CA2241380A1 - Blood-compatible and bacteria-repellent nco-reactively modified copolymer - Google Patents
Blood-compatible and bacteria-repellent nco-reactively modified copolymer Download PDFInfo
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- CA2241380A1 CA2241380A1 CA 2241380 CA2241380A CA2241380A1 CA 2241380 A1 CA2241380 A1 CA 2241380A1 CA 2241380 CA2241380 CA 2241380 CA 2241380 A CA2241380 A CA 2241380A CA 2241380 A1 CA2241380 A1 CA 2241380A1
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- modified copolymer
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- 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
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/62—Polymers of compounds having carbon-to-carbon double bonds
- C08G18/6287—Polymers of sulfur containing compounds having carbon-to-carbon double bonds
-
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- 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
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
- A61L33/06—Use of macromolecular materials
- A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/30—Introducing nitrogen atoms or nitrogen-containing groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Hematology (AREA)
- Materials For Medical Uses (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Polyurethanes Or Polyureas (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- Coating Of Shaped Articles Made Of Macromolecular Substances (AREA)
- Treatments Of Macromolecular Shaped Articles (AREA)
Abstract
The present invention relates to an NCO-reactively modified copolymer which comprises (a) at least one monomer containing sulfonate groups, (b) at least one monomer containing carboxyl groups and (c) at least one type of NCO-reactive group introduced after the copolymerization. The invention further provides a process for preparing the copolymer, a process for modifying a hydrophilic surface with the copolymer by reaction with a polyisocyanate and a product for medical use having a surface modified by the above process.
Description
BLOOD-COMPATIBLE AND BACTERIA-REPELLENT NCO-REA~llv~Y
MODIFIED COPOLYMER
Field of the Invention The invention relates to a blood-compatible and bacteria-repellent NCO-reactively modified copolymer, a process for its preparation, a process for modifying hydrophilic surfaces with this copolymer, and products having surfaces modified in this way and their use for various purposes, including for medical purposes.
Prior Art The colonization and multiplication of bacteria on surfaces is as a rule an undesirable phenomenon which is often associated with adverse consequences. Thus, in the drinking water and drinks industry, bacterial populations may lead to a reduction in quality to an extent that it may endanger health.
Bacteria on or in packaging often cause decay of foodstuffs or even cause infections in the consumer. In bioengineering plants which are to be operated under sterile conditions, bacteria foreign to the plant represent a considerable risk to the process. Such bacteria can be introduced with raw materials or remain in some or all components of the plant if sterilization is not complete. By adhesion, parts of the bacteria population can withdraw from the normal exchange of liquid during rinsing and cleaning, and multiply in the system.
It is known that bacteria colonies form in water treatment plants (for example for desalination through membranes) or else in containers which are filled with O.Z. 5178 dissolved or liquid undiluted organic substances. Such microbial occupation can lead to a considerable extent to blockage and/or corrosive destruction of the plant.
Protection against adhesion and spread of bacteria in food, care and here in particular in care of the elderly, and in medicine is of particular importance.
In mass catering or selling of drinks, considerable risks exist if disposable utensils are not used, in order to avoid waste, and reusable utensils are not cleaned adequately.
The harmful spread of bacteria in hoses and pipes which carry foodstuffs is known, as is bacterial multiplication in storage containers and in textiles in a damp and warm environment, for example in baths. Such areas are the preferred habitat of bacteria, as are certain surfaces in areas of high public use, as, for example, in public means of transport, hospitals, telephone booths, schools and, in particular, in public toilets.
In care of the elderly and sick, the often reduced defenses of those affected require careful measures against infections, in particular on intensive care wards and in home care.
The use of medical objects and equipment during medical e~m; n~tionsl treatments and operations requires particular attention, especially if such equipment or objects come into contact with living tissue or with body fluids. In the case of long-term or permanent contact, for example with implants, catheters, stents, heart valves and heart pacemakers, bacterial contamination can become a O.Z. 5178 life-threatening risk to the patient.
It has already been attempted in various ways to suppress the colonization and spread of bacteria on surfaces.
In J. Microbiol. Chemoth. 31 (1993), 261-271, S.E. Tebbs and T.S.J. Elliott describe paint-like coatings with quaternary ammonium salts as components having an antimicrobial action.
It is known that these salts are dissolved out of the coating material by water, aqueous or other polar media and by body fluids, and their action is thus only of short duration. This equally applies to the incorporation of silver salts into coatings, as described in WO 92/18098.
T. Ouchi and Y. Ohya describe in Progr. Polym. Sci.
20 (1995), 211 et seq. the immobilization or bactericidal active compounds on polymer surfaces by covalent bonding or ionic interactions. In such cases, the germicidal actions are often significantly reduced compared with the pure active compound.
Heteropolar bonds often prove to be not sufficiently stable. Furthermore, the destruction of the germs as a rule leads to undesirable deposits on the surfaces, which mask further bactericidal action and form the basis for a subsequent bacteria population.
W. Kohnen et al. report in ZBl. Bakt. Suppl. 26, Gustav Fischer Verlag, Stuttgart-Jena-New York, 1994, pages 408 to 410 that the adhesion of Staphylococcus epidermidis on a polyurethane film is reduced if the film is pretreated by a glow discharge in the presence of oxygen and then grafted with acrylic acid.
