshi Tajima
Ryou SASAKI
Hirokazu Nagai
Akihiro Omori
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Asahi Kasei Medical Co Ltd
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Asahi Kasei Medical Co Ltd
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Assigned to ASAHI KASEI MEDICAL CO., LTD. reassignment ASAHI KASEI MEDICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TAJIMA, HIROSHI, MORITA, NAOKI, OMORI, AKIHIRO, NAGAI, HIROKAZU, SASAKI, RYOU
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A61M1/1621—Constructional aspects thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
    • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687—Chemical treatment
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/58—Other polymers having nitrogen in the main chain, with or without oxygen or carbon only
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
    • B01D71/68—Polysulfones; Polyethersulfones
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/0203—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising compounds of metals not provided for in B01J20/04
    • B01J20/0211—Compounds of Ti, Zr, Hf
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/06—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/06—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04
    • B01J20/08—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising oxides or hydroxides of metals not provided for in group B01J20/04 comprising aluminium oxide or hydroxide; comprising bauxite
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/10—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B01J20/28059—Surface area, e.g. B.E.T specific surface area being less than 100 m2/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28057—Surface area, e.g. B.E.T specific surface area
    • B01J20/28061—Surface area, e.g. B.E.T specific surface area being in the range 100-500 m2/g
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28078—Pore diameter
    • B01J20/28085—Pore diameter being more than 50 nm, i.e. macropores
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2220/00—Aspects relating to sorbent materials
    • B01J2220/40—Aspects relating to the composition of sorbent or filter aid materials
    • B01J2220/46—Materials comprising a mixture of inorganic and organic materials

Definitions

  • the present invention relates to a phosphate adsorbing agent for blood processing and a blood processing system.
  • the present invention further relates to a blood processing method using the phosphate adsorbing agent for blood processing.
  • kidney disease patients such as chronic renal failure patients, who have impaired renal functions cannot properly excrete excessive phosphate from their bodies. Therefore, phosphate accumulates gradually in the body, causing a disease such as hyperphosphatemia.
  • Sustained hyperphosphatemia causes secondary hyperparathyroidism which results in renal bone disease characterized by symptoms such as painful bone, fragile bone, bone deformation, and susceptibility to fracture.
  • renal bone disease complicated with hypercalcemia increases the risk of developing heart failure due to cardiovascular calcification.
  • the cardiovascular calcification is one of the most serious complications of chronic renal failure and the like. Therefore, for chronic renal failure patients, it is very important to properly control the amount of phosphate in the body in order to prevent hyperphosphatemia.
  • phosphate accumulated in the body is regularly removed and controlled by dialysis therapy such as hemodialysis, hemodiafiltration and hemofiltration so as not to cause hyperphosphatemia.
  • dialysis therapy generally requires three times a week and a treatment time of 4 hours each time.
  • phosphate 650 mg
  • Ordinary hemodialysis is capable of removing phosphate on the order of 800 to 1000 mg by one treatment of dialysis and is capable of removing approximately 3000 mg of phosphate by dialysis three times a week.
  • the amount (3000 mg) of phosphate that can be removed by dialysis therapy falls short of the amount (4550 mg) of phosphate accumulated in 1 week. As a result, phosphate accumulates in the body.
  • maintenance dialysis patients who are chronic renal failure patients lack renal functions serving as the main elimination route of phosphate and therefore substantially lack the function of excreting phosphate into urine.
  • phosphate can be removed from the body through a diffusion event into a dialysis fluid because the dialysis fluid is free from phosphate. In fact, sufficient excretion cannot be achieved by current dialysis time and dialysis conditions.
  • the dialysis therapy alone is not sufficiently effective for removing phosphate. Therefore, in addition to the dialysis therapy, diet therapy and drug therapy based on the drinking of phosphate adsorbing agents are carried out in order to control phosphate. The important thing is to limit phosphate intakes after confirmation that patients are not nutritionally depleted by the evaluation of their nutritional conditions.
  • a serum phosphate level of 3.5 mg/dL or lower is hypophosphatemia and is responsible for rachitis or osteomalacia, whereas a serum phosphate level of 6.0 mg/dL or higher is hyperphosphatemia and is responsible for cardiovascular calcification.
  • the diet therapy which involves reducing phosphate intakes depends on the nutritional conditions of patients and must also take patients' own tastes into consideration. Therefore, it is difficult to control phosphate concentrations in the body by the diet therapy.
  • phosphate concentrations are controlled by the administration before or during each meal of an oral phosphate adsorbing agent which forms insoluble phosphate through binding to food-derived phosphate ions in the gastrointestinal tract and thereby suppresses the absorption of phosphate from the intestinal tract.
  • the amount of the phosphate adsorbing agent drunk at the time of each meal is considerably large. Therefore, vomiting, a feeling of fullness, constipation, accumulation of the drug in the body, etc. occur with high probability as adverse reactions of the administered phosphate adsorbing agent. Therefore, drug compliance is very low (reportedly 50% or less) due to these adverse reactions. Thus, it is difficult both for doctors and for patients to control phosphate concentrations by use of the drug.
  • Patent Literature 1 discloses that phosphate in blood is efficiently removed without the direct contact of a phosphate adsorbing agent with blood, by circulating a dialysis composition comprising a phosphate adsorbing agent in a dialysis fluid at the time of hemodialysis treatment.
  • Patent Literature 2 discloses a hemodialysis system in which a phosphate adsorbing agent which removes phosphate accumulated in blood is disposed, aside from a hemodialyzer, in an extracorporeal blood circuit.
  • Patent Literature 3 discloses a porous formed article suitable for an adsorbing agent which can remove phosphate and the like by adsorption at a high speed.
  • Patent Literature 1 International Publication No. WO 2011/125758
  • Patent Literature 2 Japanese Patent Laid-Open No. 2002-102335
  • Patent Literature 3 Japanese Patent No. 4671419
  • Patent Literature 1 has the difficulty in completely eliminating phosphate on a concentration gradient. Furthermore, it is considered that the effect of eliminating phosphate is decreased because the concentration gradient of phosphate is decreased with increase in the performance of a dialysis membrane. In terms of the properties of dialysis fluid composition, there is also the possibility that insoluble matter remains. Thus, it may become difficult to control water system piping during dialysis.
  • phosphate is adsorbed by exchange with hydrochloride in a polycationic polymer disclosed as a phosphate adsorbing agent so that the hydrochloride is eliminated.
  • a polycationic polymer disclosed as a phosphate adsorbing agent
  • Patent Literature 3 disclosing the porous formed article makes no mention about phosphate in blood in the body. Thus, further studies are demanded.
  • An object of the present invention is to provide a porous formed article that can properly control phosphate concentrations in blood in the body.
  • the present inventors have conducted diligent studies to solve the problems described above and consequently completed the present invention by finding that the problems described above can be solved by using, as a phosphate adsorbing agent for blood processing, a porous formed article comprising an organic polymer resin and an inorganic ion adsorbent and having the most frequent pore size within a specific range measured with a mercury porosimeter.
  • the present invention is as follows:
  • a phosphate adsorbing agent for blood processing comprising a porous formed article comprising an organic polymer resin and an inorganic ion adsorbent and having the most frequent pore size of 0.08 to 0.70 ⁇ m measured with a mercury porosimeter.
  • the phosphate adsorbing agent for blood processing according to any of [1] to [3], wherein a ratio of the most frequent pore size of a median size (the most frequent pore size/median size) measured with a mercury porosimeter, of the porous formed article is 0.80 to 1.30.
  • the phosphate adsorbing agent for blood processing according to any of [1] to [4], wherein the porous formed article is spherical particles having an average particle size of 100 to 2500 ⁇ m.
  • x is 0 to 3
  • n is 1 to 4
  • m is 0 to 6
  • M and N are different from each other and each represent a metal element selected from the group consisting of Ti, Zr, Sn, Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb and Ta.
  • the phosphate adsorbing agent for blood processing according to any of [1] to [7], wherein the organic polymer resin contains at least one component selected from the group consisting of an ethylene vinyl alcohol copolymer (EVOH), polyacrylonitrile (PAN), polysulfone (PS), polyethersulfone (PES) and polyvinylidene fluoride (PVDF).
  • EVOH ethylene vinyl alcohol copolymer
  • PAN polyacrylonitrile
  • PS polysulfone
  • PS polyethersulfone
  • PVDF polyvinylidene fluoride
  • a blood processing system comprising a phosphate adsorbing agent for blood processing according to any of [1] to [8].
  • a blood processing method comprising a phosphate adsorption step of processing blood using a phosphate adsorbing agent for blood processing according to any of [1] to [8].
  • the phosphate adsorption step before and/or after the blood purification step.
  • the present invention can provide a porous formed article that can properly control phosphate concentrations in blood in the body.
  • FIG. 1 shows an electron microscope photograph (magnification: ⁇ 10,000) showing the outer surface of a porous formed article obtained in Example 1.
