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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • 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
• • 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
  • B01D69/1411—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes containing dispersed material in a continuous matrix
• • 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
  • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
• • 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
  • B01D71/40—Polymers of unsaturated acids or derivatives thereof, e.g. salts, amides, imides, nitriles, anhydrides, esters
  • B01D71/401—Polymers based on the polymerisation of acrylic acid, e.g. polyacrylate
  • B01D71/4011—Polymethylmethacrylate
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
  • C07K16/241—Tumor Necrosis Factors
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
  • C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
  • C12N11/02—Enzymes or microbial cells immobilised on or in an organic carrier
  • C12N11/08—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer
  • C12N11/089—Enzymes or microbial cells immobilised on or in an organic carrier the carrier being a synthetic polymer obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/14—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis
  • A61M1/16—Dialysis systems; Artificial kidneys; Blood oxygenators ; Reciprocating systems for treatment of body fluids, e.g. single needle systems for hemofiltration or pheresis with membranes
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
  • Y10T436/25125—Digestion or removing interfering materials
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
  • Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
  • Y10T436/255—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.] including use of a solid sorbent, semipermeable membrane, or liquid extraction

Definitions

• the present invention relates to interaction systems for the presentation and removal of substances in liquids.
• the invention further relates to devices manufactured with these interaction systems, such as, for example, capillary tube systems, fiber material for filtering physiological liquids, filter mats, joint or vascular prostheses, etc.
• physiological active substances are coupled with polyalkylene glycols, for example polyethylene glycol (cf. for example Thrombosis and Haemostasis, 77 (1), 168-73 (1997), Peptide Research, Vol 8, No. 2 (1995)).
• polyalkylene glycols for example polyethylene glycol
• Such substances are found have a wide therapeutic application. So far, no effective functional antidotes or systems neutralizing the effect, ie systems for removing these substances, have been available for such substances.
• Typical examples of such signaling substances are the cellular messengers of the endothelial and circulating cells of the blood, e.g. CD1, CD2, CD6, CD8, CD16, tumor necrosis factor (TNF) etc.
• CD1, CD2, CD6, CD8, CD16 e.g. CD1, CD2, CD6, CD8, CD16
• TNF tumor necrosis factor
• pathogenetically important, induced proteins such as e.g. the lipoprotein-binding protein LBP are responsible for the development of the most serious complications in septic shock patients.
• the present invention is therefore based on the object of providing a simple, inexpensive and universally applicable system for removing or presenting substances in liquid.
• the system should be able to be easily adapted to the respective practical requirements. Furthermore, the system should not adversely change the liquid or environment to be treated and should be easy to remove from it. If the system is used for diagnostic and therapeutic purposes, it should be able to be used gently and should not strain the body.
• an interaction system comprising at least one active surface made of a plastic based on monomers which contain at least one structural element (A) derived from a carboxylic acid, and at least one attached to a linker with at least one structure capable of hydrogen bonding. element (B) coupled substance, wherein the interaction between the structural element (A) and (B) takes place.
• the structural element derived from a carboxylic acid is preferably located in the side chain of the monomer.
• the plastic particularly preferably comprises the structural element
• radicals R can be the same or different and represent any alkyl or aryl radical or a hydrogen atom.
• the radical X is optional and means 0, N or CH 2 .
• a membrane preferably a membrane, a porous or solid microparticle, a magnetic microparticle, a spun material or a coating made of a natural or synthetic substance.
• Combinations are also possible. For example, you can weave or associate microparticles in fiber material. This creates a network / framework structure, which prevents the microparticles from sagging or pressing together, for example in chromatography columns.
• This active surface can be incorporated in various forms, for example in systems such as capillary tube systems, filters for physiological liquids, hemodialyzers, physiological replacement liquids, enzyme delivery systems, joint or vascular prostheses or artificial organs.
• porous microparticles can be applied as an active surface on conventional hose and filter systems.
• any universally applicable systems can be put together. Due to the possibility of simple priming, substances that are difficult to couple through a covalent bond can often be easily applied to the corresponding surfaces. This is particularly advantageous when appropriate equipment items are to be sterilized. It is often difficult to sterilize covalently bound substances without damage. According to the invention, plastic surface and parallel To do this, sterilize the connection coupled to a linker and then both sterile components can easily be brought together again under sterile conditions.
• an interaction system results.
