EP4157499A1 - Hohlfasermembran für die abtrennung von blutplasma aus blut - Google Patents
Hohlfasermembran für die abtrennung von blutplasma aus blutInfo
- Publication number
- EP4157499A1 EP4157499A1 EP21730186.0A EP21730186A EP4157499A1 EP 4157499 A1 EP4157499 A1 EP 4157499A1 EP 21730186 A EP21730186 A EP 21730186A EP 4157499 A1 EP4157499 A1 EP 4157499A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hollow fiber
- fiber membrane
- weight
- blood
- spinning
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000012528 membrane Substances 0.000 title claims abstract description 240
- 239000012510 hollow fiber Substances 0.000 title claims abstract description 217
- 210000004369 blood Anatomy 0.000 title claims abstract description 140
- 239000008280 blood Substances 0.000 title claims abstract description 140
- 210000002381 plasma Anatomy 0.000 title claims abstract description 61
- 238000000034 method Methods 0.000 claims abstract description 64
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 52
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 25
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 25
- 229940046009 vitamin E Drugs 0.000 claims abstract description 25
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 25
- 239000011709 vitamin E Substances 0.000 claims abstract description 25
- 229920001600 hydrophobic polymer Polymers 0.000 claims abstract description 19
- 238000004519 manufacturing process Methods 0.000 claims abstract description 17
- 238000009987 spinning Methods 0.000 claims description 95
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 53
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 53
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 53
- 229920002492 poly(sulfone) Polymers 0.000 claims description 30
- 238000000926 separation method Methods 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 24
- 230000008569 process Effects 0.000 claims description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 238000007873 sieving Methods 0.000 claims description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 16
- 238000001556 precipitation Methods 0.000 claims description 16
- 102000007330 LDL Lipoproteins Human genes 0.000 claims description 15
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- 239000003880 polar aprotic solvent Substances 0.000 claims description 14
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- 229930003802 tocotrienol Natural products 0.000 claims description 14
- 235000019148 tocotrienols Nutrition 0.000 claims description 14
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 claims description 13
- 102000009027 Albumins Human genes 0.000 claims description 11
- 108010088751 Albumins Proteins 0.000 claims description 11
- 229940087168 alpha tocopherol Drugs 0.000 claims description 11
- 229960000984 tocofersolan Drugs 0.000 claims description 11
- 235000004835 α-tocopherol Nutrition 0.000 claims description 11
- 239000002076 α-tocopherol Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 238000004833 X-ray photoelectron spectroscopy Methods 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 108060003951 Immunoglobulin Proteins 0.000 claims description 7
- 102000018358 immunoglobulin Human genes 0.000 claims description 7
- 230000001954 sterilising effect Effects 0.000 claims description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 238000001125 extrusion Methods 0.000 claims description 3
- 206010018910 Haemolysis Diseases 0.000 abstract description 23
- 230000008588 hemolysis Effects 0.000 abstract description 23
- 230000000694 effects Effects 0.000 abstract description 12
- 238000002616 plasmapheresis Methods 0.000 abstract description 12
- 239000010410 layer Substances 0.000 description 95
- 102000004506 Blood Proteins Human genes 0.000 description 17
- 108010017384 Blood Proteins Proteins 0.000 description 17
- 238000012360 testing method Methods 0.000 description 16
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- 210000001772 blood platelet Anatomy 0.000 description 11
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- 238000002560 therapeutic procedure Methods 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
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- 229920000642 polymer Polymers 0.000 description 10
- 102000001554 Hemoglobins Human genes 0.000 description 9
- 108010054147 Hemoglobins Proteins 0.000 description 9
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- 210000003743 erythrocyte Anatomy 0.000 description 8
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- 238000000691 measurement method Methods 0.000 description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 239000000306 component Substances 0.000 description 6
- 229920001577 copolymer Polymers 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 5
- 150000003626 triacylglycerols Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 229960002897 heparin Drugs 0.000 description 4
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- 238000004382 potting Methods 0.000 description 4
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- 238000001179 sorption measurement Methods 0.000 description 4
- 125000001174 sulfone group Chemical group 0.000 description 4
- 239000002344 surface layer Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 3
- 239000004926 polymethyl methacrylate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N 4-aminoantipyrine Chemical compound CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 239000004697 Polyetherimide Substances 0.000 description 2
- 239000004642 Polyimide Substances 0.000 description 2
- 229920000491 Polyphenylsulfone Polymers 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000035508 accumulation Effects 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- IISBACLAFKSPIT-UHFFFAOYSA-N bisphenol A Chemical compound C=1C=C(O)C=CC=1C(C)(C)C1=CC=C(O)C=C1 IISBACLAFKSPIT-UHFFFAOYSA-N 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 239000012503 blood component Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- GNGACRATGGDKBX-UHFFFAOYSA-N dihydroxyacetone phosphate Chemical compound OCC(=O)COP(O)(O)=O GNGACRATGGDKBX-UHFFFAOYSA-N 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 150000002708 marine derived tocopherols Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920002239 polyacrylonitrile Polymers 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 229920001601 polyetherimide Polymers 0.000 description 2
- 229920001721 polyimide Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
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- 238000001878 scanning electron micrograph Methods 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 150000003610 tocomonoenols Chemical class 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 235000010384 tocopherol Nutrition 0.000 description 2
- 229960001295 tocopherol Drugs 0.000 description 2
- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- 229910018089 Al Ka Inorganic materials 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- -1 IgM Proteins 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229920003082 Povidone K 90 Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000274 adsorptive effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
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- 239000003058 plasma substitute Substances 0.000 description 1
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- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
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- 238000000108 ultra-filtration Methods 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
- B01D69/082—Hollow fibre membranes characterised by the cross-sectional shape of the fibre
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/08—Hollow fibre membranes
- B01D69/087—Details relating to the spinning process
- B01D69/088—Co-extrusion; Co-spinning
-
- 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
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3496—Plasmapheresis; Leucopheresis; Lymphopheresis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
- B01D63/02—Hollow fibre modules
- B01D63/021—Manufacturing thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0011—Casting solutions therefor
- B01D67/00111—Polymer pretreatment in the casting solutions
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
- B01D67/0002—Organic membrane manufacture
- B01D67/0009—Organic membrane manufacture by phase separation, sol-gel transition, evaporation or solvent quenching
- B01D67/0016—Coagulation
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/12—Composite membranes; Ultra-thin membranes
- B01D69/1212—Coextruded layers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
- B01D69/14—Dynamic membranes
- B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
- B01D69/142—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers"
- B01D69/144—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers" containing embedded or bound biomolecules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/44—Polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds, not provided for in a single one of groups B01D71/26-B01D71/42
- B01D71/441—Polyvinylpyrrolidone
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
- B01D71/06—Organic material
- B01D71/66—Polymers having sulfur in the main chain, with or without nitrogen, oxygen or carbon only
- B01D71/68—Polysulfones; Polyethersulfones
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/08—Specific temperatures applied
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/08—Specific temperatures applied
- B01D2323/081—Heating
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/15—Use of additives
- B01D2323/218—Additive materials
- B01D2323/2182—Organic additives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/60—Co-casting; Co-extrusion
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/04—Characteristic thickness
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/36—Hydrophilic membranes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2325/00—Details relating to properties of membranes
- B01D2325/38—Hydrophobic membranes
Definitions
- the subject of the invention relates to a hollow fiber membrane for separating blood plasma from blood.