  • FIG. 2 shows the pore distribution diagram of the porous formed article obtained in Example 1, wherein a log differential pore volume and a cumulative pore volume were plotted against a pore diameter measured with a mercury porosimeter.
  • FIG. 3 shows the pore distribution diagram of porous formed articles obtained in Example 1 and Comparative Examples 1, 2 and 3, wherein a log differential pore volume was plotted against a pore diameter measured with a mercury porosimeter.
  • FIG. 4 is a schematic diagram showing a production apparatus for the porous formed article according to the present embodiment.
  • FIG. 5 is a schematic diagram showing a blood flow test in Example 1.
  • FIG. 6 is a schematic diagram showing the blood processing system according to the present embodiment.
  • FIG. 7 shows the relationship between a plasma flow volume and a phosphate adsorption rate (%) in Example 1.
  • FIG. 8 is a schematic diagram showing circuit 1 for the measurement test of the amount of phosphate removed in Example 16 and Comparative Example 4.
  • FIG. 9 is a schematic diagram showing circuit 2 for the measurement test of the amount of phosphate removed in Example 16 and Comparative Example 4.
  • FIG. 10 is a schematic diagram showing circuit 3 for the measurement test of the amount of phosphate removed in Example 16 and Comparative Example 4.
  • FIG. 11 shows the relationship between a phosphate removal rate and a total blood flow volume in circuit 1 .
  • FIG. 12 shows the relationship between the amount of phosphate removed and a total blood flow volume in circuit 1 .
  • FIG. 13 shows the relationship between a phosphate removal rate and a total blood flow volume in circuit 2 in the case of using a column packed with a spherical porous formed article prepared in Example 8 (phosphate adsorbing agent for blood processing).
  • FIG. 14 shows the relationship between the amount of phosphate removed and a total blood flow volume in circuit 2 in the case of using the column packed with the spherical porous formed article prepared in Example 8 (phosphate adsorbing agent for blood processing).
  • FIG. 15 shows the relationship between a phosphate removal rate and a total blood flow volume in circuit 3 in the case of using the column packed with the spherical porous formed article prepared in Example 8 (phosphate adsorbing agent for blood processing).
  • FIG. 16 shows the relationship between the amount of phosphate removed and a total blood flow volume in circuit 3 in the case of using the column packed with the spherical porous formed article prepared in Example 8 (phosphate adsorbing agent for blood processing).
  • the phosphate adsorbing agent for blood processing of the present embodiment comprises a porous formed article.
  • the porous formed article comprises an organic polymer resin and an inorganic ion adsorbent and has the most frequent pore size of 0.08 to 0.70 ⁇ m measured with a mercury porosimeter.
  • the porous formed article has continuous holes and has a porous structure.
  • the phosphate adsorbing agent for blood processing of the present embodiment is excellent in selectivity and adsorbing properties for phosphate in blood even at a high blood flow rate at the time of treatment with extracorporeal circulation, and can eliminate a necessary amount of phosphate in blood without influencing other components in the blood. Furthermore, the phosphate adsorbing agent for blood processing can properly control phosphate concentrations in blood without the drinking of oral phosphate adsorbing agents or the like having adverse reactions, because phosphate in the blood can be effectively removed by extracorporeal circulation.
  • the phosphate adsorbing agent for blood processing can efficiently excrete phosphate from the body by combined use with hemodialysis treatment, because the phosphate adsorbing agent can be effectively used even at the time of treatment with extracorporeal circulation having a high blood flow rate.
  • use of the phosphate adsorbing agent for blood processing of the present embodiment can properly control phosphate concentrations in blood in the body without causing adverse reactions in dialysis patients even if the dialysis patients take no oral phosphate adsorbing agent or take only a small amount of an oral phosphate adsorbing agent (auxiliary use).
  • the porous formed article according to the present embodiment has the most frequent pore size of 0.08 to 0.70 ⁇ m, preferably 0.10 to 0.60 ⁇ m, more preferably 0.20 to 0.50 ⁇ m, measured with a mercury porosimeter.
  • the most frequent pore size means a pore diameter that exhibits the largest value of a log differential pore volume on a diagram in which the log differential pore volume (dV/d (log D), wherein V represents a mercury penetration volume, and D represents a pore diameter) is plotted against the pore diameter measured with a mercury porosimeter, and is based on a volume.
  • the most frequent pore size can be measured by a method described in Examples.
  • the mercury porosimeter is an apparatus for evaluating the sizes of pores in porous materials according to the mercury penetration method, and is suitable for the measurement of relatively large pore distributions (mesopores (several nm) to macropores (several hundreds of ⁇ m)) which cannot be measured by the gas adsorption method (BET method).
  • the most frequent pore size can be measured with the mercury porosimeter to thereby measure the detailed features of the porous structure (skeletal structure) consisting of the organic polymer resin in the porous formed article.
  • a median size and a specific surface area can be measured with the mercury porosimeter to thereby measure the detailed features of the porous structure (skeletal structure) consisting of the organic polymer resin in the porous formed article.
  • the most frequent pore size of 0.08 ⁇ m or larger is sufficient as the pore size of continuous holes for diffusing phosphate serving as an object to be adsorbed into the inside of the porous formed article, and accelerates a diffusion rate.
  • the most frequent pore size of 0.70 ⁇ m or smaller is suitable for adsorbing many ions at the time of high-speed flushing because voids in the porous formed article are decreased so that the abundance of the inorganic ion adsorbent per unit volume is dense.
  • the outer surface opening ratio of the porous formed article is preferably 5% or more and less than 30%, more preferably 7% or more and 28% or less, further preferably 10% or more and 25% or less.
  • the outer surface opening ratio means the ratio of the total opening area of all holes to the area of a viewing field when the outer surface of the porous formed article is observed under a scanning electron microscope.
  • the outer surface opening ratio of 5% more accelerates the diffusion rate of phosphate serving as an object to be adsorbed into the inside of the porous formed article.
  • the outer surface opening ratio of less than 30% allows ions in water to be reliably adsorbed even in high-speed fluid flow because the abundance of the inorganic ion adsorbent on the outer surface of the porous formed article is large.
  • the outer surface opening ratio is actually measured by observing the outer surface of the porous formed article at ⁇ 10,000.
  • the outer surface opening ratio can be measured by a method described in Examples.
  • the ratio of the most frequent pore size to a median size (the most frequent pore size/median size) measured with a mercury porosimeter, of the porous formed article according to the present embodiment is preferably 0.80 to 1.30, more preferably 0.85 to 1.25, further preferably 0.90 to 1.20.
  • the median size means a pore diameter corresponding to a median value in the range from the largest value to the smallest value of cumulative pore volumes in a cumulative pore volume distribution, and is based on a volume.
  • the median size can be measured by a method described in Examples.
  • the most frequent pore size/median size ratio close to 1.0 is suitable for high-speed flushing because of the uniform pore size distribution of the porous formed article.
  • a dense layer having a small pore size skin layer
  • large voids layer with the largest pore size
  • the most frequent pore size/median size ratio of 0.80 to 1.30 means that the skin layer is absent in the porous formed article.
  • the specific surface area measured with a mercury porosimeter, of the porous formed article according to the present embodiment is preferably 10 to 100 m 2 /cm 3 , more preferably 11 to 90 m 2 /cm 3 , further preferably 12 to 50 m 2 /cm 3 .
  • the specific surface area of 10 m 2 /cm 3 or larger produces sufficient adsorption performance at the time of high-speed flushing because the amount of the inorganic ion adsorbent carried is large and the pore surface area is large.
  • the specific surface area of 100 m 2 /cm 3 or smaller produces the high strength of the porous formed article because the inorganic ion adsorbent is firmly carried.
  • the specific surface area is defined according to the following expression:
  • S(Hg) means the pore surface area (m 2 /g) per unit weight of the porous formed article.
  • a method for measuring the pore surface area involves drying the porous formed article in vacuum at room temperature, followed by measurement using a mercury porosimeter. Specifically, the pore surface area can be measured by a method described in Examples.
  • a method for measuring the bulk specific gravity is as follows.
  • the porous formed article When the porous formed article is in the form of particles, a cylinder, a hollow cylinder or the like and is short in shape, the apparent volume of the porous formed article in a wet state is measured with 1 mL regarded as 1 cm 3 using a measuring cylinder or the like. Then, the porous formed article is dried in vacuum at room temperature, and its weight is determined. The bulk specific gravity is calculated according to weight/volume.
  • the porous formed article When the porous formed article is in the form of a thread, a hollow fiber, a sheet or the like and is long in shape, the cross-section area and length of the wet porous formed article are measured. The volume is calculated from the product thereof. Then, the porous formed article is dried in vacuum at room temperature, and its weight is determined. The bulk specific gravity is calculated according to weight/volume.
  • the porous formed article according to the present embodiment is preferably substantially spherical with an average particle size of 100 to 2500 ⁇ m.