O.Z. 5178 In the case of objects for use for medical purposes, i.e. for e~Am;nAtions, treatments and operations, as described above, not only the bacteria-repellent properties play a role, but also compatibility with blood, i.e. the longest possible blood coagulation time or least possible thrombogenic properties, is also important. According to the international patent application WO 94/17904, membranes for medical purposes can be modified by treatment with a low pressure plasma such that, inter alia, their thrombogenic properties are reduced compared with untreated membranes. Sulfur dioxide is also listed as one of the suitable plasma-forming gases. J.-C. Lin et al. described in Biomaterials 16 (1995), 1017-1023, the plasma treatment of the inner surface of LDPE pipes, it being possible again to employ sulfur dioxide as the plasma-forming gas. The authors report that the surfaces modified by SO2 plasma contained sulfonate groups, and were highly hydrophilic and were thrombogenic to a greater degree than the untreated surfaces.. The authors suggest that this is due to the combined action of surface chemistry, that is to say of the sulfonation, and the hydrophilicity of the surfaces.
A major object of the present invention is to provide an enduringly blood-compatible and bacteria-repellent copolymer which can be fixed to the surface of substrates, in particular substrates of plastic, by covalent chemical bonds and therefore permanently without loss of action and which is not inactivated by either bacteria which have been killed or by other deposits.
O.Z. 5178 Summary of the Invention The present invention provides an NCO-reactively modified copolymer which comprises (a) units of at least one monomer containing a sulfonate group, (b) units of at least one monomer containing a carboxyl group and (c) at least one type of an NCO-reactive group introduced after the copolymerization of the monomers (a) and (b).
The molar ratio of the carboxyl group to the sulfonate group, which acting together produce the desired blood-compatible and bacteria-repellent properties, is preferably 0.1 to 10, more preferably 0.2 to 10, and in particular 0.2 to 5.
The invention also relates to a process for the preparation of the NCO-reactively modified copolymer in which at least one monomer (a) containing sulfonate groups and at least one monomer (b) containing carboxyl groups are polymerized under free-radical initiation to give a primary copolymer, and this is reacted with a polyfunctional NCO-reactive compound to give the NCO-reactively modified copolymer.
The invention furthermore relates to a process for the modification of hydrophilic surfaces, in particular of polymer substrates, in which the NCO-reactively modified copolymer is bonded covalently to the surface by reaction with a polyisocyanate.
Finally, the invention relates to articles having surfaces modified in this way for use for hygiene, industrial, foodstuffs and bioengineering and, in particular, for medical O.Z. 5178 purposes.
The NCO-reactively modified copolymer according to the invention is capable of reducing the adhesion and multiplication of bacteria to a high degree, even over a long period of time. This action is not impaired by the fixing via covalent bonds. Bacteria affected by this action are, inter alia, StaPhYlococcus aureus, StaPhYlococcus ePidermidis, Streptococcus pyoqenes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Escherichia coli. If it is important for the copolymer to be free from monomers or oligomers which are capable of migration, in particular for medical uses, these can be extracted with suitable solvents, such as water or water-ethanol mixtures. The physical and chemical properties of the substrate material remain practically unchanged after the modification of the surface. Undesirable side effects due to exogenous substances liberated or due to bacteria which have been killed do not occur.
Description of Preferred Embodiments The invention is based on the idea of modifying a copolymer which is known ~ se and is built up from customary, readily accessible monomers such that it becomes NCO-reactive and can be fixed covalently to a hydrophilic surface by reaction with a polyisocyanate. To prepare the NCO-reactively modified copolymer according to the invention, at least one monomer (a) containing a sulfonate group and at least one monomer (b) containing a carboxyl group, which are olefinically unsaturated, are thus first polymerized in a reaction initiated by free radicals to give a copolymer. The - 5a -O.Z. 5178 copolymer is called the primary copolymer because it is reacted in a second stage to give the NCO-reactively modified copolymer according to the invention. In addition to the olefinic double bond and the sulfonate or carboxyl group, the monomers mentioned can comprise further functional groups which modify the bioactivity, the processing properties and/or the compatibility of the NCO-reactive copolymer with the particular substrate. If appropriate, at least one further monomer (d) can also be copolymerized, by which means functional groups which also have a modifying action can optionally be introduced.
1. Monomers for the primary copolymer Examples of suitable monomers (a) containing a sulfonate group which may be mentioned are vinylsulfonates and styrenesulfonates, such as sodium vinylsulfonate and, in particular, sodium styrenesulfonate (o- and p-isomers), - 5b -O.Z. 5178 as well as sodium methallylsulfonate. It is also possible to employ the corresponding olefinically unsaturated sulfonic acids as monomers for the copolymerization, and copolymers with sulfonic acid groups are then obtained. Such copolymers and the NCO-reactive copolymers prepared 5 therefrom also belong to the scope of the invention. If the sulfonic acid groups are subsequently neutralized, for example with sodium hydroxide, products which correspond to those prepared from the beginning with the corresponding sulfonate monomers are obtained.
Suitable monomers (b) containing carboxyl groups are, for example, acrylic 10 acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, methylmaleic acid, dihydroxymaleic acid, crotonic acid, isocrotonic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid and, in particular, maleic acid. Instead of the carboxyl groups, the monomers (b) employed for 15 the polymerization can initially comprise groups derived therefrom, for example ester, amide, nitrile or anhydride groups, which are converted into cal b-~xyl groups in the cu~lo,nary manner after the poly",eri~ation. Examples of these are (meth)acrylic acid derivatives, such as methyl ",etl,auylate, ethyl acrylate, acrylonitrile and acrylamide. The cail,oxyl group in the 20 monoi"er and in the primary copolymer can furthe~more also be co",plPtely or partly neutralized, for example by sodium hydroxide. Such ca,~"~xylate groups are regarded as carboxyl groups in the conte~t of this invention.
