WO2014126014A1 - 血液浄化カラム - Google Patents
血液浄化カラム Download PDFInfo
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- WO2014126014A1 WO2014126014A1 PCT/JP2014/052889 JP2014052889W WO2014126014A1 WO 2014126014 A1 WO2014126014 A1 WO 2014126014A1 JP 2014052889 W JP2014052889 W JP 2014052889W WO 2014126014 A1 WO2014126014 A1 WO 2014126014A1
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- 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
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- 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
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- 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
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3627—Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
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- 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
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3643—Priming, rinsing before or after use
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- 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
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3643—Priming, rinsing before or after use
- A61M1/3644—Mode of operation
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- 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
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3643—Priming, rinsing before or after use
- A61M1/3644—Mode of operation
- A61M1/3652—Mode of operation using gas, e.g. air
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- 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
- A61M1/3672—Means preventing coagulation
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- 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
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
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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
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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
- B01J20/261—Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
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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
- B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
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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
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
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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
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—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 form
- B01J20/28023—Fibres or filaments
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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
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—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 form
- B01J20/2805—Sorbents inside a permeable or porous casing, e.g. inside a container, bag or membrane
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- 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
- A61M2205/00—General characteristics of the apparatus
- A61M2205/75—General characteristics of the apparatus with filters
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- 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
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
- A61M60/10—Location thereof with respect to the patient's body
- A61M60/104—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body
- A61M60/109—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body incorporated within extracorporeal blood circuits or systems
- A61M60/113—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body incorporated within extracorporeal blood circuits or systems in other functional devices, e.g. dialysers or heart-lung machines
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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
- B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
- B01J20/28014—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 form
- B01J20/28016—Particle form
- B01J20/28019—Spherical, ellipsoidal or cylindrical
Definitions
- the present invention relates to a column used for blood purification and the like, and relates to a blood purification column that is excellent in air bleeding and hardly causes blood coagulation in a circuit at the time of blood introduction.
- a treatment method called apheresis therapy is known in which a patient's blood is once taken out of the body, pathogenic substances in the removed blood are removed by treatment such as adsorption and filtration, and then the blood is returned to the patient's body.
- This apheresis therapy is used to treat drug addiction, food poisoning, familial hypercholesterolemia, autoimmune diseases such as ulcerative colitis, Crohn's disease, and rheumatoid arthritis, and is considered to cause these diseases. It is used to remove substances such as drugs, toxins, cholesterol, and inflammatory cells such as white blood cells and platelets from the patient's blood.
- a primary membrane is used to separate plasma from blood, and this plasma is further passed through to the secondary membrane, and DFPP (Double Filtration Plasmapheresis) or treatment of patient's body fluid directly Direct blood perfusion therapy (DHP: Direct Hemo Perfusion) is known.
- DHP has been rapidly spreading in recent years because it is simple to process.
- the column used alone for DHP in addition to using the column alone, there is a form that is used in series with an artificial kidney in dialysis performed on patients with renal failure, etc. It is also possible to efficiently adsorb ⁇ 2 -microglobulin or the like that causes a certain dialysis amyloidosis.
- a column containing an adsorbent therein, and a substance to be removed in the blood is adsorbed and removed by the adsorbent.
- a column usually has a hollow cylindrical casing, is provided with header caps provided with blood inlets and outlets at both ends in the longitudinal direction, and an adsorbent is accommodated inside the casing.
- the blood purification column when the blood purification column is generally used as a medical instrument by DHP or the like, a so-called priming operation of passing and filling physiological saline or the like before use is performed. At this time, if air is generated in the column or circuit and remains in the column, it will impede the passage and filling of physiological saline, etc., and the contact area between the adsorbent and blood will be reduced. Adsorption / removal performance may be reduced.
- the filter used for the column is required to have excellent air release and at the same time biocompatibility, that is, a property that hardly induces coagulation in the circuit during blood circulation.
- Patent Documents 1 and 2 there are patents that use a mesh to fix the end of a column used for DHP (Patent Documents 1 and 2).
- the rule concerning the mesh only describes that the adsorbent should be designed so that the adsorbent can be held in the column, and there is no description on improving the air bleedability by the mesh design.
- meshes are provided at both ends of a column using an adsorbent made of hollow fiber or solid fiber as an adsorbent in the column (Patent Document 3).
- the adsorbent is wound with a mesh cloth for the purpose of stably maintaining the adsorbent in the column and improving the flow in the column. It is not preferable to dispose a mesh opened in parallel with the long axis direction from the viewpoint of air release.
- the present invention relates to a filter built in a blood purification column, which dramatically improves the ability to remove air mixed in the column, activates blood by the air remaining in the column, and the contact area between the adsorbent and blood.
- the purpose is to prevent a decrease in adsorption performance due to a decrease in the amount.
- the blood purification column according to the present invention has an adsorbent and a casing whose both ends are open ends.
- the adsorbent is accommodated inside the casing, one end of the casing is the blood inflow side end, and the other is the blood outflow. It is a side end, and a filter is disposed at the blood inflow end and / or the blood outflow end, and the filter satisfies the following requirements.
- Opening ratio is 5% or more and 80% or less
- Equivalent diameter of opening is 1 ⁇ m or more and 5000 ⁇ m or less
- Ratio of equivalent diameter of opening to average equivalent circle diameter of gap of adsorbent is 45 %
- the adsorbent to be accommodated has a gap inside, but in the present invention, the equivalent diameter of the filter openings and the average equivalent circle diameter of the gap in the adsorbent are close to each other. In connection with this, it has been found that the air release performance is improved by optimizing the ratio of the two.
- the hydrophilicity / hydrophobicity is important, that is, the filter preferably has a contact angle within a proper range. Therefore, it is preferable that the filter material includes at least one material selected from polyolefin resin, polyamide resin, and fluorine resin, among polypropylene, polyethylene, nylon 6, nylon 66, and derivatives thereof. More preferably, it contains at least one material selected from the group consisting of at least one of polypropylene and its derivatives.
- the present invention it is possible to provide a blood purification column in which air generated during a priming operation performed before use can be efficiently removed outside the column, and in-circuit coagulation is unlikely to occur during blood circulation.
- the blood purification column according to the present invention has an adsorbent filled in the column and a filter for holding the adsorbent, and the aperture ratio of the filter is 5% or more and 80% or less.
- the direction of blood flow when the filter is placed in the column that is, when there are blood inlets and outlets at both ends of the column, from the inlet to the outlet.
- the range surrounded by 5 mm square is arbitrarily observed, and the area occupied by the structure constituting the filter included in the range is Amm 2, and is expressed by the following formula: be able to.
- Opening ratio (%) (25 ⁇ A) / 25 ⁇ 100 This is measured by selecting an arbitrary five 5 mm square range for one target filter, and calculating the average value. The calculated aperture ratio is rounded to the first decimal place.