  • the average particle size is more preferably 150 to 2000 ⁇ m, further preferably 200 to 1500 ⁇ m.
  • the porous formed article according to the present embodiment is preferably spherical particles.
  • the spherical particles may be true spheres or oval spheres.
  • the average particle size of 100 ⁇ m or larger is suitable for high-speed flushing because pressure drop is small when a column, a tank or the like is packed with the porous formed article.
  • the average particle size of 2500 ⁇ m or smaller allows ions to be reliably adsorbed even in high-speed fluid flow because the surface area can be large when a column or a tank is packed with the porous formed article.
  • the average particle size means a median size of a sphere-equivalent diameter determined from the angle distribution of scattered light intensity of laser light diffraction when the porous formed article is regarded as a sphere.
  • the average particle size can be measured by a method described in Examples.
  • the organic polymer resin constituting the porous formed article according to the present embodiment is not particularly limited and is preferably a resin that can be rendered porous by an approach based on wet phase separation.
  • organic polymer resin examples include polysulfone polymers, polyvinylidene fluoride polymers, polyvinylidene chloride polymers, acrylonitrile polymers, polymethyl methacrylate polymers, polyamide polymers, polyimide polymers, cellulose polymers, ethylene vinyl alcohol copolymer-based polymers and many types.
  • an ethylene vinyl alcohol copolymer (EVOH), polyacrylonitrile (PAN), polysulfone (PS), polyethersulfone (PES) and polyvinylidene fluoride (PVDF) are preferred because of non-swellability in water, biodegradation resistance, and easy production.
  • EVOH ethylene vinyl alcohol copolymer
  • PAN polyacrylonitrile
  • PS polysulfone
  • PS polyethersulfone
  • PVDF polyvinylidene fluoride
  • the organic polymer resin is preferably polyethersulfone terminally having a hydroxy group.
  • the organic polymer resin having a hydroxy group as a terminal group can exert excellent carrying performance for the inorganic ion adsorbent in the porous formed article according to the present embodiment.
  • the highly hydrophobic organic polymer resin is improved in hydrophilicity because of terminally having a hydroxy group, and is less likely to cause fouling in the porous formed article.
  • the inorganic ion adsorbent constituting the porous formed article according to the present embodiment means an inorganic substance that exhibits an ion adsorption event or an ion exchange event.
  • Examples of the inorganic ion adsorbent of natural origin include various mineral substances such as zeolite and montmorillonite.
  • various mineral substances include kaolin mineral having a single-layer lattice of aluminosilicate, muscovite having a two-layer lattice structure, glauconite, Kanuma soil, pyrophyllite, talc, feldspar having a three-dimensional skeletal structure, zeolite and montmorillonite.
  • Examples of the inorganic ion adsorbent of synthetic origin include metal oxides, salts of polyvalent metals and insoluble aqueous oxides.
  • the metal oxides include mixed metal oxides, mixed metal hydroxides and aqueous oxides of metals.
  • the inorganic ion adsorbent preferably contains a metal oxide represented by the following formula (I) from the viewpoint of adsorption performance for an object to be adsorbed, particularly, phosphate:
  • x is 0 to 3
  • n is 1 to 4
  • m is 0 to 6
  • M and N are different from each other and each represent a metal element selected from the group consisting of Ti, Zr, Sn, Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Al, Si, Cr, Co, Ga, Fe, Mn, Ni, V, Ge, Nb and Ta.
  • the metal oxide may be a non-aqueous (non-hydrous) metal oxide represented by the formula (I) wherein m is 0, or may be an aqueous metal oxide (hydrous metal oxide) represented by the formula (I) wherein m is a numerical value other than 0.
  • the metal oxide represented by the formula (I) wherein x is a numerical value other than 0 is a mixed metal oxide in which each metal element contained is uniformly distributed with regularity throughout the oxide and the compositional ratio of metal elements contained in the metal oxide is represented by a fixed chemical formula.
  • such a metal oxide forms a perovskite structure, a spinel structure or the like, and examples thereof include nickel ferrite (NiFe 2 O 4 ) and aqueous ferrite of zirconium (Zr.Fe 2 O 4 .mH 2 O, wherein m is 0.5 to 6).
  • the inorganic ion adsorbent may contain a plurality of metal oxides represented by the formula (I).
  • the inorganic ion adsorbent preferably contains at least one material selected from any of the following groups (a) to (c) from the viewpoint of excellent adsorption performance for an object to be adsorbed, particularly, phosphate:
  • a material selected from any of the groups (a) to (c) may be used, materials selected from any of the groups (a) to (c) may be used in combination, or the respective materials of the groups (a) to (c) may be used in combination.
  • a mixture of two or more materials selected from any of the groups (a) to (c) may be used, or a mixture of two or more materials selected from two or more of the groups (a) to (c) may be used.
  • the inorganic ion adsorbent may contain aluminum sulfate-impregnated activated alumina from the viewpoint of inexpensiveness and high adsorbing properties.
  • the inorganic ion adsorbent In addition to the metal oxide represented by the formula (I), it is more preferred for the inorganic ion adsorbent to further solid-dissolve a metal element other than M and N, from the viewpoint of inorganic ion adsorbing properties and production cost.
  • Examples thereof include iron solid-dissolved in hydrous zirconium oxide represented by ZrO 2 .mH 2 O (m is a numerical value other than 0).
  • salts of polyvalent metals include a hydrotalcite compound represented by the following formula (II):
  • M 2+ is at least one divalent metal ion selected from the group consisting of Me, Ni 2+ , Zn 2+ , Fe 2+ , Ca 2+ and Cu 2+ .
  • M 3+ is at least one trivalent metal ion selected from the group consisting of Al 3+ and Fe 3+ .
  • a n ⁇ is a n-valent anion.
  • p is 0.1 ⁇ p ⁇ 0.5
  • q is 0.1 ⁇ q ⁇ 0.5
  • r is 1 or 2.
  • the hydrotalcite compound represented by the formula (II) is preferred because of an inexpensive raw material and high adsorbing properties as the inorganic ion adsorbent.
  • insoluble aqueous oxides examples include insoluble heteropoly acid salts and insoluble hexacyanoferrate.
  • the inorganic ion adsorbent constituting the porous formed article according to the present embodiment may contain a contaminating impurity element ascribable to a production method thereof, etc., without inhibiting the functions of the porous formed article.
  • a contaminating impurity element include nitrogen (nitrate nitrogen, nitrite nitrogen and ammonium nitrogen), sodium, magnesium, sulfur, chlorine, potassium, calcium, copper, zinc, bromine, barium and hafnium.
  • the phosphate adsorbing agent for blood processing of the present embodiment is preferably used in phosphate adsorption in the hemodialysis of dialysis patients.
  • Blood composition is divided into plasma components and blood cell components.
  • the plasma components are constituted by 91% of water, 7% of proteins, lipid components and inorganic salts. Phosphate in blood is present as a phosphate ion in the plasma components.
  • the blood cell components are constituted by 96% of red blood cells, 3% of white blood cells and 1% of platelets.
  • the size of the red blood cells is 7 to 8 ⁇ m in diameter.
  • the size of the white blood cells is 5 to 20 ⁇ m in diameter.
  • the size of the platelets is 2 to 3 ⁇ m in diameter.
  • the phosphate adsorbing agent for blood processing of the present embodiment comprises the porous formed article having a large abundance of the inorganic ion adsorbent on the outer surface, because the porous formed article has the most frequent pore size of 0.08 to 0.70 ⁇ m measured with a mercury porosimeter. Therefore, the phosphate adsorbing agent for blood processing can reliably adsorb phosphate ions even in high-speed fluid flow and is also excellent in the property of penetrating, diffusing, and adsorbing phosphate ions into the inside of the porous formed article. Furthermore, the phosphate adsorbing agent for blood processing prevents blood flowing properties from being reduced due to, for example, clogging with blood cell components or the like.
  • the phosphate adsorbing agent for blood processing of the present embodiment comprising the porous formed article comprising an organic polymer resin and an inorganic ion adsorbent and having the most frequent pore size of 0.08 to 0.70 ⁇ M measured with a mercury porosimeter can selectively and reliably adsorb phosphate ions in blood.
  • the phosphate concentration in blood brought back into the body is almost zero.
  • the blood substantially free from phosphate is brought back into the body so that phosphate migrates actively from within or without cells into the blood, probably enhancing a refilling effect.
  • the phosphate adsorbing agent for blood processing can properly control phosphate concentrations in blood in the body without causing adverse reactions in dialysis patients even if the dialysis patients take no oral phosphate adsorbing agent or take only a small amount of an oral phosphate adsorbing agent (auxiliary use).
  • An appropriate column or the like packed with the phosphate adsorbing agent for blood processing of the present embodiment can be connected in series, in parallel or the like upstream or downstream of a dialyzer, and used in dialysis.
  • a column or the like can be packed with the phosphate adsorbing agent for blood processing of the present embodiment and used as a column for phosphate adsorption.