- Such hollow fiber membranes are used in extracorporeal blood treatment therapy for patients.
- the invention also relates to a method for producing such hollow fiber membranes.
- Hollow fiber membranes are used, among other things, in the therapy of extracorporeal blood treatment in order to separate blood plasma from the blood of patients and to treat it with suitable forms of treatment. Such hollow fiber membranes are therefore also referred to as plasma membranes.
- the therapeutic procedure for separating blood plasma from blood is known as plasmapheresis.
- plasmapheresis stands for a medical procedure for extracting blood plasma from blood.
- non-specific plasmapheresis the entire blood plasma is separated from the cellular blood components. From a therapeutic point of view, a non-specific separation of blood plasma from blood requires a fluid balance, e.g. a substitution with a plasma expander during the procedure and / or an addition of fresh plasma to the patient.
- Selective plasmapheresis takes place, for example, as part of the therapy of autoimmune diseases.
- Selective hollow fiber membranes which only separate part of the plasma proteins in the blood plasma, are used here.
- Cascade filtration which is used in therapeutic procedures, should also be mentioned in this context.
- the blood plasma can initially be separated non-specifically from the blood in a first filtration and selective further plasma proteins can be separated from the separated blood plasma in a second filtration stage.
- blood plasma is understood to mean the non-cellular parts of the blood.
- Human blood plasma consists of approx. 90% water and 10% of substances dissolved in it, in particular also plasma proteins contained in it (eg albumins, lipoproteins, immunoglobulins, fibrinogen).
- Blood plasma is more viscous than water due to its plasma protein content.
- the plasma viscosity is essentially determined by the high molecular weight proteins immunoglobulins and fibrinogen.
- the proportion of blood plasma in the blood volume is around 55% by volume, and the proportion of cellular blood components is accordingly around 45% by volume.
- blood is taken from a patient as part of an extracorporeal blood treatment and passed through a hollow fiber membrane filter via an extracorporeal blood circuit.
- the plasma is separated in the hollow fiber membrane filter on suitable hollow fiber membranes by filtration.
- the blood plasma is transported by convective transport (i.e. by a pressure difference) across the membrane wall of the hollow fiber membranes and separated.
- blood is introduced into the hollow fiber membrane filter and, as a rule, flows through the lumina of the hollow fiber membrane.
- the blood plasma is transported across the membrane wall, with cellular components of the blood being retained by the membrane wall.
- the hollow fiber membranes provided for plasma separation must therefore meet a specific requirement profile in order to enable therapeutic plasma separation, as described here.
- the pores of the plasma membrane are designed so that the components, i.e. the plasma proteins, of the plasma can pass through the membrane.
- high molecular weight plasma proteins such as. B. the "Low Density Lipoprotein” (LDL) with a molecular weight of approx. 2.7 MDa
- LDL Low Density Lipoprotein
- the membrane wall of the hollow fiber membrane must be able to pass, whereby blood cells are held back due to the size of the pores.
- Hollow fiber membranes for the separation of blood plasma from blood therefore differ from known hollow fiber membranes which are used in hemodialysis in terms of their pore size.
- these hollow fiber membranes for extracorporeal blood treatment are designed in such a way that albumin with a molecular weight of approx. 66 kDa is almost completely retained by the hollow fiber membranes.
- the pore size of the selective layer of the membrane is designed as large as possible relative to the cellular components of the blood, so that the cellular components are excluded from a membrane transition, whereas the plasma proteins can pass through the membrane wall.
- the separation of blood plasma from blood by hollow fiber membranes is regularly accompanied by a disadvantageous occurrence of hemolysis. It is assumed that the membrane structure, caused by the large pores of the hollow fiber membranes, in connection with the transmembrane pressure difference necessary for the filtration, acts mechanically on the blood cells, thereby causing cell damage and in particular destroying red blood cells.
- the occurrence of hemolysis reactions during plasma separation is problematic from a therapeutic point of view.
- the separated blood plasma is contaminated with hemoglobin and cell fragments, so that in case of doubt the separated blood plasma cannot be used for further therapeutic steps.
- DE 10 2007 019 051 B3 discloses a two-layer hollow fiber membrane produced by coextrusion from two spinning masses for the separation of blood plasma from blood.
- the hollow fiber membrane is characterized by a coarse-meshed selective blood contact layer and a porous support layer.
- a first aspect was the task of providing a hollow fiber membrane for the separation of blood plasma from blood which has a reduced hemolysis activity.
- the object was to find a method with which such hollow fiber membranes can be produced for plasma separation.
- the underlying problem is solved by a hollow fiber membrane having the features of claim 1.
- the subclaims 2 to 9 represent advantageous embodiments.
- a sterile hollow fiber membrane filter having the features according to claim 15.
- a first aspect of the present invention relates to a hollow fiber membrane for separating blood plasma from blood, having a blood contact layer and a support layer, each having a hydrophobic and a hydrophilic polymer and vitamin E, in particular an ⁇ -tocopherol or a tocotrienol, the vitamin E, in particular the ⁇ -tocopherol or the tocotrienol, is present in a proportion of 0.005 to 0.25% by weight based on the total weight of the hollow fiber membrane, characterized in that the hollow fiber membrane has a sieving coefficient for albumin, determined according to DIN EN ISO 8637- 3: 2018, from 50 to 100%, or characterized in that the hollow fiber membrane has a sieving coefficient for immunoglobulin M, determined according to DIN EN ISO 8637-3: 2018, of 50 to 100%, or characterized in that the hollow fiber membrane has a Has sieving coefficients for low density lipoprotein, determined according to DIN EN ISO 8637-3: 2018, from 80 to 100%.
- the hollow fiber membrane according to the invention has an advantageously lower hemolysis activity and is therefore in particular superior to a comparable hollow fiber membrane that does not contain vitamin E.
