EP0888172A1 - Membranes specifiques de l'endotoxine - Google Patents

Membranes specifiques de l'endotoxine

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Publication number
EP0888172A1
EP0888172A1 EP97914219A EP97914219A EP0888172A1 EP 0888172 A1 EP0888172 A1 EP 0888172A1 EP 97914219 A EP97914219 A EP 97914219A EP 97914219 A EP97914219 A EP 97914219A EP 0888172 A1 EP0888172 A1 EP 0888172A1
Authority
EP
European Patent Office
Prior art keywords
endotoxin
microfiltration membrane
membrane according
endotoxins
water
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.)
Withdrawn
Application number
EP97914219A
Other languages
German (de)
English (en)
Inventor
Birger Anspach
Dagmar Petsch
Thomas Beeskow
Wolf-Dieter Deckwer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Original Assignee
Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Helmholtz Zentrum fuer Infektionsforschung HZI GmbH filed Critical Helmholtz Zentrum fuer Infektionsforschung HZI GmbH
Publication of EP0888172A1 publication Critical patent/EP0888172A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0093—Chemical modification
    • B01D67/00931—Chemical modification by introduction of specific groups after membrane formation, e.g. by grafting
    • 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
    • A61L2/00—Disinfection or sterilisation of materials or objects, in general; Accessories therefor
    • A61L2/02—Disinfection or sterilisation of materials or objects, in general; Accessories therefor using physical processes
    • A61L2/022—Filtration
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
    • 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
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0093—Chemical modification
    • B01D67/00933—Chemical modification by addition of a layer chemically bonded to the membrane
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/262—Synthetic macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. obtained by polycondensation
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B01J20/28033—Membrane, sheet, cloth, pad, lamellar or mat
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B01J20/3208—Polymeric carriers, supports or substrates
    • B01J20/3212—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
    • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
    • B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
    • B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3251—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising at least two different types of heteroatoms selected from nitrogen, oxygen or sulphur
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B01J20/3248—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such
    • B01J20/3255—Non-macromolecular compounds having a well defined chemical structure the functional group or the linking, spacer or anchoring group as a whole comprising at least one type of heteroatom selected from a nitrogen, oxygen or sulfur, these atoms not being part of the carrier as such comprising a cyclic structure containing at least one of the heteroatoms nitrogen, oxygen or sulfur, e.g. heterocyclic or heteroaromatic structures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3268—Macromolecular compounds
    • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3268—Macromolecular compounds
    • B01J20/3272—Polymers obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
    • B01J20/3274—Proteins, nucleic acids, polysaccharides, antibodies or antigens
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3289—Coatings involving more than one layer of same or different nature
    • 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
    • A61L2103/00—Materials or objects being the target of disinfection or sterilisation
    • A61L2103/05—Living organisms or biological materials