Instead of an individual ",onoi"er (a) or (b), it is of course possible to employ correspondin~ mixtures, for example instead of sodium styrenesulfonate by 2s itself, a mixture of sodium styrenesulfonate and sodium vinylsulfonate, or instead of maleic acid by itself, a mixture of maleic acid and acryiic acid.
The pnmary copolymer can consist exc!usively of the monomers (a) and (b).
Examples of further monomers (d) which can optionally also be copoly" ,e, i ~d and which can co" ~, ise func~ional groups are, inter alia, vinyl 30 ketones, such as vinyl methyl ketone and vinyl butyl ketone; vinyi~ro,n~lic monomers, such as styrene~ ~-methylstyrene and o.z. 5178 vinyltoluene; olefins, such as ethylene, propylene, 1-butene and 1-octene;
diolefins, such as butadiene and isoprene; vinyl esters, such as vinyl acetate and vinyl propionate; and N-vinylpyrrolidone. The monomers (d) are optionally employed as a rule in amounts of up to 30 percent by weight, 5 based on the sum of monomers (a), (b) and (d).
MODIFIED COPOLYMER
Field of the Invention The invention relates to a blood-compatible and bacteria-repellent NCO-reactively modified copolymer, a process for its preparation, a process for modifying hydrophilic surfaces with this copolymer, and products having surfaces modified in this way and their use for various purposes, including for medical purposes.
Prior Art The colonization and multiplication of bacteria on surfaces is as a rule an undesirable phenomenon which is often associated with adverse consequences. Thus, in the drinking water and drinks industry, bacterial populations may lead to a reduction in quality to an extent that it may endanger health.
Bacteria on or in packaging often cause decay of foodstuffs or even cause infections in the consumer. In bioengineering plants which are to be operated under sterile conditions, bacteria foreign to the plant represent a considerable risk to the process. Such bacteria can be introduced with raw materials or remain in some or all components of the plant if sterilization is not complete. By adhesion, parts of the bacteria population can withdraw from the normal exchange of liquid during rinsing and cleaning, and multiply in the system.
It is known that bacteria colonies form in water treatment plants (for example for desalination through membranes) or else in containers which are filled with O.Z. 5178 dissolved or liquid undiluted organic substances. Such microbial occupation can lead to a considerable extent to blockage and/or corrosive destruction of the plant.
Protection against adhesion and spread of bacteria in food, care and here in particular in care of the elderly, and in medicine is of particular importance.
In mass catering or selling of drinks, considerable risks exist if disposable utensils are not used, in order to avoid waste, and reusable utensils are not cleaned adequately.
The harmful spread of bacteria in hoses and pipes which carry foodstuffs is known, as is bacterial multiplication in storage containers and in textiles in a damp and warm environment, for example in baths. Such areas are the preferred habitat of bacteria, as are certain surfaces in areas of high public use, as, for example, in public means of transport, hospitals, telephone booths, schools and, in particular, in public toilets.
In care of the elderly and sick, the often reduced defenses of those affected require careful measures against infections, in particular on intensive care wards and in home care.
The use of medical objects and equipment during medical e~m; n~tionsl treatments and operations requires particular attention, especially if such equipment or objects come into contact with living tissue or with body fluids. In the case of long-term or permanent contact, for example with implants, catheters, stents, heart valves and heart pacemakers, bacterial contamination can become a O.Z. 5178 life-threatening risk to the patient.
It has already been attempted in various ways to suppress the colonization and spread of bacteria on surfaces.
In J. Microbiol. Chemoth. 31 (1993), 261-271, S.E. Tebbs and T.S.J. Elliott describe paint-like coatings with quaternary ammonium salts as components having an antimicrobial action.
It is known that these salts are dissolved out of the coating material by water, aqueous or other polar media and by body fluids, and their action is thus only of short duration. This equally applies to the incorporation of silver salts into coatings, as described in WO 92/18098.
T. Ouchi and Y. Ohya describe in Progr. Polym. Sci.
20 (1995), 211 et seq. the immobilization or bactericidal active compounds on polymer surfaces by covalent bonding or ionic interactions. In such cases, the germicidal actions are often significantly reduced compared with the pure active compound.
Heteropolar bonds often prove to be not sufficiently stable. Furthermore, the destruction of the germs as a rule leads to undesirable deposits on the surfaces, which mask further bactericidal action and form the basis for a subsequent bacteria population.
W. Kohnen et al. report in ZBl. Bakt. Suppl. 26, Gustav Fischer Verlag, Stuttgart-Jena-New York, 1994, pages 408 to 410 that the adhesion of Staphylococcus epidermidis on a polyurethane film is reduced if the film is pretreated by a glow discharge in the presence of oxygen and then grafted with acrylic acid.