- the hollow fiber membrane according to the invention advantageously also shows a reduced tendency towards blood coagulation and an improved property in terms of reducing the triglyceride concentration and is therefore also superior to comparable hollow fiber membranes without vitamin E.
- Triglycerides are preferentially adsorbed on surfaces that are not sufficiently hydrophilic and thus permanently worsen the permeation and selection properties of the filter in the course of the therapy.
- the proportion of vitamin E in the hollow fiber membrane causes the polyvinylpyrrolidone to be fixed on the membrane surface and thus an improved, ie reduced hemolysis activity in large-pore hollow fiber membranes, which are intended for the separation of blood plasma from blood.
- large-pored is understood to mean hollow fiber membranes which have the mentioned sieving coefficients for albumin, or immunoglobulin M (IgM), or low density lipoprotein (LDL).
- the openings in the surface of the blood contact layer can preferably have a width of 0.1 to 10 ⁇ m in order to achieve effective separation effect of blood plasma from blood.
- these openings are so large that blood cells penetrate into the openings in the membrane surface of the hollow fiber membrane during a process for separating blood plasma from blood and can be burst by the process-related transmembrane pressure difference.
- fewer blood cells penetrate into the openings in the membrane surface in the case of the hollow fiber membranes according to the invention, so that, as a result, a reduced hemolysis activity of the hollow fiber membrane is also observed.
- the proportion of vitamin E, in particular ⁇ -tocopherol or tocotrienol, in the hollow fiber membrane is 0.01 to 0.15% by weight, more preferably 0.03 to 0.1% by weight, based on the total weight of the hollow fiber membrane .
- the term “sieving coefficient for albumin” is understood to mean the permeability of the hollow fiber membrane for albumin, determined in accordance with DIN EN ISO 8637-3: 2018.
- Albumin is a plasma protein with a molecular weight of 66 kDa. According to this embodiment, it is possible to separate a proportion of plasma proteins from blood or, in the course of a cascade filtration, a selective region of the blood plasma proteins from blood plasma.
- the hollow fiber membrane preferably has a sieving coefficient for albumin of 60 to 100%, more preferably 70 to 100%.
- the term “sieving coefficient for immunoglobulin M” in the context of the present application is understood to mean the permeability of the hollow fiber membrane for immunoglobulin M (IgM), determined according to the DIN EN ISO 8637-3: 2018 method.
- IgM is a plasma protein with a molecular weight of 950 kDa. According to this embodiment it is possible to separate a proportion of plasma proteins from blood or in the course of a cascade filtration from blood plasma which have a larger specific molecular weight range of the blood plasma proteins.
- a hollow fiber membrane constructed in this way can be used in certain forms of therapy, for example specific plasmapheresis, which require the separation of blood plasma according to predetermined molecular weight ranges.
- the hollow fiber membrane preferably has a sieving coefficient for IgM of 60 to 100%, more preferably 70 to 100%.
- the term “sieving coefficient for low density lipoprotein” is understood in the sense of the present application as the permeability of the hollow fiber membrane for low density lipoprotein (LDL), determined according to the method DI N EN ISO 8637-3: 2018. LDL is a plasma protein with a molecular weight of 2,700 kDa. According to this embodiment, it is possible to separate the entire proportion of the plasma proteins from blood in a separation process, for example unspecific plasmapheresis. A hollow fiber membrane designed in this way can be used in forms of therapy which require the entire separation of blood plasma from blood.
- the hollow fiber membrane preferably has a sieving coefficient for LDL of 80 to 100%, more preferably 90 to 100%.
- a "blood contact layer” is understood to mean a layer of the hollow fiber membrane and, in an extracorporeal blood treatment, represents a layer exposed to the patient's blood.
- the blood contact layer advantageously has a thickness of 1 ⁇ m to 15 ⁇ m, preferably 2 to 10 ⁇ m, more preferably 3 to 6 ⁇ m, and its porous structure is geared towards enabling an effective separation of blood plasma from blood.
- the size of the pores in the blood contact layer can preferably be 0.1 to 10 ⁇ m.
- a “support layer” is understood to mean a layer which gives the hollow fiber membrane the necessary mechanical stability in order to be able to be further processed into hollow fiber membrane filters and in sterilization processes.
- the thickness of the support layer is preferably 25 to 79 ⁇ m, or 30 to 77 ⁇ m or 34 to 74 ⁇ m.
- the pore structures of the blood contact layer and the support layer are preferably different. More preferably, the pores of the blood contact layer are smaller than those of the support layer.
- the different pore structure can be selectively adjusted via the manufacturing process of the hollow fiber membranes in the nonsolvent-induced phase inversion process, for example through a “dry-wet” spinning process. A temperature-induced phase inversion process is also conceivable.
- hydrophobic polymer M is understood to mean a polymer that has a solubility in water of less than 0.1 g / l.
- hydrophobic polymers polysulfone (PSU), Polyether sulfone (PES), polyphenyl sulfone, copolymers containing sulfone groups, polyetherimide (PEI), polyamide (PA), polycarbonate (PC), polystyrene (PS), polymethyl methacrylate (PMMA), polyacrylonitrile (PAN), polyimide (PI), and polyurethane (PU) ) be used.
- a “hydrophilic polymer M” is understood to mean a polymer that has a solubility in water of at least 1 g / l.
- polyvinylpyrrolidone (PVP) or polyethylene glycol and their copolymers can be used as hydrophilic polymers.
- the term “solubility in water M ” means that the hydrophobic / hydrophilic polymer is dissolved in water and results in a visually clear solution without clouding, sol gel formation or precipitation in the visible wavelength range of light or precipitation can be observed.
- vitamin E is understood in the sense of the present application as a collective term for fat-soluble substances with antioxidant effects. In particular, the term subsumes the frequently occurring vitamin E forms tocopherol, tocotrienols, tocomonoenol (T1) and MDT (marine derived tocopherols).
- the invention is characterized in that the hollow fiber membrane consists of at least two coextruded layers, one of the at least two coextruded layers forming a blood contact layer and the other of the at least two coextruded layers forming a support layer.
- the hollow fiber membrane consists of at least two coextruded layers, one of the at least two coextruded layers forming a blood contact layer and the other of the at least two coextruded layers forming a support layer.
- the layer thickness, composition and pore properties of the blood contact layer and the support layer can be worked out differently.
- the embodiment offers the advantage that the blood contact layer is optimized with regard to the hemolysis activity, while the support layer is advantageously designed with regard to the mechanical stability, in particular also the sterilization resistance of the hollow fiber membrane.
- the invention is characterized in that the blood contact layer the inner layer and the support layer represent the outer layer of the hollow fiber membrane.