Definitions

  • the invention relates to a Mi rofiltrationsmembran to Abtren ⁇ voltage of endotoxins from liquid media as well as the V Before Using this microfiltration membrane.
  • Endotoxins are lipopolysaccharides from the outer cell membrane of Gram-negative bacteria that act as pyrogens. Due to the ubiquity of bacteria, endotoxins are also ubiquitous. However, you can not d hrough S tan ⁇ dard methods such as sterile filtration or autoclaving be removed or harmless (1) as opposed to bacteria. For this reason , sterile is not synonymous with endotoxin-free. Especially critical is t the presence of endotoxins in injection or Infusionslö ⁇ solutions (parenteral) because they already administered intravenously in amounts of 1 ng per kg body weight have fever exciting.
  • the S ymptomatik extends at an appropriately high dosage (eg., By large-volume parenterals) to severe shock death an d (3: 2). Therefore, almost all pharmacopoeias besides the germ-free i - strict endotoxin levels: e.g. B. 0.2 EU per mg chloramphenicol for injection or only 0.003 EU per heparin unit (4). In practice, meeting these requirements presents some difficulties. In particular, the production of biological medicinal products cannot be endotoxin-free in all steps.
  • the main possible endotoxin sources are:
  • Raw materials such as plasma or tissue, which can already be contaminated with bacteria.
  • thermostable active ingredients (30 minutes at 250 ° C) is just as unsuitable for the preparations as treatment with acids, alkalis or strongly oxidizing agents (H2O 2 ) (1) •
  • microfiltration membrane for separating endotoxins from liquid media, in particular water, protein solutions or parenterals
  • the microfiltration membrane being characterized by covalently bound ligands for endotoxins, the ligands being a polymer worn, which is applied to the membrane.
  • the covalently bound ligands can be any suitable covalently bound ligands.
  • an endotoxin-specific ligand preferably histamine, histidine, polyethyleneimine, poly-L-lysine or polymyxin B and / or
  • the membrane material for the microfiltration membrane according to the invention can be regenerated cellulose, cellulose acetone, polysulfone, polyethylene vinyl alcohol or polyamide, in particular nylon.
  • the polymers which are applied to the microfiltration membrane according to the invention can be a hydrophilic polymer, in particular dextran, polyvinyl alcohol or modified cellulose, preferably hydroxyethyl cellulose.
  • This hydrophilic polymer can itself be water-soluble, swellable in water or water-insoluble.
  • the polymer can be carried by the microfiltration membrane according to the invention with the aid of a spacer.
  • the covalently bound ligands can also be carried by a spacer.
  • These spacers can be spacers derived from bisoxirane, glutardialdehyde, epihalohydrin or diisocyanate, if appropriate after oxidative activation.
  • microfiltration membranes are therefore provided which are surface-modified in a suitable manner and remove endotoxins from water and aqueous solutions (buffers, protein solutions).
  • the surface modification can consist in the application of a bifunk ionic covalently bonded spacer which is reacted with a hydrophilic polymer, non-specific interactions of the membrane, especially with proteins, being reduced.
  • the covalently bound hydrophilic polymer can be reacted with endotoxin-specific ligands, if appropriate if via another spacer.
  • FIG. 1 For the principle of surface modification of the membrane, see FIG. 1.
  • Polymer-coated microfiltration membranes according to the invention with covalently bound endotoxin-specific ligands can remove endotoxins in one pass, even from highly loaded solutions (6000 EU ml -1 ).
  • the membranes are constructed in accordance with FIG. 1.
  • a hydrophilic polymer is applied via a spacer, which is then further, optionally via a spacer, reacted with endotoxin-specific ligands.
  • the following are particularly suitable as membrane materials:
  • PEVA polyethylene vinyl alcohol
  • Polyamides (especially nylon, such as N66)
  • Reactive bifunctional compounds are suitable as spacers.
  • the following are particularly suitable:
  • Bisoxiran Glutardialdehyde Epihalohydrine Diisocyanate To activate the vicinal diol bond formed when bisoxirane and epihalohydrin are used, oxidation by periodate can optionally be used, an aldehyde group being formed. The spacer bound to the membrane is further reacted with hydrophilic polymers. As such, the following are preferred:
  • Modified celluloses especially hydroxyethyl cellulose (HEC)
  • the further reaction takes place either directly with the endotoxin-specific ligand or again via the mediation of one of the spacers mentioned above, if appropriate after its oxidative activation.
  • the following act as endotoxin-specific ligands see list of abbreviations: DAH, Brain, His, PEI, PLL, PMB.
  • the usually non-endotoxin-specific ligands such as DEAE and DOC also proved to be highly specific in the membrane configuration with a high recovery of the proteins at the same time.
  • control membranes nylon without modification and with applied hydrophobic polymer with or without spacer
  • endotoxin-specific ligands No endotoxin depletion was obtained on control membranes (nylon without modification and with applied hydrophobic polymer with or without spacer) without endotoxin-specific ligands.
  • the new membranes can be used to remove endotoxins from water and parenterals. Good results are also achieved in the presence of proteins. In the case of basic proteins, however, it must be taken into account that interactions of proteins with the endotoxin that can result in endotoxic masking. Protein-bound endotoxin cannot be clearly demonstrated with the LAL test. In this connection it should be mentioned that it has not been finally clarified whether protein-bound endotoxin is still toxic.
  • the membranes according to the invention can be used in a variety of ways.
  • Hydrophilic polymers in particular dextran, polyvinyl alcohol and hydroxyethyl cellulose, are covalently bound to microfiltration membranes based on nylon (preferably 0.45 ⁇ m or larger).
  • endotoxin-specific ligands are immobilized on the applied polymers.
  • Figure 1 illustrates the structure of the membranes.
  • nylon membranes were first activated with bisoxirane: to do this, they were mixed in a mixture for 16 hours at 80 ° C of 9 ml bisoxirane, 1 ml ethanol and 1 ml 25 mM sodium carbonate buffer (pH 11) shaken (Figure 2a). After thorough washing, each membrane with 5 ml of a 20 percent. Dextran 40,000 solution (pH 11) incubated for fifteen minutes at room temperature (FIG. 2b). The membranes were then dried at 120 ° C. for 14 hours. To remove non-specifically bound dextran, the membranes were washed three times with 0.1 M sodium hydroxide solution and three more times with water.
  • the coated membranes are characterized by significantly lower non-specific interactions - expressed by the amount of hemoglobin adsorbed.
  • FIG. 3 also shows that the same effect cannot be achieved with a simple dextran coating as with PVA and HEC.
  • a further layer can achieve further improvement, while a third layer has only minor effects. Dextran was therefore always used as a double coating.
  • the ligands PLL, PMB and PEI were either immobilized directly on the periodate-activated coating polymers or after incorporation of a periodate-oxidizable spacer (bisoxirane). The procedure is shown by way of example in FIG. 4. DEAE was coupled directly to the matrices without a spacer, the other low molecular weight ligands were bound via epibromohydrin.
  • the membranes coated with hydrophilic polymers were incubated for three hours at room temperature in a mixture of 100 mg sodium borohydride, 5 ml bisoxirane and 45 ml 1 M sodium hydroxide solution. After hydrolysis of the free oxirane ring (30 minutes incubation at pH 2.5) and periodate oxidation of the vicinal diol obtained (90 minutes incubation in 0.2 M sodium periodically) the membranes were reacted for two hours with a solution of 0.5 g PEI (MW 50000) in 0.1 M phosphate buffer, which was adjusted to pH 8, at room temperature, so that the structure shown in FIG. 1 resulted . Finally, it was washed with 1 M sodium chloride solution and water.
  • Histidine was immobilized on epibromohydrin-activated coated membranes via DAH.
  • Epibromohydrin activation was carried out as described for bisoxiran. Immobilized DAH was activated by reaction for 8 minutes with a mixture of 5 ml epibromohydrin and 5 ml 4 M sodium hydroxide solution at 90 ° C. and immediately reacted with L-histidine at 80 ° C. (0.5 g L-histidine in 20 ml Was ⁇ water, pH 12). The finished membrane was washed with 1 M sodium chloride and water.
  • LAL test used. This test is based on the fact that endotoxin induces the release of the chromogen p-nitroaniline, there being a linear relationship between the amount of p-nitroaniline released and the endotoxin concentration in the range 0 to 1.2 EU / ml. From the photometric p-nitroaniline determination can be made using a calibration line
  • the LAL test was introduced in Europe in 1985 by the European Pharmacopoeia Commission for testing for endotoxins and has also replaced the rabbit test in the monograph "Water for Injection Purposes" since 1989.
  • the membranes marked with -d represent membranes in which the incorporation of a spacer has been dispensed with.
  • a PEI and a DAHHis membrane were used for depletion.
  • DEX / 2 denotes a membrane that has been coated twice in succession with dextran
  • DEX / 3 refers to a membrane that has been dextran-coated three times in a row