- the aperture ratio is too high, the strength of the filter is insufficient, and it becomes difficult to stably hold the adsorbent in the casing. On the other hand, if it is too low, the resistance of the flow increases and the air release performance deteriorates. In addition, it tends to cause an increase in pressure loss when blood passes through the column, and an increase in column pressure when a thrombus or the like is formed on the filter.
- the upper limit of the aperture ratio is 80% or less, preferably 70% or less, more preferably 66% or less.
- the lower limit is 5% or more, preferably 16% or more, and more preferably 21% or more.
- the equivalent diameter of the aperture of the filter is an important factor.
- the method for measuring the equivalent diameter of the mesh is as follows. That is, when the filter opening is uniform in the thickness direction, the filter is observed with an optical microscope from the thickness direction, and when the filter opening is uneven in the thickness direction, the thickness with the smallest opening is obtained. Slice the part with a cutter, etc., and observe with an optical microscope in the same way from the above vertical direction, arbitrarily extract 30 points of the filter gap, measure each area S, and open each mesh according to the following formula The equivalent diameter of is calculated. After that, the average of the measured values of 30 points is calculated, and the first decimal place is rounded off.
- the equivalent diameter of mesh opening 2 ⁇ (S / ⁇ ) 1/2 If the equivalent diameter of the mesh is too large, it will be difficult to hold the adsorbent in the column. In addition, in the unlikely event that foreign matter occurs in the circuit or column, the possibility that it cannot be captured by the filter increases. Therefore, specifically, the equivalent diameter of the openings is preferably 10 times or less, more preferably 5 times or less of the cross-sectional area per individual adsorbent when the column is viewed from the vertical direction. Preferably it is 2.8 times or less.
- the cross-sectional area per individual adsorbent referred to here is, for example, the cross-sectional area of the cross section per thread if it is a solid thread, and the center of the bead per bead if it is a spherical bead. It is the area of the surface obtained when cutting along a straight line.
- the equivalent diameter of the opening of the filter is too small, the flow resistance increases and the air bleedability decreases. In addition, it tends to cause an increase in pressure loss when blood passes through the column, and an increase in column pressure when a thrombus or the like is formed on the filter.
- the upper limit of the equivalent diameter of the mesh is 5000 ⁇ m or less, preferably 800 ⁇ m or less, more preferably 400 ⁇ m or less.
- the lower limit of the equivalent diameter of the mesh is 1 ⁇ m or more, preferably 5 ⁇ m or more, more preferably 10 ⁇ m or more.
- the air release property can be evaluated by the following method. Header caps equipped with a filter and an inlet and an outlet for the liquid to be treated were disposed at both ends of the blood purification column, and then the inside of the column was washed with pure water, and then each port was sealed with a cap.
- This column is set in an air bleed test circuit as shown in Fig. 2 with its longitudinal direction perpendicular to the ground, and the air removal rate in the column trapped in the mesh is measured 5 times by the following procedure, and the average is the decimal point. Calculated by rounding off the first place. (1) Circulate pure water using a pump at a flow rate of 100 ml / s until the air in the circuit is completely removed. If necessary, exhaust the air completely by hitting the column.
- the air removal rate here is preferably 43% or more, more preferably 55% or more, and further preferably 63% or more.
- the adsorbent referred to in the present invention adsorbs and removes a substance to be removed from blood, similar to the adsorbent in the medical device described above.
- the adsorbent to be packed is in the form of a flat membrane, powder, spherical particles, crushed particles, continuous lumps, fibers, tubes, hollow fibers, solid threads, granules, plates, crushed hollow fibers, crushed solids Any shape such as a thread shape may be used.
- the tube is in the shape of a straight tube, hollow fiber, or solid yarn arranged in parallel to the longitudinal direction of the column, the flow path becomes straight and the length of the flow path can be minimized, making it difficult for air to be trapped. ,preferable.
- the adsorption area can be secured efficiently by making the film thickness part and the inside of the yarn porous suitable for adsorption, and the adsorption target substance contained in the blood can be efficiently Used even when the viscosity of the liquid to be treated, such as patient whole blood, is high and the risk of coagulation in the column is high compared to ultrafine fibers, crushed hollow fibers, crushed solid threads, etc. There are merits that can be done.
- Particularly preferred is a solid thread shape.
- the gap outside the hollow fiber is not a fixed closed environment because the yarn is deformed by the movement of the yarn in the column.
- the straight shape arranged in parallel with the column longitudinal direction means a shape in which both side end faces of one yarn are in contact with the inlet / outlet end faces of the column with a length as close as possible to the shortest distance. That is.
- the yarn may be crimped such as crimp.
- the porous adsorbent preferably has a porous structure that is homogeneous in the thickness direction. Thereby, the area which contributes to adsorption
- suction can be increased.
- the pore structure has a gradient asymmetric structure or an irregular structure in the thickness direction, the specific surface area of the adsorbent decreases, which is not preferable.
- the length of the yarn is measured in a straight shape with both ends of the yarn stretched.
- a method of measuring the length of the yarn in the longitudinal direction one piece of yarn taken out from the column is fixed with tape or the like, and a weight of about 3 g is applied to the other piece, and the total length when the yarn becomes linear Measure immediately. This measurement is arbitrarily performed for 30 yarns in the column, and an average value of 30 is calculated.
- the ratio of the equivalent diameter of the filter openings to the average equivalent circle diameter of the gap between the adsorbents is 45% or more, preferably 50% or more, more preferably 56% or more.
- the ratio is preferably 400% or less, more preferably 280% or less, and further preferably 220% or less.
- the average equivalent circle diameter De is a straight shape in which the adsorbent is arranged in parallel in the longitudinal direction of the column like a tubular shape, a hollow fiber shape, a solid yarn shape or the like as described in Non-Patent Document 1. Is represented by the following equation.
- Average circle equivalent diameter De 4 ⁇ Af / Wp of adsorbent gap Af in the equation is a flow path cross-sectional area, which is a value obtained by subtracting the sum of the cross-sectional areas in the same direction occupied by the adsorbent from the cross-sectional area in the direction perpendicular to the longitudinal direction of the casing.
- the total cross-sectional area occupied by the adsorbent is obtained from the following formula using the yarn diameter D0 obtained by the yarn diameter measuring method described later and the number N of packed yarns in the column.
- Total cross-sectional area occupied by the adsorbent (D0 / 2) 2 ⁇ ⁇ ⁇ N Wp is the wet side length and is the sum of the inner surface area of the casing and the total surface area of the adsorbent.
- the total surface area of the adsorbent is obtained from the yarn diameter D0, the number N of packed yarns in the column, and the length L in the longitudinal direction of the yarn by the following formula.
