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WO2008032400A1 - Procédé pour la production d'un substrat modifié - Google Patents

Procédé pour la production d'un substrat modifié Download PDF

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Publication number
WO2008032400A1
WO2008032400A1 PCT/JP2006/318383 JP2006318383W WO2008032400A1 WO 2008032400 A1 WO2008032400 A1 WO 2008032400A1 JP 2006318383 W JP2006318383 W JP 2006318383W WO 2008032400 A1 WO2008032400 A1 WO 2008032400A1
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Prior art keywords
compound
producing
modified
base material
blood
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Japanese (ja)
Inventor
Hiroshi Takahashi
Hiroyuki Sugaya
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Toray Industries Inc
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Toray Industries Inc
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Priority to PCT/JP2006/318383 priority Critical patent/WO2008032400A1/fr
Publication of WO2008032400A1 publication Critical patent/WO2008032400A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment

Definitions

  • the present invention is a substrate suitably used in fields such as medical treatment and proteome analysis.
  • the present invention relates to a method for producing a modified base material whose surface is modified.
  • Patent Document 1 Japanese Patent Laid-Open No. 2001-213984
  • Patent Document 2 Japanese Translation of Special Publication 2003-507082
  • Patent Document 3 Japanese Patent Laid-Open No. 2001-213984
  • Non-Patent Document 1 Kazuo Ota, “Actual Artificial Kidney (Revised 4th Edition)”, Nankodo, 1993, ppl 58-164
  • Non-Patent Document 2 Tetsuzo Agishi et al., “Introduction to Dialysis”, Shujunsha, 1994, pp. 170-182
  • Non-Patent Document 3 American journal of hematology. 2006 81 (1), pp. 36-44
  • Non-Patent Document 4 Journal Biomedical Materials Research. 1998 39, pp.86- 91 Disclosure of Invention
  • an object of the present invention is to provide a method for producing a modified substrate with less elution of a blood-clotting anticoagulant with a simple production method in consideration of the above-mentioned problems, and a production method therefor It is to provide a modified substrate obtained in (1).
  • the present invention has the following configuration.
  • One of the methods for producing a modified base material of the present invention is a method for producing a modified base material characterized by irradiating a base material contacted with a compound having blood anticoagulant activity. is there.
  • Another one of the methods for producing a modified substrate of the present invention is characterized by irradiating a substrate contacted with a compound having blood anticoagulant activity in the presence of an organic solvent. This is a method for producing a modified base material.
  • the organic solvent is a solvent having a secondary or tertiary hydroxyl group, and as such a solvent, isopropano is preferable.
  • Group power of glycerol, glycerin and propylene glycol It is.
  • the compound having blood anticoagulant activity is a compound comprising a portion having blood anticoagulant activity and a polymer chain portion.
  • a polymer chain part a polyethylene glycol residue, a polybutylpyrrolidone residue, a polypropylene glycol residue, a polybutyl alcohol residue, and a group power of a copolymer containing them are preferably used. Examples include selected polymer chains.
  • the degree of Ken of polyvinyl alcohol, which is the polymer chain part, is 50 mol% or more 99.
  • the compound having blood anticoagulant activity is a compound having an amino acid as a constituent element.
  • the compound having blood anticoagulant activity is a compound having antithrombin activity, and preferably as a compound having antithrombin activity.
  • the aqueous solution of the compound having blood anticoagulant activity is an aqueous solution unstable to radiation.
  • the base material is a medical base material
  • the medical base material is a base material incorporated in the artificial kidney module.
  • the base material is a separation membrane
  • the separation membrane is a hollow fiber membrane
  • Yet another method for producing a modified base material of the present invention is to replace the water with an organic solvent after contacting the base material with a solution of a compound having blood anticoagulant activity dissolved in water. Then, it is a method for producing a modified substrate characterized by irradiating the substrate with radiation.
  • the substrate is washed after the irradiation with the radiation, and a surfactant is used for the washing.