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  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Inorganic Chemistry (AREA)
  • Manufacturing & Machinery (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Transplantation (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Water Supply & Treatment (AREA)
  • External Artificial Organs (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Separation Using Semi-Permeable Membranes (AREA)

Abstract

L'invention concerne une membrane de microfiltration servant à séparer des endotoxines contenues dans des substances, notamment de l'eau, des solutions protéiniques ou des préparations à usage parentéral. Cette membrane de microfiltration se caractérise par des ligands pour endotoxines liés de manière covalente, lesdits ligands étant portés par un polymère appliqué sur la membrane.
EP97914219A 1996-03-11 1997-03-11 Membranes specifiques de l'endotoxine Withdrawn EP0888172A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19609479A DE19609479A1 (de) 1996-03-11 1996-03-11 Endotoxin-spezifische Membranen
DE19609479 1996-03-11
PCT/EP1997/001225 WO1997033683A1 (fr) 1996-03-11 1997-03-11 Membranes specifiques de l'endotoxine

Publications (1)

Publication Number Publication Date
EP0888172A1 true EP0888172A1 (fr) 1999-01-07

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EP97914219A Withdrawn EP0888172A1 (fr) 1996-03-11 1997-03-11 Membranes specifiques de l'endotoxine

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EP (1) EP0888172A1 (fr)
JP (1) JP2002514970A (fr)
CA (1) CA2249548A1 (fr)
DE (1) DE19609479A1 (fr)
WO (1) WO1997033683A1 (fr)

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WO1997033683A1 (fr) 1997-09-18
JP2002514970A (ja) 2002-05-21
DE19609479A1 (de) 1997-09-18
CA2249548A1 (fr) 1997-09-18

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