- Total surface area of adsorbent D0 ⁇ ⁇ ⁇ L
- both ends are open ends, and examples thereof include a rectangular cylinder and a cylindrical body such as a square cylindrical body and a hexagonal cylindrical body.
- a cylindrical body particularly a cylindrical body having a perfect circular section is preferable.
- the casing does not have corners, so that the retention of blood at the corners can be suppressed.
- a casing is an instrument comprised with a plastic, a metal, etc.
- plastic for example, a thermoplastic resin excellent in mechanical strength and thermal stability is used.
- thermoplastic resins include polycarbonate resins, polyvinyl alcohol resins, cellulose resins, polyester resins, polyarylate resins, polyimide resins, cyclic polyolefin resins, polysulfone resins, polyether sulfones. Resin, polyolefin resin, polystyrene resin, polyvinyl alcohol resin, and mixtures thereof.
- polystyrene, polycarbonate, and derivatives thereof are preferable in terms of moldability, transparency, and radiation resistance required for the casing. This is because a resin with excellent transparency is convenient for ensuring safety because the internal state can be confirmed during blood perfusion, and a resin with excellent radiation resistance is preferable when radiated during sterilization.
- plastic is preferably used from the viewpoints of cost, moldability, weight, and blood compatibility.
- the average equivalent circle diameter De (32 ⁇ ⁇ ⁇ L ⁇ u / ⁇ P) 1/2 of the adsorbent gap
- ⁇ is the viscosity of the liquid to be treated
- L is the length in the longitudinal direction of the adsorbent packed portion
- u is the average flow velocity in the column
- ⁇ P is the value obtained by subtracting the pressure loss at the column outlet from the pressure loss at the column inlet. is there.
- the filter opening When the ratio of the equivalent diameter of the filter opening to the average equivalent circle diameter of the adsorbent gap is less than 45%, the filter opening is significantly smaller than the cross-sectional area of the air passing through the column. It is difficult to do so, and air tends to stay in the column.
- the ratio of the equivalent diameter of the filter openings to the average equivalent circle diameter of the gap of the adsorbent is larger than 400%, the adsorbent tends to flow out of the filter openings, and it is difficult to hold the adsorbent in the column.
- the calculated equivalent diameter of the mesh is calculated by rounding off the first decimal place.
- the yarn diameter is preferably 1000 ⁇ m or less, more preferably 450 ⁇ m or less, and further preferably 280 ⁇ m or less.
- the lower limit is preferably 5 ⁇ m or more, more preferably 30 ⁇ m or more, and further preferably 70 ⁇ m or more.
- the opening of the filter it is preferable to set the opening of the filter to such an extent that blood can pass but the adsorbent cannot pass. That is, it is preferable to set the mesh size to be equal to or smaller than the diameter per adsorbent to be filled.
- a metal material such as aluminum, a natural material such as silk, and a polymer compound can be used alone or in combination.
- a polymer compound is preferably used from the viewpoint of cost, strength, weight, biocompatibility and the like, and particularly preferably contains at least one material selected from polyolefin resin, polyamide resin, and fluorine resin. .
- the hydrophilicity / hydrophobicity control is required for the filter of the blood purification column. That is, if a material having a high contact angle between the filter material and water is used, the ability of air flowing into the column can be improved. If the contact angle of the filter with water is too low, the air release property deteriorates and air tends to remain in the column.
- the upper limit of the contact angle is preferably 125 ° or less, more preferably 108 ° or less, particularly preferably 104 ° or less, while the lower limit is preferably 66 ° or more, more preferably 72 ° or more, particularly preferably. Is 82 ° or more.
- the contact angle of a structure such as a filter is affected by the fiber diameter and fiber density
- the contact angle of the filter material and water is determined after creating a uniform film made of the same material as the filter.
- the angle inside the liquid obtained by measuring the angle between the film surface and the liquid surface.
- a solution is prepared by dissolving the filter in the good solvent, the solution is poured into an aluminum dish, and the good solvent is evaporated and solidified in a dry atmosphere to form a film.
- the contact angle can be measured at room temperature (23 ° C.) using a contact angle meter (for example, DropMaster DM500, manufactured by Kyowa Interface Science Co., Ltd.).
- the droplet method can be used for the calculation.
- a 2 ⁇ L droplet is prepared with a syringe and brought into contact with the substrate, and the tangent of the droplet drawn from the contact point between the substrate surface, the droplet and the gas phase in three phases Find the angle between the droplet and substrate interface.
- Each measured value is measured at 10 contact angles with respect to each substrate, and the average value is obtained.
- the calculated contact angle is rounded off to the first decimal place.
- the improvement in the air release property by increasing the contact angle can be explained by the decrease in the interfacial tension between the solid and the air. That is, when water contacts the surface of the solid, the tension at the interface between the solid and air is ⁇ 1, the tension at the interface between water and solid is ⁇ 2, the tension at the interface between water and air is ⁇ 3, and the tangent at the gas-liquid interface
- ⁇ is a contact angle
- ⁇ 1 can be reduced by increasing the contact angle.
- polymer compounds having a contact angle of 66 ° or more and 125 ° or less include (meth) acrylic resins, olefin resins, silicone resins, polyvinyl chloride resins, polyvinylidene chloride resins, and fluorine resins. And polyester resins or mixtures thereof.
- polyolefin resins, polyamide resins, and fluorine resins can be suitably used from the viewpoint of production cost, ease of molding, and durability to sterilization treatment, and more preferably polypropylene, polyethylene, and nylon. 6.
- a porous body and a porous body may be sufficient, the porous body in which the hole is vacant uniformly is used preferably, and a mesh, a nonwoven fabric, etc. are mentioned.
- a mesh is preferably used from the viewpoints that the openings are uniform and that there is little adhesion of blood cell components and that the eluate from the filter is less likely to be generated.
- the uniform aperture in the entire filter means that when the aperture ratio is not constant, even if any arbitrary 5 mm square range is selected over the entire filter, the variation range of the aperture ratio value is A filter included within ⁇ 30% of the average value, more preferably ⁇ 18% or less, and even more preferably ⁇ 10% or less.
- the filter thickness is preferably 3000 ⁇ m or less, and more preferably 900 ⁇ m or less.
- the lower limit of the filter thickness is preferably 0.1 ⁇ m or more, more preferably 40 ⁇ m or more.
- the filter held in the column has a surface area of the portion opened in a direction perpendicular to the major axis direction in the column as B1, and opens in a direction other than the direction perpendicular to the major axis direction in the column.
- B2 the total surface area of the portion
- a casing provided with an inlet portion into which the blood flow before purification flows and an outlet portion through which the blood flow after purification is discharged, an adsorbent housed in the casing, It comprises a filter provided inside the inlet and / or outlet, and a header cap provided with blood inlets and outlets arranged at both ends in the longitudinal direction of the casing.