  • the resulting column for phosphate adsorption is excellent in selectivity and adsorption performance for inorganic phosphate even in a state where blood has a low phosphate concentration and the space velocity is fast.
  • the column packed with the phosphate adsorbing agent for blood processing of the present embodiment is preferably connected upstream or downstream of a dialyzer and used, from the viewpoint of easily inducing a refilling effect.
  • the phosphate adsorption rate (%) (rate at which phosphate in blood is adsorbed) is preferably 50% or more, more preferably 60% or more, further preferably 70% or more, 80% or more, 85% or more, 90% or more, 95% or more or 99% or more, from the viewpoint that a refilling effect can be expected.
  • a method for producing the porous formed article according to the present embodiment comprises the steps of: (1) crushing and mixing a good solvent for the organic polymer resin and the inorganic ion adsorbent to obtain slurry; (2) dissolving the organic polymer resin and a water-soluble polymer in the slurry obtained in the step (1); (3) shape-forming the slurry obtained in the step (2); (4) promoting coagulation of the shape-formed product obtained in the step (3) by controlling the temperature and humidity of a spatial portion coming into contact with the shape-formed product, until the shape-formed product is coagulated in a poor solvent; and (5) coagulating the coagulation-promoted shape-formed product obtained in the step (4), in a poor solvent.
  • Step (1) crushing and mixing step
  • a good solvent for the organic polymer resin and the inorganic ion adsorbent are crushed and mixed to obtain slurry.
  • the inorganic ion adsorbent can be wet-crushed in the good solvent for the organic polymer resin to thereby finely pulverize the inorganic ion adsorbent.
  • the inorganic ion adsorbent carried by the porous formed article after shape forming has only a small amount of secondary aggregates.
  • the good solvent for the organic polymer resin in the step (1) is not particularly limited as long as the good solvent stably dissolves more than 1% by mass of the organic polymer resin under production conditions for the porous formed article.
  • a good solvent conventionally known in the art can be used.
  • DMSO dimethyl sulfoxide
  • NMP N-methyl-2-pyrrolidone
  • DMAC N,N-dimethylacetamide
  • DMF N,N-dimethylformamide
  • Only one of these good solvents may be used, or two or more thereof may be used as a mixture.
  • the crushing and mixing unit used to obtain slurry is not particularly limited as long as the inorganic ion adsorbent and the good solvent for the organic polymer resin can be crushed and mixed together.
  • a unit for use in a physical disruption method such as crushing under pressure, mechanical grinding or ultrasonic treatment can be used as the crushing and mixing unit.
  • crushing and mixing unit include generator shaft-type homogenizers, blenders such as Waring blenders, media agitation mills such as sand mills, ball mills, attritors and beads mills, jet mills, mortars and pestles, stone mills and ultrasonic baths.
  • blenders such as Waring blenders
  • media agitation mills such as sand mills, ball mills, attritors and beads mills
  • jet mills mortars and pestles
  • stone mills and ultrasonic baths include generator shaft-type homogenizers, blenders such as Waring blenders, media agitation mills such as sand mills, ball mills, attritors and beads mills, jet mills, mortars and pestles, stone mills and ultrasonic baths.
  • a media agitation mill is preferred because the media agitation mill has high crushing efficiency and can crush even highly viscous matter.
  • the ball size for use in the media agitation mill is not particularly limited and is preferably 0.1 to 10 mm.
  • the ball size is 0.1 mm or larger, the ball mass is sufficient. Therefore, the resulting media agitation mill has crushing power and high crushing efficiency.
  • the ball size is 10 mm or smaller, the resulting media agitation mill is excellent in finely crushing ability.
  • Examples of the material of the ball for use in the media agitation mill include, but are not particularly limited to, metals such as iron and stainless, oxides such as alumina and zirconia, and various ceramics of non-oxides such as silicon nitride and silicon carbide. Among them, zirconia is excellent in terms of excellent abrasion resistance and low contamination of products (contamination by abrasive matter).
  • a dispersant known in the art such as a surfactant, may be added into the good solvent for the organic polymer resin mixed with the inorganic ion adsorbent during the crushing and mixing, without influencing the structure of the porous formed article.
  • step (2) the organic polymer resin and a water-soluble polymer are dissolved in the slurry obtained by the step (1) to obtain slurry for shape forming.
  • the amount of the organic polymer resin added is preferably set such that an organic polymer resin/(organic polymer resin+water-soluble polymer+good solvent for the organic polymer resin) ratio is 3 to 40% by mass, more preferably 4 to 30% by mass.
  • an organic polymer resin/(organic polymer resin+water-soluble polymer+good solvent for the organic polymer resin) ratio is 3 to 40% by mass, more preferably 4 to 30% by mass.
  • the water-soluble polymer in the step (2) is not particularly limited as long as the water-soluble polymer is compatible with the good solvent for the organic polymer resin and the organic polymer resin.
  • Any of natural, semisynthetic and synthetic polymers can be used as the water-soluble polymer.
  • Examples of the natural polymer include guar gum, locust bean gum, carrageenan, gum arabic, tragacanth, pectin, starch, dextrin, gelatin, casein and collagen.
  • Examples of the semisynthetic polymer include methylcellulose, ethylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, carboxymethyl starch and methyl starch.
  • Examples of the synthetic polymer include polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, carboxyvinyl polymers, sodium polyacrylate and polyethylene glycols such as tetraethylene glycol and triethylene glycol.
  • a synthetic polymer is preferred from the viewpoint of enhancing carrying properties for the inorganic ion adsorbent, and polyvinylpyrrolidone and polyethylene glycols are more preferred from the viewpoint of improving porosity.
  • the mass-average molecular weights of the polyvinylpyrrolidone and the polyethylene glycols are preferably 400 to 35,000,000, more preferably 1,000 to 1,000,000, further preferably 2,000 to 100,000.
  • the mass-average molecular weight is 2,000 or larger, the resulting porous formed article has high surface opening properties.
  • mass-average molecular weight is 1,000,000 or smaller, shape forming tends to be easy because of the low viscosity of the slurry during the shape forming.
  • the mass-average molecular weight of the water-soluble polymer can be measured by the gel permeation chromatography (GPC) analysis of the water-soluble polymer dissolved in a predetermined solvent.
  • GPC gel permeation chromatography
  • the amount of the water-soluble polymer added is preferably set such that a water-soluble polymer/(water-soluble polymer+organic polymer resin+good solvent for the organic polymer resin) ratio is 0.1 to 40% by mass, more preferably 0.5 to 30% by mass, further preferably 1 to 10% by mass.
  • a porous formed article containing a fibrous structure where a three-dimensionally continuous network structure is formed in the outer surface and inside of the porous formed article is homogeneously obtained.
  • the amount of the water-soluble polymer added is 40% by mass or less, the outer surface opening ratio is proper.
  • the resulting porous formed article can reliably adsorb ions even in high-speed fluid flow because the abundance of the inorganic ion adsorbent on the outer surface of the porous formed article is large.
  • Step (3) Shape Forming Step
  • the slurry (slurry for shape forming) obtained by the step (2) is shape-formed.
  • the slurry for shape forming is mixed slurry of the organic polymer resin, the good solvent for the organic polymer resin, the inorganic ion adsorbent and the water-soluble polymer.
  • the form of the porous formed article according to the present embodiment can adopt any form of particles, a thread, a sheet, a hollow fiber, a cylinder, a hollow cylinder and the like, depending on a method for shape-forming the slurry for shape forming.
  • Examples of the method for shape-forming the slurry into the form of particles include, but are not particularly limited to, a rotary nozzle method which involves using a nozzle disposed on the side of a rotating container so that the slurry for shape forming contained in the container is scattered from the nozzle to form liquid drops.
  • a rotary nozzle method which involves using a nozzle disposed on the side of a rotating container so that the slurry for shape forming contained in the container is scattered from the nozzle to form liquid drops.
  • the slurry can be shape-formed into the form of particles having a uniform particle size distribution.
  • the diameter of the nozzle is preferably 0.1 to 10 mm, more preferably 0.1 to 5 mm.
  • the nozzle having a diameter of 0.1 mm or larger easily scatters liquid drops.
  • the nozzle having a diameter of 10 mm or smaller can render the particle size distribution uniform.
  • the centrifugal force is indicated by centrifugal acceleration and is preferably 5 to 1500 G, more preferably 10 to 1000 G, further preferably 10 to 800 G.
  • the centrifugal acceleration When the centrifugal acceleration is 5 G or larger, the formation of liquid drops and scattering are easy. When the centrifugal acceleration is 1500 G or smaller, the slurry for shape forming is discharged without becoming the form of a thread, and can prevent the particle size distribution from being widened.
  • the narrow particle size distribution has the advantage that a column packed with the porous formed article has uniform water flow channels and therefore prevents ions (object to be adsorbed) from leaking out (breaking through the column) from the initial stage of flushing even if ultrahigh-speed flushing is used.