- the blood contact layer can be configured particularly precisely with regard to the separation behavior.
- the invention is characterized in that the hydrophobic polymer comprises or consists of polysulfone, and / or that the hydrophilic polymer comprises or consists of polyvinylpyrrolidone.
- the polymer “polysulfone” is understood to mean a polymer that has a sulfone group in the main or side chain of the polymer.
- polysulfone is understood as a generic term for all polymers which contain sulfone groups. Typical representatives of materials based on polysulfone are polysulfone (PSU), polyethersulfone (PES), polyphenyl sulfone and copolymers containing sulfone groups. Polysulfone materials have proven to be superior to other materials in the manufacture of blood treatment membranes because they are steam sterilizable and have good hemocompatibility properties.
- the hollow fiber membrane is characterized in that the polyvinylpyrrolidone content in the hollow fiber membrane is 4 to 9% by weight, preferably 5-8%, more preferably 5-7%.
- the polyvinylpyrrolidone content of the hollow fiber membrane makes it hydrophilic for blood.
- hydrophilic hollow fiber membrane means that the hollow fiber membrane can be completely wetted by blood without having to use hydrophilizing methods beforehand, for example pressure rinsing of the hollow fiber membranes with water.
- the wettability of the hollow fiber membrane with blood enables an effective separation of blood plasma or parts of blood plasma in the plasma separation process.
- polyvinylpyrroldon is understood to mean a polymer that has repeating units of vinylpyrrolidone or derivatives thereof.
- PVP is a water-soluble polymer and improves the hemocompatibility of hollow fiber membranes made of polysulfone, since it hydrophilizes the hydrophobic polysulfone material and thus makes it easier for blood to wet it.
- Further comonomers can be added to the vinyl pyrrolidone, for example vinyl acetate polymers. These copolymers have the advantage that they form particularly stable hydrogels.
- the hollow fiber membrane is characterized in that it has an internal diameter of 250 to 400 ⁇ m, preferably 280 to 380 ⁇ m, more preferably 300 to 360 ⁇ m. If the inside diameter is too small, the transmembrane pressure and thus the tendency to hemolysis increases too much; if the inside diameter is too large, the filtration performance drops too much.
- the hollow fiber membrane is characterized in that the one wall thickness is 40 to 80 ⁇ m. The wall thickness results in an advantageous strength of the hollow fiber membrane. Too great a wall thickness greater than approx. 80 ⁇ m has a disadvantageous effect on the filtration properties of the hollow fiber membrane.
- Advantageous wall thicknesses are 50 to 70 ⁇ m, more preferably 60 to 70 ⁇ m.
- the hollow fiber membrane is characterized in that the blood contact layer in a layer near the surface, determined by XPS measurement, has a polyvinylpyrrolidone content of 30 to 60% by weight, preferably from 35 to 55% by weight, more preferably from 40 to 50% by weight.
- the polyvinylpyrrolidone content in a layer of the blood contact layer close to the surface can be adjusted in the production of the hollow fiber membrane by the ratio of the hydrophobic polymer, preferably PSU, and the hydrophilic polymer, preferably PVP, in the spinning mass.
- the composition of the spinning mass from which the blood contact layer results is selected such that there is a higher proportion of PVP than the support layer. It is assumed that the proportion of vitamin E in the spinning mass, which forms the blood contact layer in the hollow fiber membrane, fixes the PVP in a layer near the surface during the manufacturing process of the hollow fiber membrane and thus a high proportion of PVP in the blood contact layer, in particular the layer near the surface Blood contact layer, results. Electron microscope images according to FIG. 4 and FIG. 5 showed that fewer blood cells penetrate into the openings of the blood contact layer in a hollow fiber membrane according to the invention than in a comparison hollow fiber membrane which does not contain vitamin E.
- the hollow fiber membrane is characterized in that the near-surface layer of the hollow fiber membrane opposite the blood contact layer, determined by XPS measurement, has a polyvinylpyrrolidone content of 25 to 50% by weight, preferably of 30 to 45% by weight, more preferably from 30 to 40% by weight. This embodiment ensures that only a reduced adsorption of the plasma constituents takes place on the surface opposite the blood contact side.
- the hollow fiber membrane is characterized in that the difference in the PVP content in% by weight between the near-surface layer of the blood contact side and the near-surface layer of the surface of the hollow fiber membrane opposite the blood contact side , determined by XPS measurement, has a value of at least 5% by weight, preferably at least 7%, more preferably at least 10% by weight.
- This embodiment has a particularly low total adsorption of blood and plasma components.
- the hollow fiber membrane is characterized in that the blood contact layer forms an inner layer of the hollow fiber membrane.
- Such an embodiment further reduces the tendency to hemolysis compared to an embodiment in which the blood contact layer forms an outer layer of the hollow fiber membrane.
- such an embodiment is less prone to residual blood accumulations in the filter after the therapy has ended.
- the hollow fiber membrane is characterized in that the layer thickness of the blood contact layer is 1 to 15 ⁇ m. Due to its high porosity, the layer thickness of the blood contact layer makes little contribution to the mechanical stability of the hollow fiber membrane. The layer thickness of the blood contact layer should therefore not be too great compared to the support layer in order not to impair the strength of the hollow fiber membrane.
- the invention relates to a method for producing the hollow fiber membrane according to the invention, the method having the following method steps:
- a spinning mass A comprising 15 to 25% by weight of a hydrophobic polymer, 4 to 8% by weight of a hydrophilic polymer, 0.2 to 2% of a polar protic substance and 0.001 to 0.05% by weight of vitamin E, in particular a- Tocopherol or tocotrienol, 83.799 to 64.95% by weight of a polar aprotic solvent,
- a spinning mass B comprising 8 to 12% by weight of a hydrophobic polymer, 3 to 7.5% by weight of a hydrophilic polymer, 0001 to 0.05% by weight of vitamin E, in particular an ⁇ -tocopherol or tocotrienol, 88.999 to 81 , 95% by weight of a polar aprotic solvent,
- an internal precipitant comprising 70 to 90% by weight of a polar aprotic solvent and 10 to 30% by weight of a polar protic mixed liquid
- the manufacturing process is based on what is known as a “dry-wet” spinning process.
- a spinning mass is extruded through a spinneret, passed through a dry precipitation gap and then introduced into a precipitation bath.
- a “Fällspalf” denotes a vertical section between the outlet opening of the spinneret and the felling bath, through which the extruded spinning thread passes before it is introduced into the felling bath.
- a “spinning mass” is understood to be a homogeneous polymer solution.
- a “spun thread” is understood to mean the spinning mass extruded from the nozzle which has not yet formed a final membrane structure.