  • the present invention by introducing a compound having blood anticoagulant activity onto the substrate surface, it is possible to impart extremely high blood anticoagulant activity to the substrate surface. The result As a result, it is possible to bring the blood into contact with the material by reducing the amount of anticoagulant used or not using anticoagulant, which can be expected to reduce the risk of side effects and other medical costs.
  • the surface of the substrate is maintained while maintaining the activity of the compound having blood anticoagulant activity. Since the compound having anticoagulant activity can be fixed by radiation, the risk due to elution of the compound having blood anticoagulant activity introduced on the substrate surface can be reduced. At the same time, the substrate can be sterilized by irradiation.
  • FIG. 1 is a schematic system diagram illustrating a blood circuit used in a blood circulation experiment of an example of the present invention.
  • a silicon tube 7 is connected to a blood port on one side of a mini module 6, and a peristaltic pump 8 and a pressure gauge 11 are installed on the way.
  • a silicone tube is also connected to the other blood port of the mini module 6.
  • the other end of each silicon tube (the side not connected to the blood port) is inserted into a polystyrene round tube 9 to form a circulation circuit.
  • Blood 10 supplemented with “Henon sodium injection” manufactured by Shimizu Pharmaceutical Co., Ltd., Japan, is added to the polystyrene round tube 9 at a rate of 0.5 U / mL, and the blood 10 is circulated by the peristaltic pump 8. Measure the change in circulation pressure.
  • FIG. 2 is a schematic side view illustrating a minimodule used in Examples 1 to 10 and Comparative Examples 1 to 12 of the present invention.
  • the both ends of the bundled hollow fiber separation membranes 4 are not blocked by the hollow portions of the hollow fiber separation membranes 4!
  • the potting agent 5 is fixed to the module case 3.
  • the ports inside the hollow fiber separation membrane 4 blood ports 1 and 1 and the outside ports (the filtrate port) are the same as in a general hollow fiber separation membrane dialyzer. 2 and 2) are provided.
  • the method for producing a modified base material of the present invention is characterized by irradiating a base material contacted with a compound having blood anticoagulant activity.
  • Radiation used in the present invention Lines are high-energy particle beams and electromagnetic waves.
  • Examples include ⁇ rays, j8 rays, ⁇ rays, X rays, ultraviolet rays, electron rays, and neutron rays. Of these radiations, ⁇ rays and electron beams are more preferably used because they have particularly high energy and can efficiently modify the substrate. In addition, ⁇ -rays, X-rays and electron beams can be sterilized at the same time by controlling the dose, which is suitable for modifying base materials such as medical materials.
  • the radiation dose is preferably lkGy or more, more preferably 5 kGy or more.
  • the radiation dose is preferably 15 kGy or more, more preferably 25 kGy or more.
  • the dose of radiation is preferably 5000 kGy or less, more preferably lOOOkGy or less, and even more preferably lOOkGy or less.
  • the decrease in the activity can be prevented by adding an organic solvent to the base material.
  • the substrate is contacted with a compound having blood anticoagulant activity in the presence of an organic solvent.
  • Examples of the organic solvent suitably used in the present invention include a solvent containing a carbon atom, a key atom, or both of these atoms in the molecule.
  • an organic solvent having a hydroxyl group in the molecule is preferably used.
  • Hydroxyl group is a non-ionic functional group that has a high effect of stabilizing radicals generated by irradiation and has a small interaction with a compound having a strong surface charge. Because there are few.
  • Examples of the organic solvent having a hydroxyl group include alcohols such as methanol and ethanol, polyethylene glycol, and ethylene glycol.
  • secondary and tertiary hydroxyl groups are more effective in stabilizing radicals, and therefore have at least one secondary hydroxyl group, tertiary hydroxyl group, or both hydroxyl groups.
  • An organic solvent is preferably used. Examples of such an organic solvent include glycerin, propylene glycol, and isopropanol.
  • These organic solvents may be used alone or in combination of two or more.
  • a low-toxic organic solvent is used.
  • the compound having blood anticoagulant activity As a method of bringing a compound having blood anticoagulant activity into contact with a substrate in the presence of an organic solvent, the compound having blood anticoagulant activity is dissolved or dispersed in an organic solvent, and the resulting liquid is dissolved.
  • coating to a base material is mentioned.