O.Z. 5178 In the case of objects for use for medical purposes, i.e. for e~Am;nAtions, treatments and operations, as described above, not only the bacteria-repellent properties play a role, but also compatibility with blood, i.e. the longest possible blood coagulation time or least possible thrombogenic properties, is also important. According to the international patent application WO 94/17904, membranes for medical purposes can be modified by treatment with a low pressure plasma such that, inter alia, their thrombogenic properties are reduced compared with untreated membranes. Sulfur dioxide is also listed as one of the suitable plasma-forming gases. J.-C. Lin et al. described in Biomaterials 16 (1995), 1017-1023, the plasma treatment of the inner surface of LDPE pipes, it being possible again to employ sulfur dioxide as the plasma-forming gas. The authors report that the surfaces modified by SO2 plasma contained sulfonate groups, and were highly hydrophilic and were thrombogenic to a greater degree than the untreated surfaces.. The authors suggest that this is due to the combined action of surface chemistry, that is to say of the sulfonation, and the hydrophilicity of the surfaces.
A major object of the present invention is to provide an enduringly blood-compatible and bacteria-repellent copolymer which can be fixed to the surface of substrates, in particular substrates of plastic, by covalent chemical bonds and therefore permanently without loss of action and which is not inactivated by either bacteria which have been killed or by other deposits.
O.Z. 5178 Summary of the Invention The present invention provides an NCO-reactively modified copolymer which comprises (a) units of at least one monomer containing a sulfonate group, (b) units of at least one monomer containing a carboxyl group and (c) at least one type of an NCO-reactive group introduced after the copolymerization of the monomers (a) and (b).
The molar ratio of the carboxyl group to the sulfonate group, which acting together produce the desired blood-compatible and bacteria-repellent properties, is preferably 0.1 to 10, more preferably 0.2 to 10, and in particular 0.2 to 5.
The invention also relates to a process for the preparation of the NCO-reactively modified copolymer in which at least one monomer (a) containing sulfonate groups and at least one monomer (b) containing carboxyl groups are polymerized under free-radical initiation to give a primary copolymer, and this is reacted with a polyfunctional NCO-reactive compound to give the NCO-reactively modified copolymer.
The invention furthermore relates to a process for the modification of hydrophilic surfaces, in particular of polymer substrates, in which the NCO-reactively modified copolymer is bonded covalently to the surface by reaction with a polyisocyanate.
Finally, the invention relates to articles having surfaces modified in this way for use for hygiene, industrial, foodstuffs and bioengineering and, in particular, for medical O.Z. 5178 purposes.
The NCO-reactively modified copolymer according to the invention is capable of reducing the adhesion and multiplication of bacteria to a high degree, even over a long period of time. This action is not impaired by the fixing via covalent bonds. Bacteria affected by this action are, inter alia, StaPhYlococcus aureus, StaPhYlococcus ePidermidis, Streptococcus pyoqenes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Escherichia coli. If it is important for the copolymer to be free from monomers or oligomers which are capable of migration, in particular for medical uses, these can be extracted with suitable solvents, such as water or water-ethanol mixtures. The physical and chemical properties of the substrate material remain practically unchanged after the modification of the surface. Undesirable side effects due to exogenous substances liberated or due to bacteria which have been killed do not occur.
Description of Preferred Embodiments The invention is based on the idea of modifying a copolymer which is known ~ se and is built up from customary, readily accessible monomers such that it becomes NCO-reactive and can be fixed covalently to a hydrophilic surface by reaction with a polyisocyanate. To prepare the NCO-reactively modified copolymer according to the invention, at least one monomer (a) containing a sulfonate group and at least one monomer (b) containing a carboxyl group, which are olefinically unsaturated, are thus first polymerized in a reaction initiated by free radicals to give a copolymer. The - 5a -O.Z. 5178 copolymer is called the primary copolymer because it is reacted in a second stage to give the NCO-reactively modified copolymer according to the invention. In addition to the olefinic double bond and the sulfonate or carboxyl group, the monomers mentioned can comprise further functional groups which modify the bioactivity, the processing properties and/or the compatibility of the NCO-reactive copolymer with the particular substrate. If appropriate, at least one further monomer (d) can also be copolymerized, by which means functional groups which also have a modifying action can optionally be introduced.
1. Monomers for the primary copolymer Examples of suitable monomers (a) containing a sulfonate group which may be mentioned are vinylsulfonates and styrenesulfonates, such as sodium vinylsulfonate and, in particular, sodium styrenesulfonate (o- and p-isomers), - 5b -O.Z. 5178 as well as sodium methallylsulfonate. It is also possible to employ the corresponding olefinically unsaturated sulfonic acids as monomers for the copolymerization, and copolymers with sulfonic acid groups are then obtained. Such copolymers and the NCO-reactive copolymers prepared 5 therefrom also belong to the scope of the invention. If the sulfonic acid groups are subsequently neutralized, for example with sodium hydroxide, products which correspond to those prepared from the beginning with the corresponding sulfonate monomers are obtained.
Suitable monomers (b) containing carboxyl groups are, for example, acrylic 10 acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, methylmaleic acid, dihydroxymaleic acid, crotonic acid, isocrotonic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid and, in particular, maleic acid. Instead of the carboxyl groups, the monomers (b) employed for 15 the polymerization can initially comprise groups derived therefrom, for example ester, amide, nitrile or anhydride groups, which are converted into cal b-~xyl groups in the cu~lo,nary manner after the poly",eri~ation. Examples of these are (meth)acrylic acid derivatives, such as methyl ",etl,auylate, ethyl acrylate, acrylonitrile and acrylamide. The cail,oxyl group in the 20 monoi"er and in the primary copolymer can furthe~more also be co",plPtely or partly neutralized, for example by sodium hydroxide. Such ca,~"~xylate groups are regarded as carboxyl groups in the conte~t of this invention.