- the filter is preferably provided on both sides of the inlet and outlet for holding the adsorbent in the casing, but may be used alone if the adsorbent can be held only at either the inlet or outlet,
- a filter related to the present invention may be arranged on one side of the column, and a filter different from the present invention may be arranged on the opposite side.
- the upper limit of the adsorbent packing rate in the column casing is preferably less than 70%, more preferably 63% or less.
- the lower limit of the filling rate of the adsorbent is preferably 13% or more, more preferably 30% or more, and particularly preferably 45% or more.
- the spinning dope is discharged from a die having a circular stock solution discharge port and solidified into a solid yarn shape in a coagulation bath.
- the coagulation bath usually consists of a mixture with a coagulant such as water or alcohol, or a solvent constituting the spinning dope.
- the porosity can be changed by controlling the temperature of the coagulation bath. Since the porosity can be affected by the type of spinning dope, etc., the temperature of the coagulation bath is also appropriately selected. In general, the porosity can be increased by increasing the coagulation bath temperature.
- the solidification bath temperature when the solid yarn is a yarn containing polymethyl methacrylate (hereinafter referred to as PMMA) and gas is put into the inner tube Is preferably 39 ° C. or higher, more preferably 42 ° C. or higher.
- 50 degrees C or less is preferable, More preferably, it is 46 degrees C or less.
- the means for washing the solid yarn is not particularly limited, but a method of allowing the solid yarn to pass through a multi-staged water bath (referred to as a washing bath) is preferably used. What is necessary is just to determine the temperature of the water in a water-washing bath according to the property of the polymer which comprises a thread
- the solid yarn may be subjected to a step of applying a moisturizing component in order to maintain the pore diameter after the washing bath.
- a moisturizing component refers to a component capable of maintaining the humidity of the solid yarn or a component capable of preventing a decrease in the humidity of the solid yarn in the air.
- moisturizing ingredients include glycerin and its aqueous solutions.
- the heat treatment bath is filled with an aqueous solution of heated moisturizing ingredients, and when the solid yarn passes through this heat treatment bath, it shrinks due to the thermal action and becomes difficult to shrink in the subsequent process, and the yarn structure Can be stabilized.
- the heat treatment temperature at this time varies depending on the yarn material, but in the case of a yarn containing PMMA, 75 ° C. or higher is preferable, and 82 ° C. or higher is more preferable. Moreover, 90 degrees C or less is preferable and 86 degrees C or less is set as a more preferable temperature.
- An example of means for converting the obtained solid yarn into a purification column is as follows.
- the blood purification column can be obtained by attaching the inlet and outlet ports of the liquid to be treated, called header caps.
- sterilization and sterilization methods include various sterilization and sterilization methods such as high-pressure steam sterilization, gamma ray sterilization, ethylene oxide gas sterilization, chemical sterilization, and ultraviolet sterilization. Among these methods, gamma ray sterilization, high-pressure steam sterilization, and ethylene oxide gas sterilization are preferable because they have little effect on sterilization efficiency and materials.
- the usage form of the blood purification column in the present invention is preferably a method of incorporating and removing adsorption online in an extracorporeal circuit from the viewpoint of one-time throughput and ease of operation.
- the purification column of the present invention may be used alone, or may be used simultaneously in series with an artificial kidney during dialysis.
- Example 1 31.7 parts by weight of syn-PMMA having a weight average molecular weight of 400,000, 31.7 parts by weight of syn-PMMA having a weight average molecular weight of 1.4 million, and 16.7 parts by weight of iso-PMMA having a weight average molecular weight of 500,000 Then, 20 parts by weight of PMMA copolymer having a molecular weight of 300,000 containing 1.5 mol% of parastyrene sulfonic acid soda was mixed with 376 parts by weight of dimethyl sulfoxide, and stirred at 110 ° C. for 8 hours to prepare a spinning dope. The obtained spinning dope had a viscosity at 110 ° C. of 1240 poise.
- the obtained spinning dope is discharged into air at a speed of 1.0 g / min from a base having a circular discharge port with a diameter of 0.3 mm which is kept at 93 ° C., and the air portion is allowed to travel 50 cm, and then solidified. Led to the bath.
- a solid yarn was obtained by setting the water temperature (coagulation bath temperature) used in the coagulation bath to 42 ° C. After each solid yarn was washed with water, glycerin was added as a 70% by weight aqueous solution as a moisturizing agent, and then the heat treatment bath temperature was 84 ° C. After removing excess glycerin, the spacer yarn was wound and wound at 42 m / min. .
- the diameter of the obtained solid yarn was 121 ⁇ m as a result of measurement using a projector V-10A manufactured by Nikon Corporation.
- the obtained solid yarn was bundled using a known method, and the solid yarn was incorporated in a polycarbonate cylindrical casing having an inner diameter of 38 mm and an axial length of 133 mm so that the filling rate was 57%. .
- a polypropylene mesh filter having an aperture equivalent diameter of 84 ⁇ m and an aperture ratio of 36%, which was cut to a diameter equivalent to the casing inner diameter as shown in FIG.
- the equivalent diameter of the filter openings, the aperture ratio, and the column packing ratio were measured by using a projector V-10A manufactured by Nikon Corporation, and were calculated by the methods described above.
- a header cap with an inlet and an outlet for the liquid to be treated is arranged at both ends of the column, then the column interior is washed with pure water, each port is sealed with a cap, and a mesh is attached to both sides. It was created.
- the circle average equivalent diameter of the adsorbent gap of this column was 91 ⁇ m.
- This column was set in an air bleeding test circuit as shown in FIG. 2 with its longitudinal direction perpendicular to the ground, and the air removal rate in the column trapped by the mesh was measured by the following procedure. (1) Pure water was circulated using a pump at a flow rate of 100 ml / s until the air in the circuit was completely removed. The air was made easier to expel by hitting the column as needed.
- Example 2 A solid yarn was obtained in the same manner as in Example 1 except that the yarn diameter was changed to 181 ⁇ m by setting the discharge speed of the spinning dope to 1.9 g / min, and this was carried out in a casing having the same dimensions and shape as in Example 1.
- mesh filters and header caps having the same dimensions and shape as in Example 1 were arranged in the same manner on both side end faces of the casing.
- the circle average equivalent diameter of the adsorbent gap of this column was 135 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1.
- Example 3 A solid yarn was obtained by the same method as in Example 1 except that the yarn diameter was set to 56 ⁇ m by setting the discharge speed of the spinning dope to 0.5 g / min, and this was carried out in a casing having the same dimensions and shape as in Example 1.
- mesh filters and header caps having the same dimensions and shape as in Example 1 were arranged in the same manner on both side end faces of the casing.
- the circular average equivalent diameter of the adsorbent gap of this column was 42 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1.