  • the dissolution of a compound having blood anticoagulant activity means that the compound dissolves in a solvent and becomes a homogeneous mixture, that is, a solution.
  • the dispersion of a compound having blood anticoagulant activity means that the compound is scattered in a solvent.
  • the solvent when a compound having blood anticoagulant activity is difficult to dissolve in the target organic solvent, after contacting the substrate with a solution dissolved in a solvent having high solubility for the compound having blood anticoagulant activity, The solvent may be replaced with the desired organic solvent.
  • the solvent for dissolving the compound having blood anticoagulant activity may be an inorganic solvent such as water. That is, after the substrate is brought into contact with a solution of a compound having blood anticoagulant activity in water, the substrate is irradiated with radiation after water is replaced with an organic solvent.
  • a compound having blood anticoagulant activity is applied or adsorbed on a base material, and the base material on which the compound is adhered may be immersed in an organic solvent.
  • the compound having blood anticoagulant activity has low water content!
  • the moisture content is preferably 10% or less, more preferably 5% or less, and still more preferably 1% or less.
  • a desiccant such as silica gel may be used to prevent the moisture content from increasing during storage until irradiation.
  • the water content of the compound having blood anticoagulant activity in the present invention is defined as follows, and the water content is measured by the Karl Fischer method of the Japanese Pharmacopoeia.
  • Moisture content of compound with blood anticoagulant activity (%) 100 X (weight of water in compound with blood anticoagulant activity) / (weight of compound with blood anticoagulant activity)
  • the moisture content is preferably 20% or less, more preferably 15% or less, and further preferably 10% or less.
  • a desiccant such as silica gel to prevent the moisture content from increasing during storage until irradiation.
  • the moisture content in the organic solvent in the present invention is defined as follows, and the moisture content is measured by the Karl Fischer method of the Japanese Pharmacopoeia.
  • Moisture content in organic solvent 100 X (weight of compound anti-coagulant activity and water in organic solvent) / (weight of anti-coagulant compound and organic solvent)
  • the pH buffer solution refers to a solution having a buffering action against a change in pH in the solution.
  • Examples of such pH buffer include aqueous solutions containing tris (hydroxymethyl) aminomethane, glycine, potassium phthalate, sodium phosphate, and the like.
  • an antioxidant may be used in combination. This is because an antioxidant can be expected to supplement hydroxy radicals generated by irradiation and suppress the denaturation of compounds that are unstable to radiation.
  • the term “antioxidant” refers to a compound having a molecule that has the property of easily giving electrons to other molecules, but the base material is a compound that has blood anticoagulant activity and is denatured by radiation. It also has the property of suppressing
  • antioxidants examples include water-soluble vitamins such as vitamin C, polyphenols, sugars such as glucose, galactose, mannose, and trehalose, and sodium hydrosal.
  • Powers including, but not limited to, inorganic salts such as phyto, sodium pyrosulfite, sodium nithionate, polyvinyl alcohol, uric acid, cysteine, and dartathione. These antioxidants may be used alone or in combination of two or more.
  • the modified base material obtained in the present invention is used for a medical device, it is necessary to consider its safety, and therefore, an antioxidant with low toxicity is used.
  • concentration of the aqueous solution containing the antioxidant varies depending on the type of antioxidant contained and the irradiation dose of the radiation, so it should be used at the optimum concentration as appropriate.
  • the base material used in the present invention also has a material strength imparted with a compound having blood anticoagulant activity, and a polymer compound material is preferably used as the material because of its good moldability.
  • a polymer compound material include, for example, polymethylmetatalate, polypropylene, polyethylene, polyvinyl chloride, polysalt vinylidene, polyvinylidene fluoride, polyvinyl acetate, polycarbonate, senorelose, and senorelose acetate.
  • the base material used in the present invention can be suitably used as a medical base material because of its high blood compatibility.
  • medical base materials include artificial blood vessels, catheters, blood bags, contact lenses, intraocular lenses, and surgical aids. They are used in biological component separation modules and blood purification modules. Also included is a separation membrane.