  • Examples of the method for shape-forming the slurry into the form of a thread or a sheet include a method which involves extruding the slurry for shape forming from a spinneret or a die having the corresponding shape, and coagulating the extrudate in a poor solvent.
  • the method for shape-forming the slurry into a porous formed article in the form of a hollow fiber employs a spinneret consisting of a circular orifice and can thereby shape-form the slurry in the same way as the method for shape-forming the slurry into a porous formed article in the form of a thread or a sheet.
  • the method for shape-forming the slurry into a porous formed article in the form of a cylinder or a hollow cylinder may coagulate the extrudate of the slurry for shape forming from a spinneret in a poor solvent while cutting the extrudate or may coagulate the extrudate into the form of a thread and then cut the thread.
  • step (4) coagulation of the shape-formed product obtained by the step (3) is promoted by controlling the temperature and humidity of a spatial portion coming into contact with the shape-formed product, until the shape-formed product is coagulated in a poor solvent.
  • the step (4) can adjust the most frequent pore size and the outer surface opening ratio measured with a mercury porosimeter, and produces a formed article having a high abundance of the inorganic ion adsorbent.
  • the porous formed article provided thereby can remove ions, particularly, phosphate ions, in water to be processed at an ultrahigh speed and has a large adsorption capacity.
  • the temperature and humidity of the spatial portion are controlled by covering the space between a coagulation vessel in which the poor solvent is retained and the rotary container with a cover to adjust the temperature of the poor solvent.
  • the temperature of the spatial portion is preferably 20 to 90° C., more preferably 25 to 85° C., further preferably 30 to 80° C.
  • the outer surface opening ratio of the porous formed article is increased.
  • the nozzle opening in the rotary container is less likely to be clogged by the slurry.
  • the porous formed article can be stably produced for a long time.
  • the humidity of the spatial portion is relative humidity at the temperature and is preferably 65 to 100%, more preferably 70 to 100%, further preferably 75 to 100%.
  • the relative humidity is 65% or higher, the outer surface opening ratio of the porous formed article is increased.
  • the relative humidity is 100% or lower, the nozzle opening in the rotary container is less likely to be clogged by the slurry.
  • the porous formed article can be stably produced for a long time.
  • the coagulation-promoted shape-formed product obtained in the step (4) is coagulated in a poor solvent to obtain a porous formed article.
  • a solvent having an organic polymer resin solubility of 1% by mass or less under the conditions of the step (5) can be used as the poor solvent in the step (5).
  • Examples thereof include water, alcohols such as methanol and ethanol, ethers and aliphatic hydrocarbons such as n-hexane and n-heptane. Among them, water is preferred as the poor solvent.
  • the good solvent is brought in from the preceding steps so that the concentration of the good solvent varies between the start of the coagulation step and the end thereof. Therefore, the poor solvent may be supplemented with the good solvent in advance. It is preferred to perform the coagulation step by controlling the concentration while separately adding water or the like so as to maintain the initial concentration.
  • the concentration of the good solvent can be adjusted to thereby control the structure (outer surface opening ratio and particle shape) of the porous formed article.
  • the content of the good solvent for the organic polymer resin with respect to water in the coagulation step is preferably 0 to 80% by mass, more preferably 0 to 60% by mass.
  • the content of the good solvent for the organic polymer resin is 80% by mass or less, the effect of improving the shape of the porous formed article is obtained.
  • the temperature of the poor solvent is preferably 40 to 100° C., more preferably 50 to 100° C., further preferably 60 to 100° C., from the viewpoint of controlling the temperature and humidity of the spatial portion in the step (4).
  • a production apparatus for the porous formed article according to the present embodiment has a rotary container which scatters liquid drops by centrifugal force, and a coagulation vessel which retains a coagulating liquid, and has a control unit which has a cover put over a spatial portion between the rotary container and the coagulation vessel and controls the temperature and humidity of the spatial portion.
  • the rotary container which scatters liquid drops by centrifugal force is not limited by a specific structure as long as the rotary container has the function of scattering the slurry for shape forming as spherical liquid drops by centrifugal force. Examples thereof include well-known rotary discs and rotary nozzles.
  • the rotary disc is configured such that the slurry for shape forming is supplied to the center of the rotating disc and then developed in a film form with a uniform thickness along the surface of the rotating disc so that the slurry is split dropwise by centrifugal force from the rim of the disc to scatter very small liquid drops.
  • the rotary nozzle is configured such that a large number of through-holes are formed in the peripheral wall of a hollow disc-shaped rotary container or a nozzle is attached to the rotary container so as to penetrate the peripheral wall, and the slurry for shape forming is supplied into the rotary container while the rotary container is rotated so that the slurry for shape forming is discharged by centrifugal force from the through-holes or the nozzle to form liquid drops.
  • the coagulation vessel which retains a coagulating liquid is not limited by a specific structure as long as the coagulation vessel has the function of being capable of retaining the coagulating liquid.
  • Examples thereof include well-known coagulation vessels having an upper opening, and coagulation vessels having a structure where the coagulating liquid spontaneously flows downward by gravity along the inner face of a tubular body disposed so as to surround the rotary container.
  • the coagulation vessel having an upper opening is an apparatus in which the liquid drops scattered in a horizontal direction from the rotary container spontaneously flow downward and are then captured by the surface of the coagulating liquid retained in the coagulation vessel having an upper opening.
  • the coagulation vessel having a structure where the coagulating liquid spontaneously flows downward by gravity along the inner face of a tubular body disposed so as to surround the rotary container is an apparatus in which the coagulating liquid flows out in almost equal flow volumes in the circumferential direction along the inner face of the tubular body and spontaneously flows downward along the inner face so that the liquid drops are captured into the coagulating liquid flow and coagulated.
  • the control unit for the temperature and humidity of the spatial portion has a cover put over the spatial portion between the rotary container and the coagulation vessel and controls the temperature and humidity of the spatial portion.
  • the cover put over the spatial portion is not limited by a specific structure as long as the cover has the function of isolating the spatial portion from the external environment and facilitating practically controlling the temperature and humidity of the spatial portion.
  • the cover can have, for example, a box, tubular, or umbrella shape.
  • cover examples include metallic stainless steels and plastics.
  • the cover may be covered with a heat insulation material known in the art in terms of isolation from the external environment.
  • the cover may be provided with a partial opening for temperature and humidity adjustment.
  • the control unit for the temperature and humidity of the spatial portion is not limited by a specific unit as long as the control unit has the function of controlling the temperature and humidity of the spatial portion.
  • Examples thereof include heaters such as electric heaters and steam heaters and humidifiers such as ultrasonic humidifiers and heating humidifiers.
  • a unit of warming the coagulating liquid retained in the coagulation vessel and controlling the temperature and humidity of the spatial portion through the use of steam generated from the coagulating liquid is preferred in terms of a convenient structure.
  • the blood processing system of the present embodiment comprises the phosphate adsorbing agent for blood processing of the present embodiment.
  • the blood processing system further comprises a blood purifier.
  • FIG. 6 is a schematic diagram showing the blood processing system according to one embodiment.
  • the phosphate adsorbing agent for blood processing should be disposed such that blood processed by the phosphate adsorbing agent for blood processing of the present embodiment is processed by the blood purifier.
  • the phosphate adsorbing agent for blood processing is preferably disposed in series or in parallel upstream or downstream of the blood purifier.
  • Examples of the blood purifier include, but are not particularly limited to, an artificial kidney (dialyzer) for use in dialysis therapy or the like.
  • Examples of the blood purifier of the present embodiment include blood purifiers using a separation membrane comprising a polysulfone polymer and a polyvinylpyrrolidone.
  • the polysulfone polymer is a polymer containing a sulfone (—SO 2 —) group in its structure.
  • polysulfone polymer examples include polyphenylene sulfone, polysulfone, polyarylethersulfone, polyethersulfone and copolymers thereof.
  • a polysulfone polymer represented by the following formula (1) or (2) is preferred from the viewpoint of controlling fractionating properties:
  • Ar represents a benzene ring
  • n represents the repeat of the polymer and is an integer of 1 or larger.
  • Examples of the polysulfone polymer represented by the formula (1) include commercially available products under the name of “Udel (trademark)” from Solvay S.A. and under the name of “Ultrason (trademark)” from BASF Japan Ltd.
  • Examples of the polyethersulfone represented by the formula (2) include commercially available products under the name of “Sumikaexcel (trademark)” from Sumitomo Chemical Co., Ltd. Some types exist depending on the degree of polymerization, etc. Therefore, these polymers can be appropriately used.
  • the polyvinylpyrrolidone is a water-soluble hydrophilic polymer prepared by vinyl-polymerizing N-vinylpyrrolidone, and is widely used as a material for hollow fiber membranes as a hydrophilizing agent or a hole forming agent.
  • polyvinylpyrrolidones differing in molecular weight are commercially available under the name of “Luvitec (trademark)” from BASF Japan Ltd. Therefore, these polymers can be appropriately used.