• the interaction system can be separated, i.e. in different phases, or as a reaction unit.
• the active surface can also be spun into hollow fibers, yarns, press plates, filter mats, nonwoven fabrics or the like.
• the active surface is in the form of microparticles, they can be of any shape, e.g. spherical, diamond-shaped, dumbbell-shaped, diamond-shaped, etc. However, they are preferably spherical with a diameter of 0.5 to 500 ⁇ m, preferably 1 to 300 ⁇ m, more preferably 1 to 250 ⁇ m.
• the microparticles are preferably porous and thus have a larger surface area.
• the plastic comprises at least the structural element (A)
• This structural element is, for example, part of a polymer of the general formula (I)
• R represents an alkyl or aryl radical or a hydrogen atom
• n has the value 10 to 10,000.
• the radical X is optional and means O, N or CH 2 .
• the alkyl radical can be any straight-chain or branched-chain, optionally substituted alkyl radical.
• a straight-chain or branched, optionally substituted C 8 alkyl radical is preferred, such as, for example, a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t - Butyl group.
• optional substituents include one or more halogen atom (s), for example, fluorine, chlorine, bromine or iodine atoms, or hydroxyl group (s), alkyl radicals such as C L .g-alkyl radicals or alkoxy radicals, such as, for example, C x _ 6 alkoxy, such as C 1 _ 3 alkoxy, such as metal thoxy- or ethoxy groups, or thiol groups, such as C-L-.g alkyl thiol groups, for example, x _ 3 alkylthio groups such as methylthio or ethylthio groups.
• alkyl radicals such as C L .g-alkyl radicals or alkoxy radicals, such as, for example, C x _ 6 alkoxy, such as C 1 _ 3 alkoxy, such as metal thoxy- or ethoxy groups
• thiol groups such as C-L-.g alkyl thiol
• the aryl radical can be an onocyclic or bicyclic, optionally substituted aryl radical, which can optionally contain one or more hetero atoms.
• aryl radicals include phenyl, 1- or 2-naphthyl, indenyl or isoindenyl radicals. If appropriate, the aryl radicals can also be substituted.
• heteroatom-containing aryl radicals are a , for example an optionally substituted C 3 _ 9 heteroaryl radical which contains, for example, 1, 2, 3 or more heteroatoms selected from oxygen, sulfur or nitrogen atoms.
• Monocyclic heteroaryl radicals include, for example, pyrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl, N-ethylimidazolyl, oxazolyl, disoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3 -Triazo- lyl-, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, quinazolinyl, naphthylpyridinyl, quinolinyl, isoquinolylinyl, tetra.
• the tacticity of the polymer obtained in this way can be as desired, for example isotactic, heterotactic or syndiotactic.
• the linker contains at least one structural element (B) capable of hydrogen bonding.
• This structural element can be any polar hydrogen atom, as is present, for example, in OH, SH, NH or PH bonds.
• the linker can have any chain length.
• the linker is preferably a (poly) alkylene glycol, particularly preferably polyethylene glycol.
• a (poly) alkylene imine, a (poly) alkylene amine, a (poly) alkylene sulfide or a polyoxaziline are further preferred.
• the linker can also contain several of the structural elements (B). The substances are coupled to the linker by methods known per se.
• reactive derivatives such as succinimidyl succinate, succinimidyl propionate, nitrophenyl carbonate, tresylate, epoxides, aldehydes, isocyanates, maleimides and the like can be used.
• the plastic is preferably a polymethacrylate, preferably a polyalkyl (meth) acrylate (PAMA) plastic or a polyalkyl (meth) acrylate copolymer.
• the plastic is particularly preferred polymethyl (meth) acrylate (PMMA), polyethyl (meth) acrylate (PEMA), polypropyl (meth) acrylate, polybutyl (meth) acrylate (PBMA), polypentyl (meth) acrylate, polyvinyl acetate, polycyclohexyl ( meth) acrylate or polyphenyl (meth) acrylate.
• any proportions of the aforementioned polyalkyl (meth) acrylates and one or more further polymer components are also preferred.
• preferred mixtures are polymethyl methacrylate + polystyrene, polymethyl methacrylate + polyacrylonitrile + methacrylate, polymethyl methacrylate + polyacrylonitrile + methyl allyl sulfonate, polymethyl methacrylate + polyethylene polyvinyl alcohol, polymethyl methacrylate + polyamide, polymethyl methacrylate + polysulfone.