- the spinning process takes place by coextrusion of two spinning masses and an internal precipitant.
- the spinning mass A forms the support layer in the hollow fiber membrane.
- the spinning mass B forms the blood contact layer in the hollow fiber membrane.
- the composition of the spinning masses A and B and the composition of the inner precipitant as well as the selection of the spinning parameters such as temperature control of the spinning material, temperature control of the spinneret, spinning speed, height of the precipitation gap determine the porous properties of the hollow fiber membrane.
- a “polar aprotic” solvent is understood to mean a solvent that dissolves the hydrophobic and hydrophilic polymer in the spinning mass, but has only a low CH acidity.
- polar aprotic solvents are dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc) and N-methylpyrrolidone (NMP).
- DMSO dimethyl sulfoxide
- DMF dimethylformamide
- DMAc dimethylacetamide
- NMP N-methylpyrrolidone
- a “polar protic substance” is understood to mean a CH-acidic substance.
- Preferred representatives are water, ethanol or methanol.
- the falling bath temperature is set to 50 to 80.degree. C., in particular 60 to 70.degree.
- the temperature control of the felling bath enables the setting of an atmospheric humidity in the felling gap, so that the formation of pores on the outside of the spun thread is supported.
- the precipitation bath preferably consists of aqueous solutions; water with a content of less than 5% by weight of one of the aprotic polar solvents mentioned is particularly preferred.
- the proportion of the individual components in the spinning mass determines the viscosity of the spinning mass.
- the viscosity of the spinning mass solution A is 7000 to 18000 mPa ⁇ s, in particular 9000 to 14000 mPa ⁇ s.
- the spinning mass solution A typically contains 15 to 25% by weight, preferably 18 to 23% by weight, more preferably 19 to 21% by weight of a hydrophobic polymer, in particular polysulfone (PSU), 4 to 8% by weight, preferably 5 to 7 % By weight, more preferably 5 to 6% by weight of a hydrophilic polymer, in particular polyvinylpyrrolidone (PVP), 0.02 to 2% by weight, preferably 0.5 to 1.5% by weight, more preferably 0.8 to 1 , 2% by weight of a polar protic substance, preferably water, 0.001 to 0.05% by weight, preferably 0.005 to 0.03% by weight, more preferably 0.008 to 0.02% by weight of vitamin E, in particular ⁇ -tocopherol or tocotrienol , and 80.799 to 64.95% by weight, or 76.495 to 64.95% by weight, or 75.192 to 64.95% by weight of a polar aprotic solvent, preferably DMAc.
- PSU poly
- PSU 17.5 to 22.5% by weight of PSU, 5 to 8% by weight of PVP, 0.008 to 0.02% by weight of vitamin E, in particular ⁇ -tocopherol or tocotrienol, the remainder up to 100% by weight is DMAc .
- the viscosity of the spinning mass solution A was determined by means of a rotation viscometer (VT 550 from Haake, Germany) at 40 ° C. at level r.2 (6 rpm) with a rotating body “MV1 (MV- DIN) ”from Haake (shear rate 7.7 / s).
- the viscosity of the spinning mass solution B is preferably less than 1000 mPa ⁇ s and contains 8 to 12% by weight, preferably 9 to 11% by weight, more preferably 9.5 to 10.5% by weight of a hydrophobic polymer, preferably PSU, 3 to 7.5% by weight, preferably 4.5 to 7% by weight, more preferably 5 to 6% by weight of a hydrophilic polymer, preferably PVP, 0.001 to 0.05% by weight, preferably 0.005 to 0.03 %
- PVP hydrophilic polymer
- 0.001 to 0.05% by weight preferably 0.005 to 0.03 %
- vitamin E in particular ⁇ -tocopherol or tocotrienol and 88.999 to 81.95% by weight
- 86.495% by weight, or 85.492% by weight of a polar aprotic solvent preferred DMAc. 9 to 10% by weight of PSU, 5 to 6% by weight of PVP, 0.008 to 0.02% by weight of vitamin E, in particular
- the viscosity of the spinning mass solution B was determined by means of a rotation viscometer (VT 550 from Haake, Germany) at 40 ° C. at level r.3 (30 rpm) with a rotating body “MV1 (MV- DIN) ”from Haake (shear rate 38.7 / s).
- the different viscosity of the two spinning masses A and B causes a different porosity in the two coextruded layers.
- the support layer of the hollow fiber membrane results from the spinning mass A, and the blood contact layer of the hollow fiber membrane results from the spinning mass B.
- the thickness of the membrane wall and the inner diameter of the hollow fiber membrane can be varied.
- the thickness of the membrane wall of the hollow fiber membrane according to the invention is typically 40 to 80 ⁇ m, preferably 50 to 70 ⁇ m, more preferably 60 to 70 ⁇ m.
- an inner precipitant having or consisting of 70 to 90 wt.%, Preferably 75 to 85 wt.%, More preferably 78 to 82 wt.% Of a polar aprotic solvent, preferably DMAc and 10 to 30%, preferably 25 to 15% by weight, more preferably 22 to 18% by weight, of a polar mixed liquid, preferably water, results in the desired porous structure of layer B by means of the method according to the invention.
- a "polar protic mixed liquid is a CH acidic liquid, preferably water, ethanol or methanol.
- the method is characterized in that the spinning masses A and B are tempered to 60 to 80 ° C, preferably 65 to 75 ° C and / or the inner precipitant to 50 to 70 ° C, preferably 55 to 65 ° C is tempered.
- the speed of membrane formation in the spinning process is influenced by the spinning speed.
- the spinning speed is 300 to 500 mm per second, preferably 350 to 480 mm per second, more preferably 380 to 430 mm per second.
- the "spinning speed" indicates the speed at which the spinning thread is passed through the felling gap. Furthermore, the height of the felling gap has an influence on the membrane formation in the spinning process.
- the precipitation gap in the process according to the invention is 5 to 80 mm, preferably 10 to 50 mm, more preferably 15 to 40 mm.
- rinsing processes for the hollow fiber membrane are connected to the spinning process.
- the precipitated hollow fiber membrane is passed through several rinsing baths and rinsed in the process.
- the temperature of the rinsing baths is typically in the range of 60 up to 80 ° C.
- the hollow fiber membrane is freed from solvent and from excess PVP, which is not fixed in the hollow fiber membrane after the precipitation.
- the hollow fiber membrane is freed from this part of the polyvinylpyrrolidone as far as possible, since otherwise PVP that can be eluted from the hollow fiber membrane can get into the bloodstream in a therapeutic treatment.