  • the separation membrane may comprise a constituent other than the polysulfone polymer and the polyvinylpyrrolidone as its constituents.
  • additional constituent include polyhydroxyalkyl methacrylates such as polyhydroxyethyl methacrylate, polyhydroxypropyl methacrylate and polyhydroxybutyl methacrylate and polyethylene glycol.
  • the content of the additional constituent in the separation membrane is not particularly limited.
  • the content is 20% by mass or less and may be 10% by mass or less or may be 5% by mass or less.
  • the ratio of the polyvinylpyrrolidone to the polysulfone polymer is preferably 42% by mass or less because the amount of the polyvinylpyrrolidone eluted can be suppressed.
  • the ratio of the polyvinylpyrrolidone to the polysulfone polymer is preferably 15% by mass or more, more preferably 20% by mass or more.
  • the polyvinylpyrrolidone concentration on the surface of the separation membrane can be controlled to within a preferred range.
  • the resulting separation membrane for blood processing can be more effective for suppressing protein adsorption and be excellent in blood compatibility.
  • the shape of the separation membrane is not limited.
  • the separation membrane preferably has a hollow fiber shape.
  • the separation membrane is preferably crimped from the viewpoint of permeation performance.
  • the separation membrane can be produced by membrane formation according to an ordinary method using a membrane forming dope containing at least the polysulfone polymer and the polyvinylpyrrolidone.
  • the membrane forming dope can be prepared by dissolving the polysulfone polymer and the polyvinylpyrrolidone in a solvent.
  • Examples of such a solvent include dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, dimethylformamide, sulfolane and dioxane.
  • Only one of these solvents may be used, or two or more thereof may be used as a mixture.
  • the concentration of the polysulfone polymer in the membrane forming dope is not particularly limited as long as the concentration falls within a range that permits membrane formation and allows the resulting separation membrane to have performance as a permeable membrane.
  • the concentration is preferably 5 to 35% by mass, more preferably 10 to 30% by mass.
  • a lower polysulfone resin concentration is more preferred for achieving high water permeation performance.
  • the concentration of the polysulfone polymer is further preferably 10 to 25% by mass.
  • the concentration of the polyvinylpyrrolidone in the membrane forming dope is not particularly limited.
  • the ratio of the polyvinylpyrrolidone to the polysulfone polymer is preferably adjusted to 27% by mass or less, more preferably 18 to 27% by mass, further preferably 20 to 27% by mass.
  • the ratio of the polyvinylpyrrolidone to the polysulfone polymer in the membrane forming dope is 27% by mass or less
  • the amount of the polyvinylpyrrolidone eluted can be suppressed.
  • the polyvinylpyrrolidone concentration on the surface of the separation membrane can be controlled to within a preferred range.
  • the resulting separation membrane can be more effective for suppressing protein adsorption and be excellent in blood compatibility.
  • the separation membrane can be formed as a flat membrane or a hollow fiber membrane by a method usually used using the membrane forming dope as mentioned above.
  • the method for producing the separation membrane will be described by taking a hollow fiber membrane as an example.
  • a tube-in-orifice spinneret is used.
  • a membrane forming spinning dope and a bore liquid for coagulating the membrane forming spinning dope are discharged at the same time from the orifice and the tube, respectively, of the spinneret into the air.
  • Water or a liquid composed mainly of water can be used as the bore liquid.
  • a mixed solution of the solvent used in the membrane forming spinning dope and water is preferably used.
  • an aqueous solution containing 20 to 70% by mass of dimethylacetamide is used.
  • the amount of the membrane forming spinning dope discharged and the amount of the bore liquid discharged can be adjusted to thereby adjust the inside diameter and membrane thickness of the hollow fiber membrane to the desired values.
  • the inside diameter of the hollow fiber membrane is not particularly limited and can be generally 170 to 250 ⁇ m, preferably 180 to 220 ⁇ m, for the purpose of blood processing.
  • the membrane thickness of the hollow fiber membrane is preferably 50 ⁇ m or smaller from the viewpoint of the efficiency of diffusion and removal of low-molecular-weight matter by mass transfer resistance as a permeable membrane.
  • the membrane thickness of the hollow fiber membrane is preferably 10 ⁇ m or larger from the viewpoint of strength.
  • the membrane forming spinning dope discharged together with the bore liquid from the spinneret is allowed to travel in an airgap portion, then introduced into a coagulation bath which is located beneath the spinneret and composed mainly of water, and dipped for a given time to complete the coagulation.
  • a draft indicated by the ratio between the linear speed of discharge of the membrane forming spinning dope and a take-up speed should be 1 or less.
  • the air gap means the space between the spinneret and the coagulation bath.
  • the coagulation of the membrane forming spinning dope is started from the inner surface side by the poor solvent component (poor solvent component for the polysulfone polymer and the polyvinylpyrrolidone) such as water in the bore liquid discharged at the same time therewith from the spinneret.
  • the draft is preferably 1 or less, more preferably 0.95 or less, for forming smooth separation membrane surface at the start of coagulation and stabilizing the separation membrane structure.
  • the solvent remaining in the hollow fiber membrane is removed by washing with hot water or the like.
  • the resultant can be introduced into a dryer in a continuous fashion and dried in hot air or the like to obtain a hollow fiber membrane.
  • the washing is preferably carried out with hot water of 60° C. or higher for 120 seconds or longer, more preferably with hot water of 70° C. or higher for 150 seconds or longer, for removing unnecessary polyvinylpyrrolidone.
  • the water content of the separation membrane is preferably adjusted to 10% by mass or less by the drying, because the separation membrane is embedded in a urethane resin in a downstream process and sterilized by radiation in a dry state in the present embodiment.
  • the hollow fiber membrane obtained through these steps can be subjected, as a bundle with an adjusted length and number of fibers, to a module production step so as to attain the desired membrane area.
  • the hollow fiber membrane is charged into a tubular container having two nozzles in the vicinity of both lateral ends, and embedded at its both ends with a urethane resin.
  • the cured urethane moieties at both ends are cut off and thereby processed into end portions at which the hollow fiber membrane is opened (exposed).
  • Header caps having a liquid inlet or outlet nozzle are respectively fitted in these end portions to fabricate the shape of a blood processor.
  • the blood processing method of the present embodiment comprises a phosphate adsorption step of processing blood using the phosphate adsorbing agent for blood processing of the present embodiment.
  • the blood processing method preferably comprises: a blood purification step of processing blood using a blood purifier; and the phosphate adsorption step before and/or after the blood purification step.
  • the phosphate adsorbing agent for blood processing is preferably used at the time of treatment with extracorporeal circulation and more preferably used at the time of hemodialysis treatment.
  • the blood purifier for use in the treatment with extracorporeal circulation can remove phosphate in blood at a predetermined ratio by diffusion, filtration, adsorption and the like, and can therefore drastically improve the amount of blood processible by the phosphate adsorbing agent for blood processing by combined use with the phosphate adsorbing agent for blood processing.
  • the phosphate adsorbing agent for blood processing When the phosphate adsorbing agent for blood processing is disposed upstream of the blood purifier, the amount of phosphate removed based on elimination by the phosphate adsorption column is increased because of the high concentration of phosphate in blood entering the phosphate adsorption column. Also, there is a possibility that even if foreign matter is generated from the phosphate adsorbing agent due to some problem, an unsafe circumstance can be avoided by the blood purifier serving as a filter.
  • the blood purifier and the phosphate adsorbing agent for blood processing are disposed such that blood passes through the blood purifier and then the phosphate adsorbing agent and such that blood from which phosphate has already been removed at a given ratio is processed by the phosphate adsorbing agent for blood processing, there is a possibility that the amount of the phosphate adsorbing agent can be decreased by improving the amount of blood processible by the phosphate adsorbing agent for blood processing having a limited phosphate adsorption volume.
  • porous formed article sample was held on a carbon adhesive tape/alumina sample table and electro-conductively coated with osmium (Os) to prepare an outer surface SEM observation sample.
  • Os osmium
  • the porous formed article was dried in vacuum at room temperature. Then, the most frequent pore size and median size were measured with a mercury porosimeter (manufactured by Shimadzu Corp., Shimadzu AutoPore model IV9500).
  • An image of the outer surface of the porous formed article photographed using a scanning electron microscope (SEM) was analyzed using image analysis software (manufactured by Asahi Kasei Engineering Corp., A-Zo-Kun (trade name)) to determine the outer surface opening ratio. More specifically, a threshold was manually adjusted such that the obtained SEM image was recognized as a grayscale image and the dark color portion and the light color portion corresponded to an opening and a porous structure (skeletal structure), respectively. The image was divided into the opening portion and the skeletal portion, and an area ratio thereof was determined. In order to reduce errors of threshold determination, the same measurement was performed for 10 images, and an average value was calculated.
  • the porous formed article was dried in vacuum at room temperature. Then, the pore surface area S(Hg) (m 2 /g) per unit mass of the porous formed article was measured using a mercury porosimeter (manufactured by Shimadzu Corp., Shimadzu AutoPore model IV9500).