• the proportion of polymethyl methacrylate in the copolymers is preferably at least 20%, more preferably 40% or 60% of the plastic made of polymethyl methacrylate.
• mixed polymers from the mentioned exemplary polymer components can be produced.
• copolymers can be made by methods known in the art. Further components can be incorporated into the polymer, e.g. inorganic compounds such as magnetic or paramagnetic iron compounds or iron or surface-active substances such as NO-releasing compounds such as Nitroprusside sodium. Furthermore, doping with metal atoms such as e.g. Nickel, zinc, gadolinium etc. possible. As a result, the system can be specifically adapted to the respective analytical, therapeutic or diagnostic requirements.
• the interaction system is used for therapeutic or diagnostic purposes, it must be ensured that the plastic is physiologically compatible, i.e. there is no adverse interaction with the physiological fluids. If the interaction system is used in the area of food, cosmetics or commodities, it must also be ensured that it is compatible.
• the interaction system can also be converted into suitable means of transport e.g. Microsomes, liposomes, nanoparts, etc. are packaged to make it easier to infiltrate the organism.
• any substances can be coupled to the linker.
• the coupled substances can be the same or different. Several substances of different types can also be coupled to different linkers. Pharmacologically active or physiologically active substances are preferred. coupled. Examples include proteins, nucleic acids, cellular signaling substances, partners of a biological or physiological affinity pair, such as DNA / DNA binding protein, DNA / complementary DNA, RNA / complementary RNA, antigen / antibody, streptavidin / biotin, strep-TAG / - artificial peptide , Lectin / carbohydrate or marker for a biological substance / biological substance.
• the protein is particularly preferably an enzyme, for example a lipase, an esterase, a transferase, an antigen, an antibody, a tumor marker, a surface antigen, a ligand, a receptor, a surface-active cell fragment of bacteria or viruses or an immune messenger such as, for example, cytokines , Interleukins, growth factors, colony-forming factors, tumor necrosis factors, apoptosis-inducing proteins or their specific antibodies or therapeutic agents.
• the marker is, for example, a fluorescent or chemiluminescent substance, an EST (Expression Sequence Tag; Expression Sequence Code) or an enzyme.
• the pharmacologically active substance is, for example, an anticoagulant, a metabolically active enzyme or a synthetic drug, such as an antibiotic, an anti-tumor agent or an enzyme inhibitor.
• substances can also be coupled that react with inorganic ions, such as nickel, zinc, gadolinium, lanthanum or gold. Examples of this are corresponding complexing agents.
• Substances coupled to a linker also have the advantage that they can be eliminated from the organism.
• Such an interaction system now allows a wide range of applications. It is particularly suitable for Presentation of substances coupled to the linker in a liquid, the respective target substance being bound, cleaved or modified in some other way, or for the removal of substances coupled to the linker from a liquid.
• a preferred area of application is monitoring the diagnosis or therapy of metabolic disorders, coagulation disorders, viral, bacterial, mycotic or parasitic infections or malignant diseases.
• Such interaction systems can be used to put together ready-to-use kits for special applications and devices in appropriate housings and with appropriate equipment.
• FIG. 1 shows the IR spectrum of polymethyl methacrylate, polyethylene glycol (5000) and PMMA-PEG interaction particles.
• PMMA capillary dialyzers can be locally anticoagulated using polyethylene glycol-coupled hirudin or other direct antithrombines (eg Argatroban) (the patient then does not need a systemic anticoagulant), but also by coating appropriate capillary dialyzers with PEG-AN Tigen or PEG antibodies or PEG active substances for specific interaction with toxic or disease-causing or disease-maintaining blood components or metabolic products.
• the plastic capable of interaction can also be part of the surfaces of microtiter plates, cuvettes, containers. be tactical lenses. Furthermore, it is also possible to use the linker as such without a coupled substance to saturate corresponding free binding sites on the plastic capable of interaction.
• the active surface preferably has a certain enlarged surface structure, for example pores, which can be produced by the type of spinning process.
• “foreign substance components” are added to the heated polymer, for example glycerol, which cannot be mixed with the heated, liquid polymer.
• this porosity the large "inner” surface of the particles, is produced in a very similar way.
• FIG. 1 shows IR spectra of polymethyl methacrylate, polyethylene glycol (5000) and PMMA-PEG interaction particles.