- Example 4 A solid yarn was obtained in the same manner as in Example 1 and incorporated in a casing having the same dimensions and shape as in Example 1 in the same manner as in Example 1, with an opening equivalent diameter of 124 ⁇ m and an aperture ratio of 31% on both end faces of the casing.
- a polypropylene mesh filter and a header cap having the same dimensions and shape as in Example 1 were disposed in the same manner as in Example 1.
- the circle average equivalent diameter of the adsorbent gap of this column was 91 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1. Further, in order to evaluate the protein removal performance of the obtained purification column, ⁇ 2 -MG (microglobulin) clearance was measured by the following method. The results are shown in Table 3.
- ⁇ 2 -MG clearance was measured.
- ⁇ 2 -MG is known to be a causative protein of dialysis amyloidosis, which is a long-term dialysis complication.
- the bovine blood to which disodium ethylenediaminetetraacetate was added was adjusted so that the hematocrit was 30 ⁇ 3% and the total protein amount was 6.5 ⁇ 0.5 g / dL. Bovine blood within 5 days after blood collection was used.
- ⁇ 2 -MG concentration was added to 1 mg / l and stirred.
- the cow blood was divided into 2 L for circulation and 1.5 L for clearance measurement.
- the circuit was set as shown in FIG.
- Bi was taken as the inlet for taking up the liquid to be treated, and Bo as the liquid outlet after passing through the blood purification column.
- Example 5 A solid yarn was obtained by the same method as in Example 1 and incorporated in a casing having the same dimensions and shape as in Example 1 in the same manner as in Example 1, with an opening equivalent diameter of 108 ⁇ m and an aperture ratio of 40% on both end faces of the casing.
- a polyethylene terephthalate mesh filter and a header cap having the same dimensions and shape as in Example 1 were disposed in the same manner as in Example 1.
- the circle average equivalent diameter of the adsorbent gap of this column was 91 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1.
- the results are shown in Table 1.
- ⁇ 2 -MG clearance was measured in the same procedure as in Example 4. The results are shown in Table 3.
- Example 6 A solid yarn was obtained in the same manner as in Example 1 except that the yarn diameter was set to 260 ⁇ m by setting the discharge speed of the spinning dope to 4.7 g / min, and this was carried out in a casing having the same dimensions and shape as in Example 1.
- a polypropylene mesh filter having an opening equivalent diameter of 108 ⁇ m and an aperture ratio of 40% on both side end faces of the casing, and a header cap having the same size and shape as in Example 1 1 was arranged.
- the circular average equivalent diameter of the adsorbent gap of this column was 194 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1.
- Example 1 A solid yarn was obtained in the same manner as in Example 1 except that the yarn diameter was set to 260 ⁇ m by setting the discharge speed of the spinning dope to 4.7 g / min, and this was carried out in a casing having the same dimensions and shape as in Example 1.
- mesh filters and header caps having the same dimensions and shape as in Example 1 were arranged in the same manner on both side end faces of the casing.
- the circular average equivalent diameter of the adsorbent gap of this column was 194 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1.
- Example 7 A spinning dope similar to that in Example 1 was fed at a rate of 2.5 g / min from a double tube hollow fiber die having an outer diameter / inner diameter of 2.1 / 1.95 mm ⁇ of an annular slit portion kept at 93 ° C. And discharged into the air. Here, nitrogen gas was simultaneously injected into the inner tube portion of the double tube, and the air portion was allowed to travel 50 cm before being led to the coagulation bath. A hollow fiber membrane was obtained by setting the water temperature (coagulation bath temperature) used in the coagulation bath to 42 ° C.
- the heat treatment bath temperature was set to 84 ° C.
- the spacer yarn was wound and wound at 60 m / min. .
- the inner diameter was 200 ⁇ m and the outer diameter of the yarn was 260 ⁇ m.
- a polypropylene mesh filter having a diameter equivalent to 108 ⁇ m and an opening ratio of 40% on both side end faces of the casing, as in the case of the sixth embodiment.
- Example 1 A header cap having the same dimensions and shape as in Example 1 was disposed in the same manner as in Example 1.
- the equivalent circle diameter of the adsorbent gap of this column was 195 ⁇ m.
- the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 1.
- Reference example 1 As shown in FIG. 2, an opening equivalent diameter of 326 ⁇ m, which is cut into a cylindrical shape with the same diameter as the inner diameter of the outlet of the liquid to be processed, on the end surface of the liquid to be processed of the cylindrical casing having an inner diameter of 46 mm and an axial length of 100 mm.
- a polypropylene mesh filter having an aperture ratio of 51% was attached.
- header caps equipped with an inlet and an outlet for the liquid to be treated were disposed at both ends to create a one-side mesh-equipped column. The adsorbent was not built in. In this one-side mesh-equipped column, the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 2.
- Reference example 2 On the treated liquid outflow side end surface of the casing having the same dimensions and shape as in Reference Example 1, the aperture equivalent diameter 274 ⁇ m cut into a cylindrical shape with the same diameter as the inner diameter of the treated liquid outlet has an opening ratio of 45% and a thickness of 245 mm.
- a one-side mesh mounting column was prepared in the same manner as in Reference Example 1 except that a polytetrafluoroethylene mesh filter was mounted. In this one-side mesh-equipped column, the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 2.
- the treatment liquid outlet has an opening equivalent diameter of 274 ⁇ m, an opening ratio of 37%, and a thickness of 291 mm, which is cut into a cylindrical shape with the same diameter as the inner diameter.
- a one-side mesh mounting column was prepared in the same manner as in Reference Example 1 except that a nylon 66 mesh filter was mounted. In this one-side mesh-equipped column, the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 2.
- the treatment liquid outlet has an opening equivalent diameter of 308 ⁇ m cut into a cylindrical shape with the same diameter as the inner diameter, an opening ratio of 42%, and a thickness of 280 mm.
- a one-side mesh mounting column was prepared in the same manner as in Reference Example 1 except that a polyethylene terephthalate mesh filter was mounted. In this one-side mesh-equipped column, the air removal rate in the column was measured in the same procedure as in Example 1. The results are shown in Table 2.
- the yarn diameter of the adsorbent of the columns according to Example 6 and Comparative Example 1 is 260 ⁇ m. Since both columns have an adsorbent packing rate of 57%, the column with 121 ⁇ m yarn diameter and the 260 ⁇ m column have different adsorbent surface areas per column, resulting in differences in protein adsorption performance. it is conceivable that.