- the hollow fiber membrane is dried. This takes place preferably at 90 to 160.degree. C., preferably at 100 to 150.degree. C., more preferably at 120 to 140.degree.
- the method is characterized in that the hydrophobic polymer of the spinning mass A comprises or consists of polysulfone, and / or that the hydrophilic polymer of the spinning mass A comprises or consists of polyvinylpyrrolidone, and / or that the polar protic substance of the spinning mass A comprises or consists of water, and / or that the polar aprotic solvent of the spinning mass A is dimethyl sulfoxide,
- the method is characterized in that the internal precipitant does not have a hydrophilic polymer.
- a high concentration of the hydrophilic polymer, such as PVP in a near-surface layer of the blood contact layer can be produced by the method according to the invention without a corresponding hydrophilic polymer, such as PVP, having to be added to the inner precipitant.
- hollow fiber membranes are sterilized following their manufacture.
- hollow fiber membrane filters are built up from the hollow fiber membranes.
- the construction of hollow fiber membrane filters is known to the person skilled in the art and is not explained further here in detail. In this context, reference is also made to the description of the method contained herein, in which the construction of experimental hollow fiber membrane filters is described.
- the method used in the present case for sterilizing the hollow fiber membrane filters according to the invention is also known in the prior art.
- the sterilization of a hollow fiber membrane described here was carried out according to the method described in detail in DE102016224627 A1.
- the invention in a third aspect, relates to a sterile hollow fiber membrane filter comprising a plurality of hollow fiber membrane filters according to the first aspect of the invention or produced by a method according to the second aspect of the invention, wherein the hollow fiber membrane filter has been sterilized by a steam sterilization method.
- hollow fiber membranes For the construction of a hollow fiber membrane filter to be examined, hollow fiber membranes with an inner diameter of 330 ⁇ m and a wall thickness of 65 ⁇ m are used.
- the hollow fiber membranes are bundled and potted at the ends in the housing of the hollow fiber membrane filter with a hardenable potting material so that a first space is created that encompasses the interior of the hollow fiber membrane (“blood side”) and a second space (“filtrate side”) is created that contains the Includes space between the hollow fiber membranes.
- Polyurethane from BASF (Elastogran) (polyol C6947 and isocyanate 136 20) is used as the potting material.
- the housing diameter, the potting height at the bundle ends and the active length of the hollow fiber membrane match those of the commercially available plasma filters “plasmaFlux P1” and “plasmaFlux P2” from Fresenius Medical Care, Bad Homburg, Germany.
- An active length of a hollow fiber membrane is to be understood as the length of the hollow fiber membrane without potting, which is available for determining the permeation properties such as sieving coefficient, hemocompatibility data and ultrafiltration coefficient.
- the active membrane area of the investigated hollow fiber membrane filters resulting from the active hollow fiber membrane length is 0.3 and 0.6 m 2 in two different embodiments.
- the filter is steam sterilized in accordance with DE102016224627.
- the hollow fiber membranes to be examined are examined in a hollow fiber membrane filter in an apparatus which is shown schematically in FIG.
- the apparatus 1-1 comprises a hollow fiber membrane filter to be examined for plasma separation 1-2, with a structure as described in method 1.
- the apparatus also has a hose system 1-3, a hose pump 1-4, a point for taking blood samples 1-5, a reservoir for blood 1-6, a pressure sensor 1-7 at the blood outlet 1-8 of the hollow fiber membrane filter 1-2 and a pressure sensor 1-9 at the blood inlet 1-10 of the hollow fiber membrane filter 1-2.
- 113 ml of the heparinized blood as described above were used to carry out the determination.
- the blood was conveyed through the hose system 1-3 (material: PVC, manufacturer Fresenius Medical Care, Germany) through the hollow fiber membrane filter 1-2 with the aid of the hose pump 1-4 (manufacturer: Fresenius Medical Care, Germany) through the apparatus 1-1 .
- a new hose system was used for each measurement.
- the entire apparatus 1-1 was rinsed for 30 minutes with a 0.9% (w / v) physiological saline solution before the measurement.
- the rinsing solution is displaced and discharged with blood at low pump speed, which is introduced into the apparatus, until the apparatus is filled with pure blood or the filtrate side of the hollow fiber membrane filter is filled with plasma.
- the volume filled with blood was 113 ml.
- the displaced solution was discarded.
- the filtered blood plasma is discharged from the hollow fiber membrane filter and added back to the blood downstream of the blood outlet 1-8 of the hollow fiber membrane filter 1-2.
- the exposure test is carried out at 37 ° C., for example in an incubator (Memmert, Germany), over a predetermined period of time. Included at the start of the measurement and after the predetermined time, samples are taken at the point for taking blood samples 1-5.
- the pressure at the blood outlet 1-8 and at the blood inlet 1-10 is measured in order to ensure a constant course of the conditions while the determination is being carried out. If significant changes in pressure occur, the measurement must be discarded.
- the blood was fed at a rate of 200 ml / min. pumped through the apparatus.
- TMP transmembrane pressure
- the analysis data are determined with the K-4500 device from Symex (blood count determination) according to the electrical resistance measurement principle.
- a capillary suitable for erythrocytes and platelets is used in a measuring unit of the device.
- the transducers and electrodes are immersed in an electrically conductive liquid so that a constant electrical current can flow between the inner and outer electrodes.
- the electrically non-conductive platelets are sucked through the opening of the transducer. If a cell passes through it, it displaces the dilution solution. Since the electrical resistance of the cell is higher than that of the dilution solution, a voltage change proportional to the change in resistance occurs.
- the increase in voltage is proportional to the cell volume, so that a distinction can also be made between erythrocytes and platelets.
- the determined platelet count is a measure of the blood coagulation that occurs on the blood contact layer of the hollow fiber membrane.
- a high adsorptive loss Platelets increase the tendency to coagulate and thus the tendency to form blockages in the filter.
- Blood plasma samples which were taken at predetermined times before and after the exposure test are evaluated.
- the HGB is measured using the Sodium Lauryl Sulphate Method (SLS).
- SLS Sodium Lauryl Sulphate Method
- the hemoglobin concentration in an HGB cuvette is determined at a wavelength of 555 nm.
- an EVOLUTION 210 spectrophotometer (Thermo Fisher Scientific, Dreieich) with a 7-fold cuvette holder in the "free hemoglobin" measurement method is used.
- Disposable cuvettes 1.5 ml, semi-micro PMMA from Brand, Giessen, Germany, are used.
- the hemoglobin comes from blood cells, especially the erythrocytes, which are destroyed during the separation of the blood plasma.