  • the porous formed article in a state wetted with water was tapped using a measuring cylinder, and its apparent volume V (cm 3 ) was measured. Then, the porous formed article was dried in vacuum at room temperature, and the dry mass W (g) of the porous formed article was determined.
  • the specific surface area of the porous formed article was determined according to the following expression:
  • S(Hg) is the surface area (m 2 /g) per unit mass of the porous formed article
  • W is the dry mass (g) of the porous formed article
  • V is the apparent volume (cm 3 ) thereof.
  • the average particle size of the porous formed article and the average particle size of the inorganic ion adsorbent were measured using a laser diffraction/scattering particle size distribution measurement apparatus (LA-950 (trade name) manufactured by HORIBA, Ltd.). Water was used as a dispersion medium.
  • LA-950 laser diffraction/scattering particle size distribution measurement apparatus
  • Water was used as a dispersion medium.
  • hydrous cerium oxide as the inorganic ion adsorbent
  • the sample was assayed by using the value of cerium oxide as a refractive index.
  • the sample was assayed by using the value of zirconium oxide as a refractive index.
  • the phosphate ion concentration was measured by the direct molybdate method.
  • a sample having an amount of phosphate adsorbed of 1.5 (mg-P/mL-porous formed article) or larger at a fluid flow rate of SV120 was assessed as being a good phosphate adsorbing agent having a large adsorption capacity.
  • the obtained slurry solution for shape forming was warmed to 60° C. and supplied to the inside of a cylindrical rotary container in which a nozzle having a diameter of 4 mm was opened on the lateral side. This container was rotated to form liquid drops from the nozzle by centrifugal force (15 G). Subsequently, the spatial portion between the rotary container and a coagulation vessel was covered with a polypropylene cover to control the temperature and relative humidity of the spatial portion to 50° C. and 100%, respectively.
  • the liquid drops were allowed to travel in this spatial portion and arrive at a coagulating liquid (content of NMP with respect to water: 50% by mass) warmed to 80° C., which was retained in a coagulation vessel having an upper opening, to coagulate the slurry for shape forming.
  • a coagulating liquid content of NMP with respect to water: 50% by mass
  • Washing and classification were further performed to obtain a spherical porous formed article.
  • FIG. 1 An electron microscope photograph (magnification: ⁇ 10,000) showing the surface of the obtained porous formed article is shown in FIG. 1 .
  • Blood was collected from healthy human donors. To 100 mL of the blood, 14 mL of a CPD solution (anticoagulant solution) was added, and the mixture was centrifuged to separate between blood cell components and plasma components.
  • CPD solution anticoagulant solution
  • the phosphate concentration (measurement method: direct molybdate method) in the plasma components was 11.1 mg/dL.
  • a saline solution a saline solution
  • the phosphate concentration in the plasma was measured.
  • the amount of phosphate adsorbed to the porous formed article was calculated to be 8.7 mg/mL-porous formed article.
  • the amount of phosphate adsorbed to the porous formed article mixed at room temperature for 2 hours in an aqueous system (phosphate concentration: 12 mg/dL) was 11.2 mg/mL-porous formed article.
  • the obtained porous formed article had high phosphate selectivity and a large amount of phosphate adsorbed even in plasma, though the amount of phosphate adsorbed in the plasma was slightly lower as compared with the aqueous system.
  • the blood flow test was conducted for a flow time of approximately 200 minutes, and a sample solution was fractionated at 3 mL/min. The degree of hemolysis of each sample was measured. As a result, all of the samples had 0.5% or less degree of hemolysis, and no hemolysis was observed. This demonstrated that the porous formed article was actually used without any problem.
  • the blood flow test was conducted for a flow time of approximately 200 minutes, and a sample solution was fractionated at 3 mL/min and analyzed.
  • the blood flow test was conducted for a flow time of approximately 200 minutes, and a sample solution was fractionated at 3 mL/min and analyzed.
  • the biuret method was used in the analysis.
  • the absorbance of standard serum and the samples was measured at a wavelength of 540 nm to measure the amount of proteins adsorbed from the stock.
  • the amount of proteins adsorbed from the first fraction was 8 mg/mL-porous formed article for the porous formed article and 45 mg/mL-Hemosorba CHS-350 for Hemosorba CHS-350.
  • the amount of proteins adsorbed on the porous formed article was smaller.
  • the adsorption rates from the fractions subsequent to the first one were as small as 0 to 2 mg/mL for both the samples. This demonstrated that the porous formed article was actually used without any problem.
  • the inorganic phosphate concentration in blood at the outlet of a dialyzer at the time of dialysis treatment was 0.2 to 1.0 mg/dL. Therefore, the amount of phosphate adsorbed in this concentration range must be measured. Therefore, the phosphate concentration of a test plasma fluid was adjusted.
  • bovine serum was centrifuged (3500 rpm, 5 min) to prepare 2000 mL of a supernatant plasma.
  • the phosphate concentration in the plasma was 10.8 mg/dL.
  • Example 2 To half (1000 mL) the amount of the obtained plasma, the porous formed article obtained in Example 1 was added, and the mixture was agitated at room temperature for 2 hours and centrifuged (3500 rpm, 5 min) to obtain approximately 950 mL of plasma having a phosphate concentration of 0.
  • a column packed with 1 mL of the porous formed article was assembled according to the schematic diagram shown in FIG. 5 .
  • 450 mL of the obtained plasma was injected thereto at a flow rate of 2 mL/min. 10 mL was collected for the first fraction, and 20 mL/sample was collected for subsequent fractions.
  • the flow volume of plasma is 33600 mL. Since this experiment was conducted on a scale of 1/100, fluid flow of 340 mL was used as a guideline.
  • Table 1 shows the plasma flow volume, the column-outlet plasma concentration, the adsorption rate (%) and the total amount adsorbed. Also, FIG. 7 shows the relationship between the plasma flow volume and the phosphate adsorption rate (%).
  • the amount of phosphate adsorbed to the porous formed article at a plasma flow volume of 350 mL was 2.28 mg-P/mL-porous formed article.
  • the phosphate adsorption rate was 100% up to a plasma flow volume of 110 mL, and the adsorption rate was 86% even at the completion of dialysis. Therefore, a refilling effect can be expected.
  • the amount of phosphate eliminated by dialysis alone can be measured by analyzing the amount of a dialysis fluid. For example, data shows that the amount of phosphate eliminated by 4-hour dialysis can be 1100 mg. From a phosphate concentration in blood processed by a dialyzer in this dialysis, the amount of phosphate eliminable by a phosphate adsorbing member disposed downstream of the dialyzer can be calculated. For example, it can be estimated that 240 mg of phosphate is eliminable. This value is as large as 20% or more of the amount of phosphate eliminated by dialysis. However, this estimated value does not take a refilling effect on phosphate in the body into consideration. If the refilling effect can be expected, the amount of phosphate eliminated by dialysis may be increased while the amount of phosphate eliminated by the phosphate adsorbing member may also be increased. Thus, the total amount of phosphate eliminated may be considerably increased.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that: the temperature of the coagulating liquid was set to 60° C.; and the temperature and relative humidity of the spatial portion were controlled to 37° C. and 100%, respectively.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that the amount of the hydrous cerium oxide powder added was increased from 200 g to 300 g.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that the amount of the hydrous cerium oxide powder added was decreased from 200 g to 150 g.
  • a spherical porous formed article was obtained in the same way as the method described in Example 3 except that the nozzle on the lateral side of the cylindrical rotary container had a narrower diameter of 3 mm changed from 4 mm and was used in shape forming into the porous formed article.
  • a spherical porous formed article was obtained in the same way as the method described in Example 3 except that the nozzle on the lateral side of the cylindrical rotary container had a thicker diameter of 5 mm changed from 4 mm and was used in shape forming into the porous formed article.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that: the good solvent for the organic polymer resin was changed to 160 g of dimethyl sulfoxide (DMSO, Kanto Chemical Co., Inc.); the organic polymer resin was changed to 20 g of an ethylene vinyl alcohol copolymer (EVOH, The Nippon Synthetic Chemical Industry Co., Ltd., Soarnol E3803 (trade name)); the amount of the hydrous cerium oxide powder added was set to 250 g; the coagulating liquid was water; and the nozzle diameter was 5 mm.
  • DMSO dimethyl sulfoxide
  • EVOH ethylene vinyl alcohol copolymer
  • the amount of the hydrous cerium oxide powder added was set to 250 g
  • the coagulating liquid was water
  • the nozzle diameter was 5 mm.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that: the organic polymer resin was changed to 30 g of polyethersulfone (Sumitomo Chemical Co., Ltd., Sumikaexcel 5003PS (trade name), OH-terminated grade, terminal hydroxy group composition: 90 (% by mol)); the water-soluble polymer was changed to 4 g of polyethylene glycol (PEG35,000, Merck Japan); the amount of the hydrous cerium oxide powder was set to 100 g; the coagulating liquid was water; and the nozzle diameter was 5 mm.