• FIG. 2 shows the binding of polyethylene glycol 10000 hirudin to microparticles made from different polyalkyl methacrylates.
• FIG. 3 shows the binding of thrombin to a PMMA dialyzer loaded with synthetic PEG 10kD thrombin inhibitor during repeated circulations of thrombin solutions.
• FIG. 4 shows the binding of a synthetic PEG 10kD thrombin inhibitor to a PMMA dialyzer during 30-minute circulations.
• the protruding capillary tubes are cut off flush with a sharp scalpel, and the two ends of the tube system are each connected with polyethylene catheter material, which enables a corresponding pump-operated flushing of the capillary sections.
• the systems are filled with saline solution completely and without air bubbles. In this way, these capillary tube systems are to be stored and used at 4 ° C for weeks. 2) blood filter
• these manufactured microcapillary or microcolumn modules can be sterilized using ETO or ⁇ -rays. Steam sterilization is also possible for this material.
• the polyalkylene glycol-coupled active ingredients are only applied to the surface of the poly (meth) acrylate structures shortly before the corresponding system is used. The procedure is as follows: The poly (meth) acrylate carrier modules are rinsed with sterile physiological saline solution for about 10 minutes before use in order to remove toxic products that or sterilization process have arisen to flush out of the systems (standard technology for all external therapy systems, such as hamodialyzers or oxygenators in medicine).
• the substances to be applied for example PEG-coupled substances
• the substances to be applied are applied to the surface of the modules in a recirculation mode by priming the systems with the PEG active ingredient solution for 5-10 minutes.
• PEG active ingredient solution for example PEG-coupled substances
• the filters are rinsed again with table salt for 1-2 minutes in order to remove residues of the PEG active substances that have not been completely bound from the system.
• the external therapeutic system is then connected veno-venously or arterio-venously using the conventional single- or two-needle technique.
• the veno-venous passive application has the advantage that with the help of the miniature blood pumps, which are also introduced into the extracorporeal circuit, a precise control of the blood flow through the system can be guaranteed.
• the effectiveness of the specific substrate "fishing" is checked on the basis of the disappearance of the target pathogens. Appropriate detection methods exist for almost all active ingredients used.
• kits of the external therapeutic systems are such that different sizes of blood filters are available to match the required amount of primed Adjust substance. There is a conversion measure for this, which is known from the preclinical testing of such systems.
• the treating physician can use a reservoir of different pegylated active ingredients and different blood filters to put together the therapeutic principle that is individually required for his patient with regard to the therapeutic agents to be used and the size of the system, according to a kind of “modular principle”.
• kits may contain suitable reagents, buffer solutions, reaction vessels and the like.
• the kit can also be in a suitable packaging.
• Such application kits can also be put together in the same way as biochemical cleaning systems.
• the module size is adapted to the corresponding preparative use.
• biochemical preparative questions for in vitro investigations, not only the column method but also the batch method is to be used.
• the corresponding micro- or macroparticles are mixed intensively in a "batch" volume, and after priming with the polyalkylated active ingredients and centrifugation of the supernatant, these loaded particles are washed twice with sodium chloride and then mixed with the corresponding preparation solution.
• a separation between antigens and antibodies or chemically interactive substances can then take place, and this is e.g. preparative affinity purification with almost 100% efficiency possible.
• the existing monoclonal or polyclonal antibodies are coupled with polyethylene glycol and these PEG antibodies are then brought onto the PMMA surface.
• the detection of the epitopes of the substance to be removed, which is as specific as possible, is of great importance for the fast and firm binding to the prepared surface.
• the PEG antibodies are pressed onto the selected blood filter size, and by adding a pegylated antithrombin, e.g. PEG-hirudin, local anticoagulation of the systems should be aimed for.
• a pegylated antithrombin e.g. PEG-hirudin
• human factor VIII antihemophilic globulin
• polyethylene glycol polyethylene glycol
• the inhibitor-hemophilia modules produced by this method are used at regular intervals in the affected patients as an external therapeutic system.
• the time intervals of this treatment depend on the measurable "consumption" of factor VIII in the patient.
• the factor VIII level should not drop below 25-30% of normal.
• Antimicrobial treatment options With the methods of molecular medicine, it is possible to produce monoclonal or polyclonal antibodies against almost all viruses that have protein-containing shells, against bacteria, but also against fungi. These antibodies directed against microbe-specific proteins can be primed onto the active substance carriers made of polyalkyl acrylate after coupling with polyethylene glycol of suitable size (preferably 5-10 kDa).