Instead of an individual ",onoi"er (a) or (b), it is of course possible to employ correspondin~ mixtures, for example instead of sodium styrenesulfonate by 2s itself, a mixture of sodium styrenesulfonate and sodium vinylsulfonate, or instead of maleic acid by itself, a mixture of maleic acid and acryiic acid.
The pnmary copolymer can consist exc!usively of the monomers (a) and (b).
Examples of further monomers (d) which can optionally also be copoly" ,e, i ~d and which can co" ~, ise func~ional groups are, inter alia, vinyl 30 ketones, such as vinyl methyl ketone and vinyl butyl ketone; vinyi~ro,n~lic monomers, such as styrene~ ~-methylstyrene and o.z. 5178 vinyltoluene; olefins, such as ethylene, propylene, 1-butene and 1-octene;
diolefins, such as butadiene and isoprene; vinyl esters, such as vinyl acetate and vinyl propionate; and N-vinylpyrrolidone. The monomers (d) are optionally employed as a rule in amounts of up to 30 percent by weight, 5 based on the sum of monomers (a), (b) and (d).
2 Preparation of the pnimary copolymer The ~ono~ers (a), (b) and ~i~ n~l ly (d) nE~y be ~JL~;~ the pr ~ ry copolymer and in the NC ~ reactively modified copolymer according to the invention as biocks or in random distribution, depending on the reaction 10 procedure in the polyll,e,i,~ion. rhe sulfonate group and the carboxyl group produce the desired blood-compatible and bacteria-repellent properties of the copolymer which has been i~C0-reactively modified according to the invention, while the NCO-reactive groups thereof render covalent fixing (or bonding) of the copolymer to the hydrophilic surface of the substrate possible 15 by reaction with a polyisocyanate.
The primary copolymer is prepared in the cus(oll~aly ",a",ler by polvmerization, initiated by free radicals, of the monomers (a), (b) and opti~n~lly (d), preferably ky ~olllti~n or em~lsion polymerization. A
particularly suitable solvent is water, in which the monomers and also the 20 copolymer are as a rule readily soluble. Strongly polar organic solvents, such as dimethylro",la"~i-le, dimethylaceta",ide and dimethyl sulfoxide, are also particularly suitable. Other suitable solvents include tetrahydrofuran (THF) and acetone. A suitable solvent for a given combination of monomers can easily be found by means of prelLminary experiments.
25 Suitable pol~",e,i~lion initiators are, inter alia, azonitriles, alkyl paro~i~Jes, acyl peroxides, hydr~peroxides, peroxyketones, peroxyesters and perca,L,or~ates, and all the cs~stoi~la,y~ photoinitiators.
The polymerization is initiated by heat, for example by heating to 60 to 1 00~C, or by r~ tion of a~ro,uriate wa~elength. it is possible, for exan~Jle, o.z. 5178 23 l~3-640 CA 0224l380 l998-06-22 initially to introduce a portion of the monomers (a) and (b) and op~ l 1 y (d), to start the polymerization and to introduce the remainder of the monomers as a mixture into the reactor, a temperature of 60 to 100~C
preferably being maintained by cooling. A random copolymer is obtained in 5 this manner. If a certain monomer or a portion thereof is initially introducedand the other monomer or monomers and, if appropriate, the remainder of the monomer initially introduced are added in each case by themselves in portions, a block copolymer is formed. These variants are of course ideally typical limit cases. In practic~, merely as a result of the different rates of 10 reaction of the various monomers, regions with a predominantly block structure are also obtained in addition to those which have a largely random distribution.
When the polymerization has ended, a solution or emulsion of the primary copolymer with solids contents which can be, for example, 5 to 20% by 15 weight, is obtained, depending on the proportions of the monomers (a), (b~
and, if appro~u, iate, (d) and the solvent used.
The primary copolymer is prepared in the cus(oll~aly ",a",ler by polvmerization, initiated by free radicals, of the monomers (a), (b) and opti~n~lly (d), preferably ky ~olllti~n or em~lsion polymerization. A
particularly suitable solvent is water, in which the monomers and also the 20 copolymer are as a rule readily soluble. Strongly polar organic solvents, such as dimethylro",la"~i-le, dimethylaceta",ide and dimethyl sulfoxide, are also particularly suitable. Other suitable solvents include tetrahydrofuran (THF) and acetone. A suitable solvent for a given combination of monomers can easily be found by means of prelLminary experiments.
25 Suitable pol~",e,i~lion initiators are, inter alia, azonitriles, alkyl paro~i~Jes, acyl peroxides, hydr~peroxides, peroxyketones, peroxyesters and perca,L,or~ates, and all the cs~stoi~la,y~ photoinitiators.
The polymerization is initiated by heat, for example by heating to 60 to 1 00~C, or by r~ tion of a~ro,uriate wa~elength. it is possible, for exan~Jle, o.z. 5178 23 l~3-640 CA 0224l380 l998-06-22 initially to introduce a portion of the monomers (a) and (b) and op~ l 1 y (d), to start the polymerization and to introduce the remainder of the monomers as a mixture into the reactor, a temperature of 60 to 100~C
preferably being maintained by cooling. A random copolymer is obtained in 5 this manner. If a certain monomer or a portion thereof is initially introducedand the other monomer or monomers and, if appropriate, the remainder of the monomer initially introduced are added in each case by themselves in portions, a block copolymer is formed. These variants are of course ideally typical limit cases. In practic~, merely as a result of the different rates of 10 reaction of the various monomers, regions with a predominantly block structure are also obtained in addition to those which have a largely random distribution.