  • the biological component separation module refers to a module that separates a biological substance by filtration or dialysis and collects a part thereof, and is not limited to a medical substrate.
  • the blood purification module is a module having a function of removing waste and harmful substances in the blood by adsorption, filtration and diffusion when circulating blood outside the body.
  • Such blood purification modules include artificial kidneys and exotoxin adsorption columns.
  • the form of the separation membrane incorporated in the blood purification module is not particularly limited, and is used in the form of a flat membrane or a hollow fiber membrane. However, considering the processing efficiency, that is, securing the surface area in contact with blood, the hollow fiber membrane type is preferred.
  • a compound having blood anticoagulant activity used in the present invention a compound having an amino acid as a constituent element can be used.
  • Amino acids have various functional groups in their side chains, and are suitable because they can exhibit their own activity or be bound to active groups.
  • a compound that has an amino acid as a constituent element is a compound that contains a naturally occurring amino acid. For example, a compound that is composed only of amino acids such as proteins and peptides, a glycoprotein, an amino acid complex, etc. In addition, amino acids such as aminoacyl aderic acid and those other than amino acids are also included.
  • a compound having blood anticoagulant activity refers to a compound whose prothrombin time is increased by 30% or more when added to blood to a concentration of 10 ⁇ gZmL compared to unadded blood. .
  • the prothrombin time can be measured by the method described in the following document.
  • Examples of the compound having blood anticoagulant activity used in the present invention include heparin, nafamostat mesylate, sodium citrate, sodium oxalate, ⁇ 1 antitrypsin, ⁇ 2 macroglobulin, C1 inhibitor, Examples include thrombomodulin and protein C.
  • the compounds having blood anticoagulant activity there are compounds having a strong blood anticoagulant effect by inhibiting the activity of thrombin, that is, compounds having antithrombin activity.
  • the compound having antithrombin activity used in the present invention is a compound that suppresses the activity of thrombin, which is a coagulation-related substance in blood, and is obtained by plasma concentration of the compound at a concentration of gZmL.
  • Measured power in HEAMOSYS “ECA-Tkit” Compound A compound that increases by 50% or more compared to that of plasma without added plasma.
  • PEG represents a polyethylene glycol residue having a number average molecular weight of 2000, Me represents a methyl group
  • 4-methoxy-benzenesulfo-luene Asn PEG2000—Ome
  • Examples include Pro-4-amidinobenzylamide (hereinafter sometimes abbreviated as Compound A), antithrombin III and hirudin.
  • the polymer chain portion can bind to the substrate, and blood The decrease in activity can be prevented by binding the portion having anticoagulant activity to the base material.
  • the polymer chain refers to a molecular chain in which repeating units having a specific chemical structure are linked by a covalent bond and having a molecular weight of 1000 or more. Examples of such a polymer chain moiety include compounds having a hydrophilic polymer chain such as polyethylene glycol, polybutylpyrrolidone, polypropylene glycol, polyvinyl alcohol, and any of these copolymers.
  • Such a compound having a hydrophilic polymer chain is not easily lowered in water solubility as a compound having blood anticoagulant activity, and derivatives having an amino group or a carboxyl group are commercially available. Since a method for producing a compound having blood anticoagulant activity by introduction into a polymer chain portion is relatively easy, it can be particularly preferably used.
  • n The number of monomer repeating units in the polybutyl alcohol represented by: n is the following repeating unit: [0052] [Chemical Formula 3]
  • [0053] represents the number of monomer repeating units in the polybutyl alcohol represented by
  • the degree of keying is preferably 50 mol% or more, more preferably 74 mol% or more, and further preferably 78 mo 1% or more.
  • the key strength is preferably 99.9 mol% or less, preferably 95 mol% or less, more preferably 90 mol% or less.
  • the dissolution rate of a compound having blood anticoagulant activity in an organic solvent is low! In the case of hemorrhoids, as described above, the dissolution rate is large in advance.