• the treatment of the patients with such external therapeutic systems makes it possible to remove the germs which trigger and maintain the disease from the bloodstream.
• This method is particularly suitable, e.g. also treat malaria.
• the disease can be interrupted and the patient healed quickly through the cyclical use of specific active ingredient carriers.
• Enzymes which are directly or indirectly integrated in control mechanisms of the body, for example activating or inhibiting special coagulation factors.
• the enzyme Protac activates Protein C to Protein C A , which interferes with the clotting by inhibiting the activated factors V and VIII.
• PEG hemoglobin which is obtained from bovine blood, for example, is currently being tested as an "artificial blood component"("oxyglobin"). PEG hemoglobins should be applied to appropriate sized paramagnetic polymethyl methacrylate or polyalkyl methacrylate particles and then used accordingly. Ideally, the particles have the same specific weight as blood. Polyalkyl methacrylate-polystyrene copolymers are therefore preferably used in a 50/50 mixing ratio, more preferably in a 30/70 mixing ratio.
• the weight refers to the hemoglobin content.
• the polymethyl methacrylate particles (PMMA polystyrene) used for this purpose have been specially prepared by using in the production process during the polymer Fe 2 0 3 was introduced in finely dispersed form into the polymerizing mass. These Fe 2 0 3 -containing particles are paramagnetic and can then be removed from the circulation again in the manner described above.
• Such magnetically active particles are suitable in various forms for direct circulatory use in the blood.
• NO donors specific inhibition of platelet activation
• specific interaction partners for cells preferably tumor cells
• the antitumor agent-carrying particles can be "fixed" by means of magnetic fields in the tumor area.
• the hemoglobin particles have a high oxygen binding function and can take over the oxygen transport in the entire blood circulation in a similar way as the function of the red blood cells. As a result, these hemoglobin microparticles are suitable as universal oxygen carrier systems for disaster medicine.
• the particles can be removed quantitatively from the circulation with the aid of magnetic retention systems.
• These magnetic restraint systems are, for example, microcapillary ETS, which are from are surrounded by a permanent magnet ring. The magnetic particles are removed from the circulation by adhering to the hollow fibers of the ETS.
• the described basic principle of attaching active substances to specific polymer materials is also suitable for coating other plastic surfaces, cell separators or cell growth materials, in which an increased growth spurt is achieved by applying thin growth layers of the finest microparticles made of PMMA to apply cell growth factors (e.g. pegylated BMP-2 or BMP-4) is possible.
• cell growth factors e.g. pegylated BMP-2 or BMP-4.
• this can also be used to coat vascular prostheses with growth factors in such a way that endothelial cells settle very quickly and intensively on the blood side of the vascular prostheses and initiate naturalization (“endothelialization") of the vascular prosthesis there.
• the specific doping of the tissue side of the prosthesis for the purpose of ingrowth of connective tissue cells and smooth muscle cells, for example by applying basic fibroblast growth factor (bFGF), also makes it possible to naturalize the entire prosthesis material.
• the coating of joint prosthesis material with pegylated rBMP-2 or rBMP-4, two recombinantly produced osteoblast growth factors, or the admixture of porous microparticles made of PAMA with rBMP-2 or rBMP-4 in bone cements can greatly shorten the ingrowth phase. In this way, much improved fixation results are achieved.
• PMMA-PEG particles to remove unwanted substances from foods, for example for dealcoholization of alcoholic beverages such as beer, wine etc., presentation of special lipases or enzymes that break down excessive food fats into non-absorbable derivatives or corresponding compounds bind to their surface, removal of cholesterol, targeted removal of certain protein components in certain metabolic disorders (e.g. gluten in zoeliacsia), removal of special carbohydrates in diabetes etc.)
• alcoholic beverages such as beer, wine etc.
• presentation of special lipases or enzymes that break down excessive food fats into non-absorbable derivatives or corresponding compounds bind to their surface removal of cholesterol, targeted removal of certain protein components in certain metabolic disorders (e.g. gluten in zoeliacsia), removal of special carbohydrates in diabetes etc.)
• design food and diet products for certain nutritional specialties can be produced by adding appropriately coated microparticles according to the invention to the product or by treating the product beforehand. It is also possible to take the corresponding microparticles separately before, during and after enjoying the corresponding dishes.