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Abstract
Description
(1)開口率が5%以上、80%以下
(2)目開きの相当直径が1μm以上、5000μm以下
(3)目開きの相当直径の前記吸着体の間隙の平均円相当直径に対する比率が45%以上
上記(3)について、収容される吸着体は内部に間隙を有するものであるが、本発明においては、上記フィルタ目開きの相当直径と上記吸着体における間隙の平均円相当直径とが密接に関連し、両者の比率を適正化することにより、エア抜け性が向上することを見出したものである。
開口率(%)=(25-A)/25×100
これを対象となるフィルタ1枚について任意の5箇所の5mm四方範囲を選んで測定し、その平均値を求める。尚、算出した開口率は、小数点以下第1位を四捨五入する。
目開きの相当直径=2×(S/π)1/2
目開きの相当直径は、大きすぎるとカラム内に吸着体を保持することが困難となる。また、万一、回路やカラム内で異物が発生した際にフィルタで捕捉できない可能性も高まる。そのため、具体的には、目開きの相当直径はカラムを縦方向から見た際の個々の吸着体1つ当りの断面積の10倍以下とすることが好ましく、より好ましくは5倍以下、さらに好ましくは2.8倍以下である。ここで言う個々の吸着体当りの断面積とは、例えば中実糸であれば糸1本当りの横断面の断面積であり、球状のビーズであれば、ビーズ1個当りについて、ビーズ中心部を通る直線で切断した際に得られる面の面積のことである。一方で、フィルタの目開きの相当直径が小さすぎると、流れの抵抗が増しエア抜け性が低化する。また、カラム内血液通液時の圧力損失の増大や、フィルタに血栓などが形成された際にカラム圧の上昇を引き起こしやすくなる。以上のことから、目開きの相当直径の上限としては5000μm以下であり、好ましくは800μm以下、より好ましくは400μm以下となる。目開きの相当直径の下限としては1μm以上であり、好ましくは5μm以上、より好ましくは10μm以上となる。
(1)ポンプを用いて流速100ml/sで、回路内のエアが完全に抜けるまで純水を循環する。必要に応じてカラムを叩くなどして完全にエアを追い出す。
(2)ポンプを停止し、エアが混入しないよう注意しながらカラムを回路から外し、被処理液の流入口および流出口それぞれに蓋をする。このときのカラム重量を測定し、Aとする。
(3)重量測定後のカラムを再び回路に戻し、流速100ml/sで純水を循環する。
(4)カラムの被処理液流入口から回路の上流部1cmの所からシリンジを用いて10mlの乾燥エアを5秒間かけて注入する。
(5)そのまま流速100ml/sで純水を1分間循環する。この間、回路は静置した状態である。
(6)ポンプを停止し、エアが混入しないよう注意しながらカラムを回路から外し、被処理液の流入口および流出口それぞれに蓋をする。このときのカラム重量を測定し、Bとする。
(7)カラム内エア除去率を、以下の式から算出する。
カラム内エア除去率(%)=(A―B)/A×100。
尚、ここでいうエア除去率は、好ましくは43%以上、より好ましくは55%以上、さらに好ましくは63%以上である。
ここでいう上記カラム長手方向に並行に配置されているストレートな形状とは、1本の糸の両側端面が、可能な限り最短距離に近い長さでカラムの入口・出口端面に接している形状のことである。ただし、糸にクリンプ等の捲縮がかかっていてもよい。 また、多孔質の吸着体は、その多孔質構造が厚み方向に均質であることが好ましい。これにより、吸着に寄与する面積を増大させることができる。一方孔構造がグラジエントである非対称構造や厚み方向に不規則な構造を持つ場合、吸着体の比表面積が低下するため好ましくない。
吸着体間隙の平均円相当直径De=4×Af/Wp
式中のAfは流路断面積であり、ケーシングの長手方向に対し垂直な方向の断面の断面積から、吸着体が占める同方向の断面の断面積の総和を引いた値である。かかる吸着体が占める断面積の総和は、後述する糸径の測定方法で得た糸径D0とカラム内充填糸本数Nから以下の式で求められる。
吸着体が占める断面積の総和=(D0/2)2×π×N
また、Wpは濡れ辺長であり、ケーシングの内側表面積と吸着体の総表面積の和である。吸着体の総表面積は、糸径D0とカラム内充填糸本数Nおよび糸の長手方向長さLから以下の式で求められる。
吸着体の総表面積=D0×π×L
ケーシングの形状としては、両端が開放端であり、例えば四角筒体、六角筒体等の角筒体や円筒体が挙げられ、中でも円筒体、特に断面が真円状の筒体が好ましい。これはケーシングが角をもたないことで、角部での血液の滞留を抑制できるためである。また、両側を開放端とすることで、血液の流れが乱流になりにくく圧力損失を最小限に抑えることができる。また、ケーシングはプラスチックや金属等により構成される器具であることが好ましい。プラスチックの場合は、例えば機械的強度、熱安定性に優れる熱可塑性樹脂が用いられる。このような熱可塑性樹脂の具体例としては、ポリカーボネート系樹脂、ポリビニルアルコール系樹脂、セルロース系樹脂、ポリエステル系樹脂、ポリアリレート系樹脂、ポリイミド系樹脂、環状ポリオレフィン系樹脂、ポリスルホン系樹脂、ポリエーテルスルホン系樹脂、ポリオレフィン系樹脂、ポリスチレン樹脂、ポリビニルアルコール系樹脂、及びこれらの混合物が挙げられる。これらの中でもケーシングに求められる成形性、透明性、放射線耐性の点においてポリスチレン、ポリカーボネートおよびそれらの誘導体が好ましい。透明性に優れた樹脂は、血液灌流時に内部の様子を確認できるため安全性の確保に好都合であり、放射線耐性に優れる樹脂は滅菌時に放射性照射する場合に好ましいためである。前者の場合には、金型による射出成形や、素材を切削加工することにより製作され、後者の場合には、素材を切削加工することにより器具が製作される。中でもコストや成型性、重量、血液適合性の観点からプラスチックが好適に用いられる。
吸着体間隙の平均円相当直径De=(32×μ×L×u/ΔP)1/2
式中のμは被処理液の粘度、Lは吸着体充填部の長手方向の長さ、uはカラム内平均流速、ΔPはカラム入部の圧力損失からカラム出部の圧力損失を差し引いた値である。
γ1=γ3×cosθ+γ2
ここで、θは接触角であり、接触角を大きくすることでγ1を低下させることができる。
また、フィルタの形態としては、多孔体、多孔質体いずれでもよいが、孔が均一に空いている多孔質体が好ましく用いられ、メッシュ、不織布などが挙げられる。中でも、目開きが均一であるため血球成分の付着が少ないこと、フィルタからの溶出物が発生しにくい等の点からメッシュが好適に用いられる。
重量平均分子量が40万のsyn-PMMAを31.7重量部、重量平均分子量が140万のsyn-PMMAを31.7重量部、重量平均分子量が50万のiso-PMMAを16.7重量部、パラスチレンスルホン酸ソーダを1.5mol%含む分子量30万のPMMA共重合体20重量部をジメチルスルホキシド376重量部と混合し、110℃で8時間撹拌し紡糸原液を調製した。得られた紡糸原液の110℃での粘度は1240poiseであった。得られた紡糸原液を93℃に保温された径0.3mmの円形吐出口をもつ口金から、1.0g/minの速度で、空気中に吐出し、空中部分を50cm走行させた後、凝固浴に導いた。凝固浴に用いた水温(凝固浴温度)を42℃として中実糸を得た。それぞれの中実糸を水洗後、保湿剤としてグリセリンを70重量%水溶液として付与した後、熱処理浴温度を84℃とし、余分のグリセリンを除去した後にスペーサー糸を巻き付けて42m/minで巻き取った。得られた中実糸の糸径は、ニコン社制の投影機V-10Aを用いて測定した結果、121μmであった。