  • ⁇ Prepare a solution in which a compound having blood anticoagulant activity is dissolved in a solvent, and after bringing the solution into contact with the substrate, the target organic solvent and It is also possible to adjust the solution of the target organic solvent by contacting and mixing, separating the solvent with a high dissolution rate by operations such as extraction, drying and distillation.
  • the base material is a separation membrane
  • the solute radius of the solute molecule is equal to or larger than the pore radius of the membrane, the membrane may become clogged and the originally planned membrane performance may not be obtained.
  • the substrate After applying a compound having blood anticoagulant activity to the substrate surface, the substrate can be washed before or after irradiation or both before and after irradiation to reduce elution of these compounds. is there.
  • compounds with blood anticoagulant activity are covalently bonded to the substrate surface!
  • the risk of excessive removal of compounds is low.
  • water, physiological saline, pH buffer solution or organic solvent can be used. Further, the surfactant solution has a high cleaning effect.
  • the term "surfactant” generally means a surfactant, which is strong against water and exhibits surface activity, and has a hydrophilic portion and a hydrophobic (lipophilic) in the molecule. It is a substance that has both parts.
  • ionic surfactants can change the physical properties of the surface due to binding of surfactants due to electrostatic interaction when a substrate having an ionic functional group is used. I cannot deny sex. Therefore, a nonionic surfactant is preferably used.
  • nonionic surfactants polyoxyethylene alkyl ether and polyoxyethylene alkyl ether are particularly excellent in cleaning effect.
  • the surfactant when the surfactant is often a solid or viscous liquid, it is preferably in the form of a solution in terms of handleability. If the concentration of the solution is too low, a sufficient cleaning effect may not be obtained. On the other hand, if the concentration is too high, not only the production cost increases but also the substrate may be modified. Accordingly, the concentration of the aqueous surfactant solution is preferably in the range of 0.001% to 20% by weight, more preferably in the range of 0.005% to 10% by weight, and still more preferably 0.001%. The range is from 01% by weight to 5% by weight.
  • a method for cleaning the base material a method of bringing a base material into contact with a cleaning agent such as a surfactant or a solution added with a surfactant so that excess compounds having blood anticoagulant activity can be leached. If it is.
  • a cleaning agent such as a surfactant or a solution added with a surfactant so that excess compounds having blood anticoagulant activity can be leached.
  • a method of cleaning by flowing a cleaning agent in a predetermined direction at a predetermined flow rate is the most efficient and can be cleaned well.
  • a method of immersing the substrate in a surfactant may be employed.
  • Surfactant is added to the base material, or the surfactant added with the surfactant may be circulated around the base material when it is circulated in a predetermined direction, but the surfactant from which the compound having blood anticoagulant activity is eluted Reusing can lead to reduced cleaning efficiency. If the cleaning agent is flowed at a predetermined flow rate for cleaning, if the flow rate is too small, a sufficient cleaning effect may not be obtained. If the flow rate is too high, the cleaning time will be long. Productivity decreases. Therefore, the flow rate per substrate surface area is 0.5LZm2 or more 3
  • 00LZm2 or less is preferred, more preferably lLZm2 or more and 200LZm2 or less, and further preferably 3LZm2 or more and 100LZm2 or less.
  • the surfactant can be further washed with water or physiological saline to prevent the surfactant from remaining on the substrate.
  • washing with water and physiological saline means washing using these separately.
  • the amount of the ungrafted compound having blood anticoagulant activity can be reduced, and the amount of washing after irradiation can be reduced.
  • the amount of the compound having blood anticoagulant activity on the substrate surface is preferably not less than 0.OOl / zg / cmS and less than 0. Ig / cm2, more preferably less than 0.005 ⁇ g / cm2 and less than 0.01 g / cm2, more preferably less than 0. 01 g / cm2 or more 0. Less than OOlg / c m2.
  • FIG. 1 is a schematic system diagram illustrating a blood circuit used in a blood circulation experiment of each example of the present invention.
  • the outer space of the hollow fiber membrane is filled with physiological saline (Otsuka Pharmaceutical Factory's “Otsuka Raw Food Injection”)!
  • a silicon tube 7 having a length of 8 mm and a length of 52 cm was connected, and a peristaltic pump 8 and a pressure gauge 11 (AP-32A manufactured by Keyence Corporation) were installed on the way.