• the microparticles can For this purpose, they are packaged in gastric juice or intestinal juice-resistant tablets or capsules.
• a so-called cava screen which has the shape of a wire cage, is stretched out and installed in the vena cava in order to prevent larger thrombotic masses from washing away into the pulmonary duct.
• This cava screen technology could also be used as a holder or carrier material for micro blood filters. The same coating materials are used as described above.
• a corresponding system should have the shape of a flat blood filter with the largest possible exchange area.
• certain particles according to the invention which receive a permanent digestive enzyme coating, can also be used. These particles can have essential digestive functions during their passage in the gastrointestinal tract.
• a permanent instillation of digestive intestinal probes is possible if the enzymes in the body have a corresponding fibrillar or similar structure
• Small intestine can be used on a specific polyalkyl acrylate matrix.
• a permanent gastric indwelling tube in the form of a structured plastic cage is equipped, for example, with filamentary PMMA structures to which the enzymes are permanently attached over a distance of 30-50 cm via the PMMA-PEG coupling. They are washed into the small intestine with the food porridge and still have firm contact with the stomach lining at one end.
• the corresponding enzymes could imitate the digestive function in the gastrointestinal tract for a longer period of time; they then take action when the corresponding food components pass through the fibrillar structures.
• a special application is, for example, the use of pegylated monoclonal antibodies against the tumor necrosis factor (TNF).
• the monoclonal antibody against the tumor necrosis factor (MAK-195) is an experimental preparation from the company Knoll and is currently being evaluated in clinical trials in shock patients for clinical efficacy.
• This monoclonal antibody can easily be coupled with PEG and applied to a corresponding PMMA structure.
• the monoclonal antibody is bound to the solid phase and binds an epitope of the tumor necrosis factor in a highly specific manner. In this way, high TNF levels that are pathophysiologically harmful to the further course of a shock reaction can be reduced.
• LBP lipopolysaccharide-binding protein
• inhibitors for activated coagulation factors for example the recombinant TFPI, a natural inhibitor of the factor VII tissue factor complex, the most important starting mechanism for blood coagulation, can also be used.
• These can be bound to the membrane in a correspondingly pegylated form in order to completely inhibit blood clotting in the first activation mechanisms, without this to influence normal clotting potential of the organism.
• any pathological mechanism of the organism that uses the blood path to transmit signals can be modified by such an extracorporeal therapeutic system.
• a number of specific tumor antigens on the cell surfaces of tumor cells are known from molecular immunology, for which corresponding antibodies are also available for in vitro investigations for diagnostic purposes.
• these antibodies bound to PEG linkers on the surface of a PMMA membrane, can enter into a specific interaction with tumor cells in the blood and specifically remove them from the circulation, similar to hemofiltration. This is the first time that an arrangement has been made available in which, with existing surface material that is biocompatible and approved, a specific interaction in the blood is possible between cells or cell parts of the organism and specific opponents bound to the solid phase.
• the interaction systems according to the invention can be applied to many other therapeutic applications, in particular to in-vivo plasma cleaning.
• ultrafiltration membranes of the PMMA type on which special PEG-coupled enzymes are attached, can be used for detoxification in patients with kidney disease.
• PEG-coupled urease to PMMA membranes, increased urea values in the blood can be broken down or by applying PEG-coupled creatinine-metabolizing enzymes, a lowering of further urinary nitrogen products can be caused.
• the interaction systems according to the invention preferably PMMA membranes in capillary dialyzers.
• the only manufacturer of PMMA capillary dialyzers is Toray, Japan.
• the capillary dialyzer modules are rinsed intensively on both the dialysate side and on the blood side, on the blood side with physiological saline solution, on the dialysate side with dialysate liquid (saline solution) to contain toxic products and substances that are in the system during the production process Have come into contact with the capillary dialyzer.
• the dialysate side is closed by blind plugs for the preparation of the external therapeutic system; A recirculation is switched on on the blood side, the pegylated application substance being dissolved in the initial charge of about 200 ml.
• hirudin In its recombinant, nature-identical form, hirudin represents a highly specific and effective antithrombotic principle, which will gain increasing interest in the coming years for the adequate therapy of thromboembolic disorders and their subsequent conditions.
• Initial clinical applications and large phase III studies have proven the effectiveness of this novel, therapeutically valuable substance.