  • the organic polymer resin was changed to 30 g of polyethersulfone (Sumitomo Chemical Co., Ltd., Sumikaexcel 5003PS (trade name), OH-terminated grade, terminal hydroxy group composition: 90 (% by mol)); the water-soluble polymer was changed to 4 g of polyethylene glycol (PEG35,000, Merck Japan); the amount of the hydrous cerium oxide
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.
  • the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.
  • a spherical porous formed article was obtained in the same way as the method described in Example 7 except that: the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.; and the nozzle diameter was 4 mm.
  • the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.; and the nozzle diameter was 4 mm.
  • a spherical porous formed article was obtained in the same way as the method described in Example 8 except that: the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.; and the nozzle diameter was 4 mm.
  • the inorganic ion adsorbent used was a hydrous zirconium oxide powder (Daiichi Kigenso Kagaku Kogyo Co., Ltd., R Zirconium Hydroxide (trade name)) dried with a constant mass in a dryer of 70° C.; and the nozzle diameter was 4 mm.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that: the temperature of the coagulating liquid was set to 50° C.; and the temperature and relative humidity of the spatial portion were controlled to 31° C. and 80%, respectively.
  • the obtained slurry solution for shape forming was warmed to 60° C. and supplied to the inside of a cylindrical rotary container in which a nozzle having a diameter of 4 mm was opened on the lateral side. This container was rotated to form liquid drops from the nozzle by centrifugal force (15 G).
  • the spatial portion between the rotary container and a coagulation vessel was covered with a polypropylene cover to control the temperature and relative humidity of the spatial portion to 30° C. and 70%, respectively.
  • the liquid drops were allowed to travel in this spatial portion and arrive at a coagulating liquid (content of NMP with respect to water: 10% by mass) warmed to 40° C., which was retained in a coagulation vessel having an upper opening, to coagulate the slurry for shape forming.
  • Washing and classification were further performed to obtain a spherical porous formed article.
  • a spherical porous formed article was obtained in the same way as the method described in Example 1 except that: 160 g of N-methyl-2-pyrrolidone (NMP, Mitsubishi Chemical Corp.) was used; the organic polymer resin was changed to 30 g of polyethersulfone (Sumitomo Chemical Co., Ltd., Sumikaexcel 5003PS (trade name), OH-terminated grade); the water-soluble polymer was changed to 4 g of polyethylene glycol (PEG35,000, Merck Japan); and the amount of the hydrous cerium oxide powder added was set to 100 g.
  • NMP N-methyl-2-pyrrolidone
  • the organic polymer resin was changed to 30 g of polyethersulfone (Sumitomo Chemical Co., Ltd., Sumikaexcel 5003PS (trade name), OH-terminated grade)
  • the water-soluble polymer was changed to 4 g of polyethylene glycol (PEG35,000, Merck Japan); and the amount of the hydrous cerium oxide powder
  • a spherical porous formed article was obtained in the same way as the method described in Example 14 except that: the temperature of the coagulating liquid was set to 60° C.; and the temperature and relative humidity of the spatial portion were controlled to 37° C. and 90%, respectively.
  • a porous formed article was obtained in the same way as the method described in Example 2 except that the spatial portion between the rotary container and the coagulation vessel was not covered with a polypropylene cover.
  • the temperature and relative humidity of this spatial portion were 26° C. and 63%, respectively.
  • a porous formed article was obtained with reference to Example 1 of Patent Literature 3 (International Publication No. WO 2011/062277).
  • a spherical porous formed article was obtained in the same way as the method described in Example 8 except that: the spatial portion between the rotary container and the coagulation vessel was not covered with a polypropylene cover; and the temperature of the coagulating liquid was set to 60° C. The temperature and relative humidity of this spatial portion were 26° C. and 63%, respectively.
  • a porous formed article was obtained with reference to Example 2 of Patent Literature 1 (International Publication No. WO 2005/056175).
  • a spherical porous formed article was obtained in the same way as the method described in Example 7 except that: the spatial portion between the rotary container and the coagulation vessel was not covered with a polypropylene cover; and the temperature of the coagulating liquid was set to 60° C. The temperature and relative humidity of this spatial portion were 26° C. and 63%, respectively.
  • Tables 2 and 3 show the physical properties of the porous formed articles obtained in Examples 1 to 15 and Comparative Examples 1 to 3 and their amounts of phosphate adsorbed (mg/mL-porous formed article) at a plasma flow volume of 350 mL under the same conditions as in Example 1.
  • a membrane forming spinning dope was prepared by dissolving 17 parts by mass of polysulfone (manufactured by Solvay S.A., P-1700) and 4 parts by mass of polyvinylpyrrolidone (manufactured by BASF Japan Ltd., K-90) in 79 parts by mass of dimethylacetamide (manufactured by Kishida Chemical Co., Ltd., special grade reagent).
  • the membrane forming spinning dope and the bore liquid were discharged from a tube-in-orifice spinneret.
  • the temperature of the membrane forming spinning dope at the time of discharge was set to 40° C.
  • the discharged membrane forming spinning dope was passed through a hooded fall portion, dipped in a coagulation bath of 60° C. consisting of water, and coagulated.
  • the spinning speed was set to 30 m/min.
  • the resultant was washed with water and dried to obtain a hollow fiber separation membrane.
  • the water washing temperature was set to 90° C., and the water washing time was set to 180 seconds.
  • the amounts of the membrane forming spinning dope and the bore liquid discharged were adjusted such that the membrane thickness and the inside diameter after drying were 45 ⁇ m and 185 ⁇ m, respectively.
  • the obtained hollow fiber separation membrane was incorporated in a blood processing container and shape-formed, and a module having an effective area of 0.02 m 2 was fabricated to obtain a blood processor.
  • the amount of phosphate removed was measured in circuit 1 ( FIG. 8 ) using the obtained blood processor.
  • Example 16 the amount of phosphate removed was measured in circuit 2 ( FIG. 9 ) and circuit 3 ( FIG. 10 ) using the blood processor and a column packed with the spherical porous formed article prepared in Example 8 (phosphate adsorbing agent for blood processing).
  • Comparative Example 4 the amount of phosphate removed was measured in circuit 2 and circuit 3 using a column packed with the spherical porous formed article prepared in Comparative Example 2 instead of the column packed with the spherical porous formed article prepared in Example 8.
  • circuit 1 The results obtained in circuit 1 are shown.
  • Blood purifier 0.02 m 2 membrane (effective length: approximately 85 mm, the number of hollow fibers: 420) Amount of the porous formed article: 0.5 mL column Total bovine blood flow rate: 2 ml/min Dialysis fluid flow rate: 5 ml/min
  • Ht 32% (hematocrit: numerical value indicating the volume ratio of blood cells to blood)
  • TP 6.027 g/dL (protein concentration)
  • IP 4.99 mg/dL (inorganic phosphate concentration)
  • the amount of phosphate removed was compared when the flow volume reached 480 mL.
  • Amount of phosphate removed with the blood purifier alone D out concentration ⁇ Amount sampled
  • Amount of phosphate removed with(Blood purifier+Porous formed article column)connection ( B in concentration ⁇ B out concentration) ⁇ (Amount sampled) ⁇ (100 ⁇ Ht)/100
  • the sampling position was changed for measurement, depending on the presence or absence of the porous formed article column. However, it was confirmed that values were constant among all of the measurement methods.
  • Removal rate (%) 100 ⁇ ( B in concentration ⁇ B out concentration)/( B in concentration)
  • the initial concentration was sampled from the blood pool, and the blood outlet concentration (Bout) and the dialysis fluid outlet concentration (Dout) were sampled at 10 minutes, 20 minutes, 30 minutes, 60 minutes and 90 minutes after the start of flow, and subsequently every 30 minutes up to 240 minutes.
  • the phosphate adsorbing agent for blood processing of the present invention disposed upstream or downstream of the blood purifier was confirmed to drastically increase the amount of phosphate removed.
  • the phosphate adsorbing agent for blood processing of the present invention can be preferably used in dialysis therapy and the like and as such, has industrial applicability.

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US11224871B2 (en) 2017-05-17 2022-01-18 Asahi Kasei Medical Co., Ltd. Phosphate adsorbing agent for blood processing, blood processing system and blood processing method
EP3903855A4 (en) * 2018-12-25 2022-03-09 Asahi Kasei Medical Co., Ltd. BLOOD PURIFICATION DEVICE AND EXTRACORPORAL BLOOD CIRCULATION SYSTEM WITH BLOOD COMPONENT SETTING DEVICE
US11806461B2 (en) 2018-03-30 2023-11-07 Asahi Kasei Medical Co., Ltd. Blood purification device and method for producing same
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JP2021074577A (ja) 2021-05-20
JP7074898B2 (ja) 2022-05-24
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