  • the other blood port of the mini module 6 was connected to a silicon tube with an inner diameter of 0.8 mm and a length of 16 cm.
  • the side not connected to the blood port of both silicon tubes was inserted into a 5 mL polystyrene round tube 9 (352054) manufactured by BECTON DICKINSON to produce the circulation circuit shown in FIG.
  • the solvent contained in the hollow fiber membrane of the mini module immediately before irradiation was squeezed out.
  • the moisture content of the solvent was measured using Hiranuma Sangyo Co., Ltd. AQ-7 Hiranuma trace moisture measuring device, and Hiranuma Sangyo Hydranal Aqualite RS and Aqualite CN as the electrolyte. I went according to the book.
  • Polysulfone (Solvay "Udel” (registered trademark) P-3500) 18 parts by weight and polypyrrole pyrrolidone (BASF K30) 9 parts by weight N, N, 72 parts by weight dimethylacetamide and water In addition to 1 part by weight of the mixed solvent, it was dissolved by heating at a temperature of 90 ° C. for 14 hours to obtain a film-forming stock solution.
  • This film-forming stock solution was discharged from the outer tube of an orifice type double cylindrical die having an inner diameter of 0.3 mm and an inner diameter of 0.2 mm.
  • As a core solution 58 parts by weight of N, N′-dimethylacetamide and 42 parts by weight of water were discharged from the inner tube.
  • the discharged membrane forming solution passed through a distance of 350 mm from the base to the coagulation bath liquid level, and was then introduced into a 100% water coagulation bath to obtain a hollow fiber membrane.
  • the structure of the obtained hollow fiber membrane was confirmed with an electron microscope (S800 manufactured by Hitachi, Ltd.), it had an asymmetric structure.
  • the resulting hollow fiber membrane had an inner diameter of 0.2 mm and a film thickness of 0.03 mm.
  • FIG. 2 is a schematic side view illustrating a mini-module.
  • Two hollow fiber membranes 4 are bundled and both ends are fixed to a polycarbonate module mini-module case 3 with a polyurethane potting agent 5 so that the hollow portion of the hollow fiber membrane 4 is not blocked.
  • a mini module was created.
  • This mini-module has an inner diameter of about 5mm and a length of about 12cm.
  • blood port 1 blood port 1
  • an outer port It has 2 (dialysate port 2).
  • the hollow fiber membrane in the mini module and the inside of the mini module were washed with distilled water to obtain a hollow fiber membrane mini module.
  • the water inside and outside the hollow fiber of the polysulfone hollow fiber membrane mini-module was removed using compressed air of 0.2 kgfZcm2.
  • Tris (hydroxymethyl) aminomethane (code30-5000 manufactured by Katayama Chemical Co., Ltd.) and sodium chloride (sold by Sigma-Aldrich Japan code28-2270-5) were added to ultrapure water at concentrations of 0. O5mol ZL and 0. ImolZL, respectively.
  • a solution was prepared as follows. Hydrochloric acid (code 080-01066 manufactured by Wako Pure Chemical Industries, Ltd.) was added to the solution, and the pH was adjusted to 7.8 to prepare a buffer solution.
  • a solution of Compound A and 2-pronool V (codel 0982-7, manufactured by Aldrich), which is a compound having blood anticoagulant activity, was prepared in the buffer so that the concentrations were 100 ppm by weight and 10% by weight, respectively.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 1 except that ultrapure water was used instead of the buffer solution in Example 1.
  • the time during which the circulation pressure exceeded lOkPa was 77 minutes.
  • the moisture content was 90.2%. The results are shown in Table 1.
  • the water inside and outside the mini module hollow fiber was removed using compressed air of 0.2 kgfZcm2.
  • a solution was prepared using ultrapure water so that the compound A had a concentration of 10 ppm by weight. 20 mL of the same solution was circulated by a peristaltic pump in the same manner as in Example 1 for 15 minutes.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 3 except that 2-propanol in Example 3 was replaced with propylene glycol (Code: 164-04996 manufactured by Wako Pure Chemical Industries, Ltd.). The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 3 except that 2-propanol in Example 3 was replaced with glycerin (Sigma Aldrich release code: 12-1120-5). The results are shown in Table 1.
  • Example 1 The polysulfone hollow fiber membrane mini-module in Example 1 was replaced with a polymethyl methacrylate hollow fiber membrane mini-module, and two washings with a polyoxyethylene octylphenol ether water solution were performed with 20 L of ultrapure water at lmL / min.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 1 except that the one-pass cleaning was used. The results are shown in Table 1.