When the polymerization has ended, a solution or emulsion of the primary copolymer with solids contents which can be, for example, 5 to 20% by 15 weight, is obtained, depending on the proportions of the monomers (a), (b~
and, if appro~u, iate, (d) and the solvent used.
3 NCO-reactive modiflcaffon of the primary cop~lymer T~e primary copolymer of the monomers (a), (b) and opti~lly (d) is modified NCO~eactively in a second reaction step by reacting it with a 20 polyfunctional NCO-reactive c~""~ound. As a result, at least one type of NCO~eactive group is introduced or additionally introd~ u~i into the primary copolymer, these groups including, in partics~lar, hydroxyl and primary or secondary amino groups. These groups are at the same time carboxyl-reactive and, during the NCO-reactive modification, react with a ~alL,o,tyl 25 group of the ~ii"~ary copolymer to form an ester group or, resp~li~Jely, a car6Oka"~ide group. Suitable polyf~ n~lio"al NCOfeactive cG",paunds are ~referdbly polyols, such as diols or triols; amino alc~hols, such as amino- or N-alkylaminoalkanols; and polya",;nes, such as diamines and llid",i"es.
i xamples which may be ~l~erltioned are ethylene ~Iycol, propylene giycol, 3 0 1 ,4butanediol, 1 ,6~exanediol, ~ i, l ,etl ,ylolpropane, aminoell ,anol, N- methylaminoethanol, ethylenediamine, propylenediamine, O.Z. 5178 hexamethylenediamine and diethylenetriamine. As a result of the reaction, an NC0-reactively modified primary copolymer in which the NC0-reactive groups are located in side chains which are bonded via carboxylic ester or carboxamide groups to the skeleton of the primary copolymer consisting of carbon atoms is obtained.
The NCO-reactive groups render covalent fixing (or bonding) of the copolymer to the hydrophilic surface of the substrate possible by reaction with a linking polyisocyanate.
The proportion of NCO-reactive groups of the total functionality of the modified primary copolymer (i.e.
sulfonate, carboxyl and NC0-reactive groups) is preferably about 5 to 20 mol percent. Such a molar proportion renders possible and ensures firm bonding to hydrophilic surfaces with the aid of a polyisocyanate.
Since some carboxyl groups are consumed in the reaction of the primary copolymer with the polyfunctional NC0-reactive compound to give the NC0-reactive copolymer, as explained above, the molar proportion of carboxyl groups of the total functionality of the primary copolymer (ie.
sulfonate plus carboxyl groups) must be correspondingly higher if a certain ratio of carboxyl and sulfonate groups and a certain molar proportion of the NC0-reactive group of the total functionality of the NC0-reactive copolymer are specified. The amount of the polyfunctional NC0-reactive compound employed in this reaction depends on the functionality thereof (bi- or trifunctional), the molar proportion of carboxyl groups in the primary copolymer and the o.z. 5178 desired molar ratio of carboxyl and sulfonate groups in the NCO-reactively modified copolymer according to the invention.
For the NCO-reactive modification, the primary copolymer can be reacted with an amino alcohol, for example ethanolamine, or a diamine, for example hexamethylenediamine, in an autoclave at elevated temperature under increased pressure. The course of the reaction can be monitored by means of potentiometric titration or NMR spectroscopy.
Alternatively, the modification can also be carried out under normal pressure by heating the primary copolymer and the modifying component in a high-boiling solvent, desirably in the presence of an entraining agent for water.
Use of the modified copolymer as a coating composition A solution or emulsion of the NCO-reactively modified copolymer can be used for modification of hydrophilic surfaces, in particular of hydrophilic surfaces of plastic.
In this case, the copolymer is fixed to the surface of the hydrophilic substrate by covalent bonds by means of a polyisocyanate, preferably a diisocyanate. Any known commercially available polyisocyanates are suitable for this, such as hexamethylene diisocyanate (HMDI), tolylene diisocyanate (TDI), methylene 4,4'-bis(phenyl isocyanate) (MDI), methylene 4,4'-bis(cyclohexyl isocyanate) (H-MDI) and isophorone diisocyanate (IPDI). The polyisocyanate reacts with the hydroxyl or amino groups of the copolymer and with hydroxyl or amino groups which are present on the hydrophilic surface of the substrate, to form urethane or urea bridges.
Some polyisocyanate molecules will of course react exclusively O.Z. 5178 with hydroxyl or amino groups of the NCO-reactively modified copolymer, with chain lengthening or linkage. At the abovementioned molar proportions of the NCO-reactive groups of the total functionality of the NCO-reactively modified copolymer according to the invention, however, the desired fixing to the substrate surface always takes place to an adequate extent.
Surprisingly, it has been found that the co-use of a chain-lengthen;ng agent during bonding of the NCO-reactively modified copolymer according to the invention leads to a higher concentration - detectable by means of ESCA - bioactive groups on the substrate and thus to an intensified action.