- the determined hemoglobin value is a measure of the hemolytic activity of the hollow fiber membrane examined. The lower the determined hemoglobin value, the lower the hemolytic activity of the hollow fiber membrane. Free hemoglobin is a measure of the destruction of red blood cells.
- triglyceride concentration in the blood is determined. The percentage loss of triglycerides is determined from the difference.
- the triglyceride concentration is determined by the following method: A whole blood sample is drawn into a 1.2 ml Li-heparin monovette (Ref. No. 06.1666.001 from Sarstedt, Nümbrecht) and centrifuged for 10 minutes at 4000 revolutions. The blood plasma is transferred to a sample vessel. The triglyceride is converted and made available for a color reaction. Using lipoprotein lipase, the Wahlefeld method leads to glycerol in complete hydrolysis with subsequent oxidation to dihydroxyacetone phosphate and hydrogen peroxide.
- the resulting hydrogen peroxide forms a red dye, which can be determined photometrically proportional to the triglyceride, under the catalytic action of the peroxidase with 4-aminophenazone and 4-chlorophenol in an end-point reaction according to T rinder.
- the Cobas analyzer is used for this INTEGRA 400 plus (Roche Diagnostic, Mannheim, Germany) using the "TRIGL” method.
- the method can be used to calculate the decrease in the concentration of triglycerides in mg / dl after the exposure time.
- the pumping speed is increased until a desired transmembrane pressure (TMP) is established.
- TMP transmembrane pressure
- a TMP of 130 mmHg was set; in the case of the exemplary embodiment described below, a TMP of 183 mmHg was set.
- the experiment is then interrupted and the filter is washed with isotonic saline solution.
- Individual hollow fiber membranes are removed from the hollow fiber membrane filter.
- the removed hollow fiber membranes are opened so that the inner surface of the hollow fiber membranes is exposed and can be examined with the scanning electron microscope. Scanning electron microscopy is carried out at an accelerating voltage of 5 kV and a magnification of 3000 times.
- a qualitative description of the penetration behavior of the erythrocytes into the membrane is carried out.
- the content of polyvinylpyrrolidone in a layer of the blood contact layer near the surface was determined with the aid of photoelectron spectroscopy (XPS or ESCA).
- XPS photoelectron spectroscopy
- This method is used to determine the proportion of polyvinylpyrrolidone in a layer of 5 to 10 nm adjacent to the surface of the blood contact layer of the hollow fiber membrane.
- This layer which is examined with the aid of the XPS method, is referred to in the context of the present application as a “layer close to the surface. To examine the layer near the surface, predetermined measurement conditions are set for this.
- a hollow fiber membrane is cut lengthways with the help of a scalpel, so that the inner surface of the hollow fiber membrane, which in this case represents the surface of the blood contact layer is exposed.
- This sample is fixed on a sample plate and brought into the sample space. The following measurement conditions are specified:
- Excitation radiation monochromatic X-ray radiation, Al Ka, 75 W diameter of the sample spot: 200 pm Pass energy: 30 eV
- the charge was compensated with the help of a flood gun.
- the XPS measurements were carried out at Nanoanalytics in Munster, Germany.
- the content of PVP in the layer near the surface was determined with the aid of the values determined in atomic% of nitrogen (N) and sulfur (S) using formula 4.
- N nitrogen
- S sulfur
- the known molecular weights of the repeating unit in PVP and polysulfone are used.
- PVP content [in% by weight] 100 * (N * 111) / (N * 111 + S * 442)
- Formula 4 applies to the use of bisphenol A-based polysulfone.
- the molecular weight of the repeating unit containing the sulfur must be taken and derived.
- the proportion of the sulfur-containing recurring unit in the copolymer must be taken into account.
- the PVP content in the layer near the surface is carried out on three hollow fiber membrane samples and the mean value of these measurements is calculated.
- a hollow fiber membrane filter as described according to method 1 is used. Human whole blood based on the DIN EN ISO 8637-3: 2018 standard is used for the measurement. An apparatus according to FIG. 2 is used to measure the LDL sieving coefficient. Before starting the measurement the system is filled with 2 l of physiological saline solution and rinsed with complete deaeration. The hollow fiber membrane filter 2-2 is emptied on the filtrate side after the rinsing process, while the blood outlet 2-3 must be closed. The filtrate is collected in the measuring mode at the lower filtrate outlet 2-4. Human whole blood of the following composition is used for the measurement:
- the blood side of the hollow fiber membrane filter 2-2 is filled with human whole blood; the first 200 ml are discarded to avoid dilution effects.
- the whole blood is then circulated in the apparatus 2-1.
- the filtrate pump 2-5 is switched on so that blood plasma passes over to the filtrate side.
- the pressures are recorded, the samples are taken at sampling points 2-10 (blood inlet) and 2-20 (filtrate) and the respective concentrations of LDL and IgM and albumin are determined.
- the automatic analysis device "Cobas Integra 400 plus" from Roche Diagnostic is used with the corresponding specified method.
- the sieving coefficient S is calculated according to formula 5: 100 [%]
- TMP transmembrane pressure
- Exemplary embodiment production of a hollow fiber membrane according to the invention
- a spinning mass A For the production of a hollow fiber membrane according to the invention, a spinning mass A, a spinning mass B and an inner precipitation medium are provided.
- the spinning mass A is made by mixing 20% by weight of polysulfone (Solvay Udel 3500. LCD), 6% by weight of polyvinylpyrrolidone (ISP, PVP K90), 1% by weight of water, 0.01% by weight of vitamin E and 72 , 99% by weight of dimethylacetamide (DMAc).
- the spinning mass B is produced by mixing 10% by weight of polysulfone, 5.5% by weight of polyvinylpyrrolidone, 0.01% by weight of vitamin E and 84.49% by weight of DMAc.
- the spinning masses are tempered to 72 ° C and carefully degassed until they are constant. Constancy is achieved when no more gas bubbles appear for a period of one hour.
- the spinning masses are tempered to 70 ° C for the spinning process.
- the inner precipitant consists of 80% by weight of DMAc and 20% by weight of water.
- the precipitant is tempered to 60 ° C for the spinning process.
- a spinneret was used as described in DE10211051.
- the inner precipitant, spinning mass A and spinning mass B were coextruded through the spinneret to form a spun thread.
- the precipitant was extruded through the central bore of the spinneret.
- the spinning mass B was extruded through the first concentric annular gap which surrounds the central bore of the spinneret.
- the spinning mass A was extruded through the second concentric annular gap which surrounds the first concentric annular gap and the central bore.
- the gap width of the Annular gaps and the diameter of the central bore are selected so that a hollow fiber membrane with the geometric dimensions described herein can be obtained.