  • Example 2 The polysulfone hollow fiber membrane mini-module in Example 2 was replaced with a polymethyl methacrylate hollow fiber membrane mini-module, and two washings with a polyoxyethylene octylphenol ether water solution were performed with 20 L of ultrapure water at lmL / min. A hollow fiber membrane mini-module was obtained in the same manner as in Example 2 except that the one-pass cleaning was used. The results are shown in Table 1. [0084] (Example 8)
  • Example 3 The polysulfone hollow fiber membrane mini-module in Example 3 was replaced with a polymethyl methacrylate hollow fiber membrane mini-module, and two washings with a polyoxyethylene octylphenol ether water solution were performed with 20 L of ultrapure water at lmL / min.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 3 except that the one-pass cleaning was used. The results are shown in Table 1.
  • Example 4 The polysulfone hollow fiber membrane minimodule in Example 4 was replaced with a polymethylmethacrylate hollow fiber membrane minimodule, and two washings with polyoxyethylene octylphenol ether water solution were performed with 20 L of ultrapure water at 1 mL / min.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 4 except that the one-pass cleaning was used. The results are shown in Table 1.
  • Example 5 The polysulfone hollow fiber membrane minimodule in Example 5 was replaced with a polymethylmethacrylate hollow fiber membrane minimodule, and two washings with a polyoxyethylene octylphenol ether water solution were performed with 20 L of ultrapure water at lmL / min.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 5 except that the one-pass cleaning was used. The results are shown in Table 1.
  • Example 1 A hollow fiber membrane mini-module was obtained in the same manner as in Example 1 except that ⁇ -ray irradiation in Example 1 was applied. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 2 except that ⁇ -ray irradiation in Example 2 was applied. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 3 except that ⁇ -ray irradiation in Example 3 was applied. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 4 except that ⁇ -ray irradiation in Example 4 was applied. The results are shown in Table 1.
  • Example 5 A hollow fiber membrane mini-module was obtained in the same manner as in Example 5 except that ⁇ -ray irradiation was applied in Example 5. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 6 except that ⁇ -ray irradiation was applied in Example 6. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 7, except that ⁇ -ray irradiation in Example 7 was applied. The results are shown in Table 1.
  • Example 8 A hollow fiber membrane mini-module was obtained in the same manner as in Example 8 except that ⁇ -ray irradiation in Example 8 was applied. The results are shown in Table 1.
  • a hollow fiber membrane mini-module was obtained in the same manner as in Example 9 except that ⁇ -ray irradiation in Example 9 was applied. The results are shown in Table 1.
  • Example 10 A hollow fiber membrane mini-module was obtained in the same manner as in Example 10 except that ⁇ -ray irradiation in Example 10 was applied. The results are shown in Table 1.
  • the polysulfone hollow fiber membrane mini-module was filled with ultrapure water and irradiated with ⁇ rays with the four ports sealed. At this time, the absorbed dose of ⁇ rays was 26 kGy.
  • the mini-module hollow fiber separation membrane 4 and the inside of the mini-module are circulated and washed in the same manner as in Example 1 using the same polyoxyethylene octyl ether solution lOOmL as in Example 1. volume 0/0 of polyoxyethylene O Chi le Hue - was carried out in the same manner as 4 hours washed with ether aqueous 10 OML.
  • Example 12 Thereafter, 300 mL of ultrapure water similar to that in Example 1 was passed through the mini-module in the same manner as in Example 1, and then washed and discharged. After that, 300 mL of physiological saline was passed through the same path as the above ultrapure water at a flow rate of 1 OmLZmin at a flow rate of 1 OmLZmin, so that the solution in the minimodule was replaced with physiological saline to obtain a hollow fiber membrane minimodule. . The results are shown in Table 1. [0098] (Comparative Example 12)
  • a hollow fiber membrane mini-module was obtained in the same manner as in Comparative Example 11 except that the polysulfone hollow fiber membrane mini-module in Comparative Example 11 was replaced with a polymethyl methacrylate hollow fiber membrane mini-module. The results are shown in Table 1.
  • the present invention is a modified base material in which a compound having blood anticoagulant activity is immobilized on the base material surface by irradiation, and the amount of blood anticoagulant used can be reduced. Therefore, it can be expected to reduce the risk of side effects on blood anticoagulants.