Chain-lengthening agents are compounds with as a rule terminal NCO-reactive groups, such as hydroxyl or amino groups.
Particularly suitable compounds are, for example, diamines, amino alcohols, and diols, in particular polyalkylene glycols having (where appropriate mean) molecular weights of about 100 to 3000.
If the NCO-reactively modified copolymer is present as a solution or emulsion in a aqueous medium or another medium which is reactive with NCO
- lOa -O.Z. 5178 CA 0224l380 l998-06-22 groups, the isocyanate groups of the polyisocyanate must first be blocked (or masked). This is effected in the customary manner with compounds which add onto the NCO groups at low temperatures, such as 20 to 60~C, and are split off again at higher temperatures. Such compounds are, for example, s methyl ethyl ketoxime and ~aprolactam. A particularly suitable polyisocyanate for use in aqueous systems is, for example, isophorone diisocyanate (IPDI) blocked with methyl ethyl ketoxime. If the copolymer is present as a solution or emulsion in a non-aqueous medium which is not reactive with NCO groups, for example in dimethylformamide, a non-blocked 10 polyisocyanate can be used, for example IPDI again, or hexamethylene diisocyanate (HDI), methylene 4,4'-~is(phenyl isocyanate, ~JlDI), methylene 4,4'-bis(cyclohexyl isocyanate) (H-MDI) or tolylene diisocyanate (TDI).
The substrates of plastic, the surfaces of which are modified with the copolymer accordin~ to the invention, can be homo- or copolymefs which are 15 h~dlopl,ilicorhyd,opl,ilized in nature, as explained below, i.e. carry hydroxyl groups and/or amino groups on the surface. Hydrophilic and hydrophilized (co)polymers are desiynated here in com",on as hydrophilic. The base (co)palymers which are sl ~it~h!e in principle include, for example, polyolefins, such as polyethylene, polypropylene, polyisobutylene, polybutadiene, 20 palyisoprene, naturally occurring rubbers and polyethylene~o~ropylene;
halogen~ontaining polymers, such as polyvinyl chloride, polyvinylidene ~lol ide, poly~ ropre,~e, polytetrafluoroethylene and polyvinylidene fluoride; polymers and copolymers of vinylaromatic monomers, such as polystyrene, polyvinyltoluene, polystyrene~o-vinyltoluene, polystyrene-co-2 5 acrylonitrile, and polystyrene~obl ~t~iene-co-acrylonitrile; polycondensates, for example polyesters, such as palyethylene terephthalate and polybutylene tefe~.htl,alale; poly~l,idPs, such as polycaprolactam, polylaurolactam and the polyconde"sala of adipic acid and he~ca,l,aU ,~lenediamine; polyether-~lock amides, for example of laurolactam or caprolactam and polyethylene glycoi 3 o having on average 8, 12 or 16 ethoxy groups; and furthermore poly~ tl,anesl polyethers, polyc~,~o"ales, polysulfones, polyether-ketones, polyester-amides and-imides, polyacrylonitrile and polyacrylates and Illethdcrylates.
-- 1 1 _ O.Z. 5178 If the polymers or copolymers are not sufficiently hydrophilic, they must be hydrophilized. This is the case if the contact angle of water at 25~C, measured by the method of R.J. Good et al., Techniques of Measuring Contact Angles in Surface and Colloid Sciences, Volume 11, Plenum Press New York, N.Y., 1979, is ~30~. Even if this condition is met, an additional hydrophilization improves the adhesion of the NCO-reactive polymer applied.
A whole range of methods are available for the hydrophilization. Thus, monomers containing hydroxyl sroups, such as hydroxyethyl (meth)acrylate or hydroxybutyl (meth)acrylate, can be grafted onto a polymeric substrate surface ~y a radiation-induced reaction . Instead of using nDna~rs, a c~olyrer ~taining ~ly~xyl groll~s can also ~e ryldLLe~ anto the dl~ surfaoe.
Such copolymers can further~,ore be applied to the substrate surface in the customary manner, for example by spraying, dipping or spin coating with soiutions of the copolymers. Polymers or copolymers ~hich are not s~fficiently hydrophilic can furthermore be hydrophilized by treatment with argon plasma or irradiation with UV rays of 100 to 400 nm. Treatment with a~"."o"ia ~las",a achieves not only hydrophilization but, by introduction of amino groups, additional bonding possibilities and physiological effects.
2 o Finally, e~c~ ,;ng with strong acids, such as sulfuric acid, hydrochloric acid and nitric acid, or bases, such as alkali metal hydroxides, also leads to an adequate hydrophilization of hydrophobic polymers or cop~lymers.
The hydrophilic or hydrophilized substrate surfaces are coated in the clJslollld~ c~ " ,er, for e~a"~le by cli~p;"g, spraying or spin coating, with the solution or emulsion of the NC0-reactively modified copolymer accordi,lg to the invention, which comprises a polyisocyanate, which is blocked if apyro~rhte. After evaporali,lg the solvent and, if approp, iate, splitting off the blocl<ing agent, fixing of the copolymer to the sul~ ate surface takes place at 120 to 150~C. This temperature is expediently maintained for 10 seconds to 5 minutes, to give a ~e"~ically bonded coating which not infrequently fails more cohesively (i.e. in itself) than adhesiveiy (i.e. at the interfaces). The coating cannot be detached selectively from the substrate of plastic using sclvents, which corresponds to covalent bondiny to the surface .hereof.