(1)ポンプを用いて流速100ml/sで、回路内のエアが完全に抜けるまで純水を循環した。必要に応じてカラムを叩くなどして衝撃を与えることでエアを追い出しやすくした。
(2)ポンプを停止し、エアが混入しないよう注意しながらカラムを回路から外し、被処理液の流入口および流出口それぞれに蓋をした。このときのカラム重量を測定し、Aとした。
(3)重量測定後のカラムを再び回路に戻し、流速100ml/sで純水を循環した。
(4)カラムの被処理液流入口から回路の上流部1cmの所からシリンジを用いて10mlの乾燥エアを5秒間かけて注入した。
(5)そのまま流速100ml/sで純水を1分間循環した。この間、回路は静置した状態であった。
(6)ポンプを停止し、エアが混入しないよう注意しながらカラムを回路から外し、被処理液の流入口および流出口それぞれに蓋をした。このときのカラム重量を測定し、Bとした。
(7)カラム内エア除去率を、以下の式から算出した。結果を表1に示す。
カラム内エア除去率(%)=(A―B)/A×100。
紡糸原液の吐出速度を1.9g/minとすることで糸径を181μmとした以外は実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、ケーシング両側端面に実施例1と同じ寸法、形状のメッシュフィルタ、ヘッダーキャップを同様に配した。このカラムの吸着体間隙の円平均相当直径は135μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。
紡糸原液の吐出速度を0.5g/minとすることで糸径を56μmとした以外は実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、ケーシング両側端面に実施例1と同じ寸法、形状のメッシュフィルタ、ヘッダーキャップを同様に配した。このカラムの吸着体間隙の円平均相当直径は42μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。
実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、ケーシング両側端面に、目開き相当直径124μm、開口率31%のポリプロピレン製メッシュフィルタ、および実施例1と同じ寸法、形状のヘッダーキャップを実施例1と同様に配した。このカラムの吸着体間隙の円平均相当直径は91μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。また、得られた浄化カラムのタンパク質除去性能を評価するため、以下に示す方法でβ2-MG(ミクログロブリン)のクリアランス測定を行った。結果を表3に示す。
吸着カラムの性能評価として、β2-MGのクリアランスを測定した。β2-MGは、長期透析合併症である透析アミロイドーシスの原因タンパク質であることが知られている。
エチレンジアミン四酢酸二ナトリウムを添加した牛血液について、ヘマトクリットが30±3%、総タンパク量が6.5±0.5g/dLとなるように調整した。採血後、5日以内の牛血液を用いた。
回路は図5のようにセットした。回路のうち、被処理液を取り込む入り口部をBi、血液浄化カラム通液後の液出口部をBoとした。
Biを上記で調整した牛血液2L(37℃)の入った循環用ビーカー内に入れ、流速を200mL/minとしてポンプをスタートし、Boから排出される液体90秒間分を廃棄後、ただちにBoを循環用ビーカー内に入れて循環状態とした。
循環を1時間行った後ポンプを停止した。
次に、Biを上記で調整したクリアランス測定用の牛血液内に入れ、Boを廃棄用ビーカー内に入れた。
流速は200mL/minとして、ポンプをスタートしてから2分経過後、クリアランス測定用の牛血液(37℃)からサンプルを10ml採取し、Bi液とした。スタートから4分30秒経過後に、Boから流れたサンプルを10ml採取し、Bo液とした。これらのサンプルは-20℃以下の冷凍庫で保存した。
各液のβ2-MGの濃度からクリアランスを下記I式によって算出した。牛血液のロットによって測定値が異なる場合があるので、実施例、比較例には全て同一ロットの牛血液を使用した。
I式において、CO=β2-MGクリアランス(ml/min)、CBi=Bi液におけるβ2-MG濃度、CBo=Bo液におけるβ2-MG濃度、QB=Biポンプ流量(ml/min)である。
実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、ケーシング両側端面に、目開き相当直径108μm、開口率40%のポリエチレンテレフタラート製メッシュフィルタ、および実施例1と同じ寸法、形状のヘッダーキャップを実施例1と同様に配した。このカラムの吸着体間隙の円平均相当直径は91μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。また、実施例4と同様の手順でβ2-MGのクリアランスを測定した。結果を表3に示す。
紡糸原液の吐出速度を4.7g/minとすることで糸径を260μmとした以外は実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、実施例5と同様に、ケーシング両側端面に目開き相当直径108μm、開口率40%のポリプロピレン製メッシュフィルタ、および実施例1と同じ寸法、形状のヘッダーキャップを実施例1と同様に配した。このカラムの吸着体間隙の円平均相当直径は194μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。また、実施例4と同様の手順でβ2-MGのクリアランスを測定した。結果を表3に示す。 比較例1
紡糸原液の吐出速度を4.7g/minとすることで糸径を260μmとした以外は実施例1と同じ方法で中実糸を得て、実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、ケーシング両側端面に実施例1と同じ寸法、形状のメッシュフィルタ、ヘッダーキャップを同様に配した。このカラムの吸着体間隙の円平均相当直径は194μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。また、実施例4と同様の手順でβ2-MGのクリアランスを測定した。結果を表3に示す。
実施例7
実施例1と同様の紡糸原液を、93℃に保温された環状スリット部分の外径/内径=2.1/1.95mmφの2重管中空糸用口金から、2.5g/minの速度で、空気中に吐出した。ここで、同時に2重管の内管部分には窒素ガスを注入し、空中部分を50cm走行させた後、凝固浴に導いた。凝固浴に用いた水温(凝固浴温度)を42℃として中空糸膜を得た。それぞれの中空糸膜を水洗後、保湿剤としてグリセリンを70重量%水溶液として付与した後、熱処理浴温度を84℃とし、余分のグリセリンを除去した後にスペーサー糸を巻き付けて60m/minで巻き取った。得られた中空糸の糸径は、ニコン社制の投影機V-10Aを用いて測定した結果、内径200μm、糸外径260μmであった。実施例1と同じ寸法、形状のケーシング内に実施例1と同様に内蔵し、実施例6と同様に、ケーシング両側端面に目開き相当直径108μm、開口率40%のポリプロピレン製メッシュフィルタ、および実施例1と同じ寸法、形状のヘッダーキャップを実施例1と同様に配した。このカラムの吸着体間隙の円平均相当直径は195μmであった。このカラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表1に示す。