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  • Surgery (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • External Artificial Organs (AREA)

Abstract

L'invention concerne un procédé pour introduire un composé ayant une activité anti-coagulante du sang instable aux rayons de rayonnement dans une surface de substrat par l'exposition aux rayons de rayonnement pour ainsi modifier la surface de substrat, en particulier, un procédé pertinent pour produire un substrat modifié avec une surface modifiée dans laquelle une dénaturation du composé par les rayons de rayonnement peut être remarquablement réduite ; et un substrat modifié obtenu par le procédé de modification de surface ci-dessus. L'invention concerne un procédé pour produire un substrat modifié, caractérisé en ce qu'un substrat amené en contact avec un composé ayant une activité anti-coagulante du sang, de préférence, en présence d'un solvant organique, est exposé aux rayons de rayonnement. En tant que solvant organique, on utilise de préférence un solvant ayant un hydroxyle secondaire ou tertiaire, tel que l'isopropanol, le glycérol ou le propylène glycol.
PCT/JP2006/318383 2006-09-15 2006-09-15 Procédé pour la production d'un substrat modifié Ceased WO2008032400A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2006/318383 WO2008032400A1 (fr) 2006-09-15 2006-09-15 Procédé pour la production d'un substrat modifié

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2006/318383 WO2008032400A1 (fr) 2006-09-15 2006-09-15 Procédé pour la production d'un substrat modifié

Publications (1)

Publication Number Publication Date
WO2008032400A1 true WO2008032400A1 (fr) 2008-03-20

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Country Link
WO (1) WO2008032400A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009225824A (ja) * 2008-03-19 2009-10-08 Toray Ind Inc 基材およびその製造方法
JP2010082067A (ja) * 2008-09-30 2010-04-15 Toray Ind Inc 生体成分接触用途の膜の製造方法
CN103842003A (zh) * 2011-11-04 2014-06-04 旭化成医疗株式会社 血液处理用分离膜、以及安装有该膜的血液处理器

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004018085A1 (fr) * 2002-08-21 2004-03-04 Toray Industries, Inc. Substrat modifie et procede de production d'un substrat modifie
JP2004525888A (ja) * 2001-01-23 2004-08-26 ヘモジュス ゲーエムベーハー オリゴまたはポリアルキレングリコール結合トロンビン阻害剤
JP2005065711A (ja) * 2003-08-21 2005-03-17 Toray Ind Inc 吸着材料および吸着材料の製造方法
JP2005230408A (ja) * 2004-02-23 2005-09-02 Toray Ind Inc 基材の処理方法および該方法を用いた分離膜の製造方法
JP2005230407A (ja) * 2004-02-23 2005-09-02 Toray Ind Inc 改質基材
JP2005270645A (ja) * 2004-02-23 2005-10-06 Toray Ind Inc 改質基材

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Publication number Priority date Publication date Assignee Title
JP2004525888A (ja) * 2001-01-23 2004-08-26 ヘモジュス ゲーエムベーハー オリゴまたはポリアルキレングリコール結合トロンビン阻害剤
WO2004018085A1 (fr) * 2002-08-21 2004-03-04 Toray Industries, Inc. Substrat modifie et procede de production d'un substrat modifie
JP2005065711A (ja) * 2003-08-21 2005-03-17 Toray Ind Inc 吸着材料および吸着材料の製造方法
JP2005230408A (ja) * 2004-02-23 2005-09-02 Toray Ind Inc 基材の処理方法および該方法を用いた分離膜の製造方法
JP2005230407A (ja) * 2004-02-23 2005-09-02 Toray Ind Inc 改質基材
JP2005270645A (ja) * 2004-02-23 2005-10-06 Toray Ind Inc 改質基材

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009225824A (ja) * 2008-03-19 2009-10-08 Toray Ind Inc 基材およびその製造方法
JP2010082067A (ja) * 2008-09-30 2010-04-15 Toray Ind Inc 生体成分接触用途の膜の製造方法
CN103842003A (zh) * 2011-11-04 2014-06-04 旭化成医疗株式会社 血液处理用分离膜、以及安装有该膜的血液处理器
JPWO2013065819A1 (ja) * 2011-11-04 2015-04-02 旭化成メディカル株式会社 血液処理用分離膜、及びその膜を組み込んだ血液処理器
US9956334B2 (en) 2011-11-04 2018-05-01 Asahi Kasei Medical Co., Ltd. Separation membrane for blood processing and blood processing apparatus having the membrane installed therein

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