• Recombinant hirudin can, of course, also lead to intoxication, either due to the type of therapy regimen carried out, through overdosing or through objective elimination difficulties that are caused by sudden or temporary kidney insufficiency.
• hirudin in which the molecular weight is increased by two 5000-D polyethylene glycol chains. After application, up to 4-5 times the amount of substance in the organism and a greatly extended plasma residence time of hirudin is achieved.
• dialyzers can be used in different ways:
• a PMMA dialyzer For example, you can connect a PMMA dialyzer to a normal dialysis unit and use it as a functional anti-dot principle for PEG-hirudin in appropriate clinical applications, or you can also use simple hemofiltration pump systems such as those used in intensive care medicine for continuous hemoperfusion (see example), the PMMA dialyzers operate with the dialysate side closed, so that a relatively problem-free, low volume "blood wash" of the patient concerned can be carried out. In these cases, the blood wash time required even for high concentrations of PEG-hirudin in the blood would have to be given as less than 2 h, preferably 30-45 min.
• PEG-modified hirudin goat antibodies can be applied to a PMMA membrane, which means that when used in an extracorporeal therapeutic system, high levels of hirudin in the blood can be gently reduced.
• a Fresenius A2008C hemodialysis unit is used to pre-rinse the blood and dialysate side of the dialyzer.
• the PMMA dialyzers are prepared for dialysis according to the manufacturer's instructions.
• the peristaltic pump on the dialysis unit is connected to a storage vessel and to the arteriovenous side.
• the removed and PEG-hirudin-anticoagulated bovine blood is poured into the siliconized glass storage vessel and immediately afterwards the recirculation of the blood side is started.
• FIG. 3 shows the surface binding of a synthetic small-molecular thrombin inhibitor which is mixed with polyethylene glycol (10 kD) according to the instructions of W. Stüber et al. (Peptide Research 8 (2) 1995, pp. 78-85) as a pegylated inhibitor.
• the effective thrombin inhibitor principle is the substance Mtr-Asn-D-Adf-Pip, which, in previous studies (Dickneite G. et al. Thrombosis Research 77, pp. 537-568), has proven to be a highly specific and highly effective inhibitor of thrombin.
• FIG. 4 shows the thrombin binding to a PMMA dialyzer loaded with PEG (10 kD) thrombin inhibitor. From this figure it can be seen that thrombin binds to the coupled thrombin inhibitor during recirculation and accordingly quickly disappears from the recirculation solution.
• MAK 195 100 mg are dissolved in 50 ml of 0.1 mol borate buffer (pH 8) and 200 mg of methoxypolyethylene glycol (20,000) -4-nitrophenyl carbonate are added and the mixture is incubated at 25 ° C. for 3 h.
• the coupling reaction is stopped with a 500-fold molar excess of TRIS, dialyzed against 20 mmol of TRIS-HC1 and on an HP-Q-Sepharose column (Pharmacia) with a linear NaCl gradient (from 0-400 mmol of NaCl) in 20 mmol of TRIS -HC1 (pH 8) applied.
• the PEG-MAK 195 conjugate elutes at about 200-250 mmol NaCl.
• the binding ability of the monoclonal antibody is tested on a recombinant human ⁇ -TNF using an ⁇ -TNF ELISA. A loss of activity of the monoclonal antibody cannot be determined.
• the pegylated monoclonal antibody against TNF is applied to an experimental PMMA capillary dialyzer module with a surface area of 50 cm 2 . The binding capacity for a surface area of 50 cm 2 was 4 mg, based on the protein content of the PEG-MAK 195. In human plasma spiked with TNF (100 ng / ml), no tumor necrosis factor was found after 10 minutes in the recirculation liquid determine.
• Urease (EC 3.5.1.5., Available from Sigma, order no. U 1500) is used as the model enzyme.
• Preparation of a PEG-coupled urease preparation 100 mg urease (type III, specific activity 20,000 to 30,000 U / g) are dissolved in 80 ml 0.1 mol borate buffer (pH 8) and with 250 mg methoxypolyethylene glycol (25,000) -4 -Nitrophenyl carbonate added and incubated at 5 ° C for 24 h. The reaction is stopped with a multiple molar excess of TRIS, dialyzed against TRIS-HC1 (pH 8) and developed in a HP-Q-Sepharose column with a linear NaCl gradient (pH 8).