- the spinning block and thus the spinneret were heated to 60 ° C. for the spinning process.
- the extruded filament was passed through a felling gap of 20 mm at a spinning speed of 400 mm per second.
- the temperature of the precipitation bath (water) was 65 ° C.
- the hollow fiber membrane obtained by precipitation in a precipitation bath is rinsed in 6 water baths and dried at 130 ° C. for 10 minutes.
- the hollow fiber membrane has an inner diameter of 330 ⁇ m, the wall thickness was 65 ⁇ m, the layer thickness of the selective inner layer obtained from the spinning mass B, which also represents the blood contact layer, was 4 ⁇ m.
- the hollow fiber membrane is reeled up and bundled and processed into hollow fiber membrane bundles with 1296 or 2592 hollow fiber membranes.
- the spinning mass A and the spinning mass B were provided without vitamin E.
- the proportion of DMAc in spinning mass A was accordingly 73% by weight
- the proportion of DMAc in spinning mass B was 85% by weight.
- the respective proportions of PSU, PVP and water in the spinning masses A and B were retained. All other parameters of the hollow fiber membrane production of the exemplary embodiment were also retained.
- Example 1 and Comparative Example 1 were processed into hollow fiber membrane filters with the structure described according to Method 1 and also sterilized by steam sterilization as in the exemplary embodiment.
- the hollow fiber membranes of the example and the comparative example were examined according to the methods described above.
- the results are given in Table 1: Table 1
- Table 1 The total content of PVP in the hollow fiber membrane of the exemplary embodiment is significantly higher than in the comparative example.
- the values relating to the drop in the triglyceride concentration, the thrombocyte concentration in the hemolysis test and the free hemoglobin in the exemplary embodiment are significantly improved compared with the comparative example. Based on the results, it is clear that the hollow fiber membrane manufactured according to the exemplary embodiment has a lower hemolysis activity and a lower tendency to adsorb thrombocytes and triglycerides than the hollow fiber membrane manufactured according to the comparative example.
- FIG. 3 shows a cross section through a hollow fiber membrane according to the comparative example, which was subjected to a hemolysis test.
- the support layer 3-1 and the blood contact layer 3-2 can be seen.
- the blood cells adhering to the hemolysis attempt can be seen on the blood contact layer.
- the blood cells to be recognized are erythrocytes.
- FIG. 3 also shows that some of the blood cells have penetrated the blood contact layer.
- FIG. 4 shows a cross section through a hollow fiber membrane produced according to the exemplary embodiment, which was subjected to a hemolysis test.
- the support layer 4-1 and the blood contact layer 4-2 can be seen in FIG. Furthermore, as in FIG. 4, the blood cells adhering to the surface of the blood contact layer from the hemolysis test can be seen. In contrast to FIG. 3, however, no blood cells can be seen in FIG. 4 which have penetrated into the blood contact layer 4-2.
- the process of penetration of blood cells into the blood contact layer does not take place in the hollow fiber membranes according to the invention to the same extent as in the hollow fiber membrane of the comparative example. It is assumed that this process of penetration of the blood cells into the blood contact layer is decisive for the destruction of the blood cells and that the hemolytic activity of large-pored hollow fiber membranes, as used in plasmapheresis, is based to a significant extent on this process.
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Abstract
Description
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DE102020206867.4A DE102020206867A1 (de) | 2020-06-02 | 2020-06-02 | Hohlfasermembran für die abtrennung von blutplasma aus blut |
PCT/EP2021/064666 WO2021245075A1 (de) | 2020-06-02 | 2021-06-01 | Hohlfasermembran für die abtrennung von blutplasma aus blut |
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US (1) | US20230321610A1 (de) |
EP (1) | EP4157499A1 (de) |
JP (1) | JP2023529298A (de) |
KR (1) | KR20230018433A (de) |
CN (1) | CN115697537A (de) |
AU (1) | AU2021286166A1 (de) |
BR (1) | BR112022024758A2 (de) |
CA (1) | CA3182682A1 (de) |
DE (1) | DE102020206867A1 (de) |
WO (1) | WO2021245075A1 (de) |
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DE69629421T2 (de) * | 1995-06-22 | 2004-07-01 | Asahi Medical Co. Ltd. | Verfahren zur Herstellung einer Hohlfasermembran, Hohlfasermembran und Dialysator |
DE10211051A1 (de) | 2002-03-13 | 2003-10-02 | Fresenius Medical Care De Gmbh | Kapillarmembran und Vorrichtung zur Herstellung derselben |
DE102007019051B3 (de) | 2007-04-23 | 2008-10-09 | Fresenius Medical Care Deutschland Gmbh | Hohlfaserkapillarmembran und Verfahren zu deren Herstellung |
JP5409816B2 (ja) * | 2010-01-25 | 2014-02-05 | 旭化成メディカル株式会社 | 中空糸膜型血液浄化装置 |
DE102016224627A1 (de) | 2016-12-09 | 2018-06-14 | Fresenius Medical Care Deutschland Gmbh | Hohlfasermembran mit verbesserter Trennleistung und Herstellung einer Hohlfasermembran mit verbesserter Trennleistung |
DE102017201630A1 (de) | 2017-02-01 | 2018-08-02 | Fresenius Medical Care Deutschland Gmbh | Hohlfasermembran mit verbesserter Biokompatibilität |
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2020
- 2020-06-02 DE DE102020206867.4A patent/DE102020206867A1/de active Pending
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2021
- 2021-06-01 KR KR1020227045528A patent/KR20230018433A/ko active Search and Examination
- 2021-06-01 BR BR112022024758A patent/BR112022024758A2/pt unknown
- 2021-06-01 JP JP2022572357A patent/JP2023529298A/ja active Pending
- 2021-06-01 AU AU2021286166A patent/AU2021286166A1/en active Pending
- 2021-06-01 CN CN202180036217.6A patent/CN115697537A/zh active Pending
- 2021-06-01 EP EP21730186.0A patent/EP4157499A1/de active Pending
- 2021-06-01 CA CA3182682A patent/CA3182682A1/en active Pending
- 2021-06-01 WO PCT/EP2021/064666 patent/WO2021245075A1/de active Application Filing
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JP2023529298A (ja) | 2023-07-10 |
CA3182682A1 (en) | 2021-12-09 |
DE102020206867A1 (de) | 2021-12-02 |
BR112022024758A2 (pt) | 2022-12-27 |
CN115697537A (zh) | 2023-02-03 |
AU2021286166A1 (en) | 2022-12-15 |
WO2021245075A1 (de) | 2021-12-09 |
US20230321610A1 (en) | 2023-10-12 |
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