内径46mm、軸方向長さ100mmの円筒状ケーシングの被処理液流出側端面に、図2に示すように、被処理液の流出口と内径と同じ径に円柱状にカットした目開き相当直径326μm、開口率51%のポリプロピレン製メッシュフィルタを装着した。さらに、被処理液の流入口および流出口を備えたヘッダーキャップを両端に配し、片側メッシュ装着カラムを作成した。尚、吸着体は内蔵しなかった。この片側メッシュ装着カラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表2に示す。
参考例1と同じ寸法、形状のケーシングの被処理液流出側端面に、被処理液の流出口の内径と同じ径に円柱状にカットした目開き相当直径274μm、開口率45%、厚み245mmのポリテトラフルオロエチレン製メッシュフィルタを装着したこと以外は参考例1と同様にして片側メッシュ装着カラムを作成した。この片側メッシュ装着カラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表2に示す。
参考例1と同じ寸法、形状のケーシングの被処理液流出側端面に、被処理液の流出口に内径と同じ径に円柱状にカットした目開き相当直径274μm、開口率37%、厚み291mmのナイロン66製メッシュフィルタを装着したこと以外は参考例1と同様にして片側メッシュ装着カラムを作成した。この片側メッシュ装着カラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表2に示す。
参考例1と同じ寸法、形状のケーシングの被処理液流出側端面に、被処理液の流出口に内径と同じ径に円柱状にカットした目開き相当直径308μm、開口率42%、厚み280mmのポリエチレンテレフタラート製メッシュフィルタを装着したこと以外は参考例1と同様にして片側メッシュ装着カラムを作成した。この片側メッシュ装着カラムを、実施例1と同様の手順でカラム内エア除去率を測定した。結果を表2に示す。
表2の結果から、開口率と目開き相当直径がほぼ同等のメッシュを用いても、接触角が高い程、カラム内エア除去率は高い値を示すことがわかる。これは、接触角を大きくすることで、固体と空気の界面の張力を低下させられるためと考えられる。
表3の結果から、吸着体の糸径、充填率が同等であるカラムについて、カラム内エア除去率とβ2-MGのクリアランスの関係は、カラム内エア除去率が低い程β2-MGのクリアランスは低下する傾向、すなわちタンパク質の吸着性能は低下する傾向であった。尚、表3の結果において、実施例4および実施例5に係るカラムの吸着体の糸径は121μmである。一方で実施例6および比較例1係るカラムの吸着体の糸径は260μmである。いずれのカラムも吸着体の充填率は57%であることから、糸径121μmのカラムと260μmのカラムでは、カラム当りの吸着体の表面積が異なるため、これによりタンパク質吸着性能に差が生じたものと考えられる。
2 被処理液流出口
3 被処理液流入口
4 出口側フィルタ
5 入口側フィルタ
6 ケーシング
7 吸着体
8 血液浄化カラム
9 エア注入用シリンジ
10 ポンプ
11 ビーカー
12 純水
13 片側メッシュ装着カラム
14 湯浴(37℃)
15 廃棄用ビーカー
16 循環用血漿
17 クリアランス測定用血漿
Claims (9)
- 吸着体と、両端が開放端であるケーシングとを有し、前記ケーシングの内部に吸着体が収容され、前記ケーシング両端の一方が血液流入側端部、他方が血液流出端部であり、前記ケーシングの血液流入側端部および/もしくは血液流出側端部にフィルタが配置され、該フィルタは以下の要件を満たすことを特徴とする血液浄化カラム。
(1)その開口率が5%以上、80%以下
(2)その目開きの相当直径が1μm以上、5000μm以下
(3)その目開きの相当直径の前記吸着体の間隙の平均円相当直径に対する比率が45%以上 - 前記フィルタがポリオレフィン系樹脂、ポリアミド系樹脂、フッ素系樹脂の中から選ばれる少なくとも1種類の素材を含むことを特徴とする請求項1に記載の血液浄化カラム。
- 前記吸着体の形態が中空糸状および/もしくは中実糸状であることを特徴とする請求項1または2に記載の血液浄化カラム。
- 前記中空糸状および/もしくは中実糸状の吸着体がカラム長手方向に平行に配置されていることを特徴とする請求項3に記載の血液浄化カラム。
- 前記フィルタにおいて、カラム内の長手方向に対して垂直方向に開口している部分の表面積をB1と、カラム内の長手方向に対して平行方向に開口している部分の総表面積をB2とした場合に、以下の関係を満たす請求項1~4のいずれかに記載の血液浄化カラム。
B1/B2≧1 - 前記フィルタの形状がメッシュ状であることを特徴とする請求項1~5のいずれかに記載の血液浄化カラム。
- 前記吸着体の前記カラム内収容空間における充填率が30%以上、70%未満であることを特徴とする請求項1~6のいずれかに記載の血液浄化カラム。
- 前記中空糸もしくは中実糸の糸径または外径が10μm以上、1000μm以下であることを特徴とする請求項3~7のいずれかに記載の血液浄化カラム。
- 人工腎臓と直列に接続する用途に用いられることを特徴とする請求項1~8のいずれかに記載の血液浄化カラム。
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KR102435360B1 (ko) * | 2014-10-28 | 2022-08-23 | 도레이 카부시키가이샤 | 다공질 섬유, 흡착 재료 및 정화 칼럼 |
JP2016193178A (ja) * | 2015-03-31 | 2016-11-17 | 東レ株式会社 | 浄化カラム |
CN105771014A (zh) * | 2016-03-29 | 2016-07-20 | 艾沃生物科技(苏州)有限公司 | 一种吸附氧自由基的血浆滤器 |
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CN104902941A (zh) | 2015-09-09 |
US20150374898A1 (en) | 2015-12-31 |
TWI652078B (zh) | 2019-03-01 |
JP6638787B2 (ja) | 2020-01-29 |
EP2957306A1 (en) | 2015-12-23 |
KR20150118085A (ko) | 2015-10-21 |
ES2714832T3 (es) | 2019-05-30 |
JP6414049B2 (ja) | 2018-10-31 |
TW201446289A (zh) | 2014-12-16 |
CN104902941B (zh) | 2017-05-03 |
JPWO2014126014A1 (ja) | 2017-02-02 |
EP2957306A4 (en) | 2016-10-19 |
JP2019010549A (ja) | 2019-01-24 |
CA2897711A1 (en) | 2014-08-21 |
US10213543B2 (en) | 2019-02-26 |
CA2897711C (en) | 2020-04-28 |
EP2957306B1 (en) | 2019-01-02 |
KR102300302B1 (ko) | 2021-09-09 |
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