• the PEG-urease conjugate elutes at 180 to 200 mmol NaCl.
• the The yield of the PEG-urease conjugate is 30-40%.
• Enzyme activity is measured using a urea assay.
• the cleavage activity is monitored by means of pH titration and compared with non-conjugated urease.
• the pegylation of urease has a slight activity-increasing influence on the urea-splitting activity of the enzyme.
• the urease coupled with 25 kD polyethylene glycol is applied in a concentration of 2 mg (based on the protein content of the conjugate) to a miniaturized experimental capillary dialyzer with a 50 cm surface.
• microparticles made of polyalkyl methacrylate are also able to bind these polyethylene glycol-coupled substances on their surface.
• the PAMA microparticles are produced in a manner known per se and coated with the respective active ingredients. Different particle sizes were examined. Microparticles made of polyalkyl methacrylate between 0.5 ⁇ m and 250 ⁇ m in diameter bind large amounts of PEG active substances. These particles can be used in a variety of ways:
• These particles can be administered intravascularly after specific PEG drug doping and then remain in the blood circulation for a long time. It is possible to remove these particles from the body again if they contain magnetically excitable compounds (eg Fe 2 0 3 ). A specific external treatment of the blood with magnetic retention systems removes these particles from the bloodstream at the end of the therapy.
• prodrugs substances that are only converted into their active form in the blood by the enzymes present here
• Specific polyclonal or monoclonal antibodies against coat proteins (highly specific recognition sites) of the viruses are primed on the PAMA particles.
• the particles are able to "catch" the viruses quantitatively and remove them from the organism.
• TNF- ⁇ tumor necrosis factor
• Monodisperse particles in the preferred size of 1 ⁇ m, 5 ⁇ m or 10 ⁇ m are covered with a suitable adhesive film ("PAMA adhesive") firmly connected to the replacement material.
• PAMA adhesive a suitable adhesive film
• the PAMA particle-coated materials are primed with polyalkyl glycol-coupled growth factors for bone, connective tissue or muscle cells (for example rBMP-2 or rBMP-4, bFGF and others) and then introduced into the body. This makes it possible for the first time to achieve firm retention connections between prosthetic material and muscle (restoring traumatology!).
• Goretex or Dacron vascular prostheses are covered with a PAMA particle (0.5 ⁇ m 0) layer and primed with pegylated endothelial growth factor before use.
• PAMA particle 0.5 ⁇ m 0
• pegylated endothelial growth factor The additional application of basic fibroblast growth factor, which was previously PEG-coupled, enables better vitalization through connective tissue and microcapillary growth induction.
• Biocompatible tissue layers made of plastic materials that have been coated with monodisperse PAMA particles or copolymers with PAMA as the base material are primed with organ-specific pegylated cellular growth factors. This enables a quick and controlled coating of the organ replacement materials.
• Biosensors e.g. Silicon chips and other electronic circuit materials can be coated locally with monodisperse PAMA particles (preferably 0.5 to 5 ⁇ m 0). Priming with pegylated cell growth factors enables the growth of special cell endings. This technology enables information to be exchanged between tissues, preferably nerve tissue and intelligent circuits.
• These particles can be treated with a variety of active ingredients, enzymes, antibodies, antithrombotics (direct and indirect), such as hirudin, synthetic small-molecule thrombin inhibitors, protein C-activating snake venom, but also thrombolytics, such as fibrinolase, tPA, streptokinase activator. Complex, among others, can be primed. In miniaturized "tube columns", these particles are inserted directly into a venous (passive) or arteriovenous (active) shunt.
• the size of the particles is such that the corpuscular components of the blood can pass unhindered.
• the inner surface of these modules is so large that even intravascular "temporary" systems are possible.
• the "multiple" priming of PAMA surfaces makes it possible to induce specific enzymatic reactions in the blood.
• Leukocytes, monocytes, poly- morphonuclear white blood cells on the surface of the ETS can be specifically changed (e.g. elimination of inflammation-specific determinants).
• This particle size is preferably suitable for the oral application of dietary active ingredients. Due to the large inner surface of the particles, an intensive stocking with digestion-modifying enzymes is possible (fat and cholesterol-degrading enzymes or binding structures). Binding of pegylated alcohol dehydrogenase can reduce alcohol ingestion in the gastrointestinal tract.

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• 1997
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