O.Z. 5178 In one variant of the coating process, the hydrophilic or hydrophilized substrate surface is first treated with the polyisocyanate, which is blocked if appropriate, in order to fix the polyisocyanate to the surface by means of one of its NCO groups, and the solution or emulsion of the NCO-reactively s modified copolymer is then applied to the pretreated area, the hydroxyl or amino groups of said copolymer reac~ing with the remaining NCO groups of the polyisocyanate.
6. Products according to the invention Products, such as devices, equipment and other objects, having surfaces 10 co"~, ,lateiy or partly modified according to the invention are suitable for many uses in which it is important to avoid or suppress adhesion and growth of bacteria. ~hey are thus suitable, inter alia"'or hygiene, industrial, foodstuffsand bioengineering purposes, such as have been described by way of example above. The objects are preferably s~litable for medical uses, 15 especially if bacteria-repellent properties and compatibility with blood are simultaneously ir~ o~lan~. However, the advantageous properties of the objects according to the invention also manifest themselves in contact with body fluids other than blood, such as Iymph, or with tissue. Medical uses are, for exa""~le, those as Iymph drainages, wound dressings, tubes, stents, 20 heart valves, membranes, blood bags or as catheters, for example for peritoneal dialysis.
The following examples are intended to illustrate the invention further, but not to limit its scope as presented in the patent claims.
Examples 1 to 4 25 Preparation of the primary copolymer 200 ml of a 1 M solution of maleic acid in water were mi~d with 200 ml of a 1 M solution of sodium styrene sulroi,ate in water. rhe reaction mixture ~as provided with 1 mol~/O, based on the total amount of monomers, of potassium ~IUAi~ ff~'' as an initiator, and nitrogen ~s passed U~ for 15 minutes.
O,Z. 5178 CA 0224l380 l998-06-22 The batch was heated to 60~C and stirred under a nitrogen a~-~sphere for 4 hours. The reacticn nixture WRS then stirred into eth~n~l, the oopolymEr precipitating out.
Polymer-analogous conversion of the primary copolymer into NCO-5 reactive copolymers (i) With ethanolamine in an autoc~ave (Examples 1 to 3) In each case 60 9 of the primary copolymer were L~a~ed with the ccn4~nl~lLs shown in Table 1 and under the conditions shown there in a 200 ml autoclave. The conversion was determined by potentiometric determination lo of the residual acid.
O,Z, 5178 Table 1 Example 1 Example 2 Example 3 Acid units of the 2.768 2.768 2.768 copolymer (mmol) NaOH (mmol) 1.384 - -Ethanolamine (mmol) 1.384 2.768 2.768 Water (g) 29.9 38.0 36.0 Reaction time (hours) 10 10 10 Temperature (~C) 140 180 180 Pressure (bar) 3.7 9.9 9.9 Conversion (%) 29.8 79.4 92.2 (ii) With ethylene glycol under normal pressure (Example 4) 60 g of the copolymer were dissolved in 600 ml of ethylene glycol and 600 ml of ethanol (as an entraining agent for the water of reaction). The mixture was heated at 100~C
for 6 hours, while stirring. After in each case 0.5 hour, the ethanol/water mixture which had distilled off was replaced with ethanol (250 ml in total). The volatile portions were then distilled off under reduced pressure (20 mbar) at a temperature up to 120~C. The residue was washed twice with acetone and dried. The conversion, according to Karl-Fischer titration, was 85%.
Modification of hydrophilic polymer surfaces with NCO-reactive copolymers by means of polyisocyanates To fix the NCO-reactive copolymers from Examples 1 to 4 on various polymer substrates, the polyisocyanate components and the NCO-reactive copolymers were dissolved in a suitable solvent and applied to the surface of the polymer substrate by dipping. The solvent was then evaporated and the o.z. 5178 NC0-reactive copolymer was fixed to the polymer substrate by heating. To remove residual monomers and oligomers, the coated substrate was washed with water with a temperature of 60~C.
The coating was detected by means of ESCA
measurements. It was detectable with the aid of the changed elemental composition compared with the non-coated polymer substrates, and in particular by the sulfur added.
Determination of the Primary bacterial adhesion under static conditions An overnight culture of the bacteria strain Klebsiella pneumoniae in yeast extract-peptone-glucose nutrient medium (1%+1%+1%) was centrifuged off and take up again in phosphate-buffered saline (=PBS; 0.05 M KH2P04, pH
7.2 + 0.9% NaCl). The mixture was diluted to a cell concentration of 108 cells/ml with PBS buffer. The suspended bacteria were brought into contact for 3 hours with the piece of film to be investigated. For this, circular pieces of film coated on both sides and having a diameter of 1.6 cm (=4.02 cm2) were pricked onto a dissecting needle and shaken with the cell suspension. Films coated on one side were clamped in the form of a circular, flat disk of 4.5 cm diameter with a supporting membrane of flexible PVC 2-3 cm thick into a membrane filter apparatus. The cell suspension was poured onto the side facing upwards, with the coating to be tested, and the system was shaken for 3 hours. The membrane filter apparatus must be tight, i.e. no cell O.Z. 5178 suspension must flow out through leaking cells.
At the end of the contact period, the bacteria suspension was sucked off with a water pump and, for washing, the pieces of film were shaken with 20 ml of sterile PBS
solution in a 100 ml glass beaker for 2 minutes. The piece of film was dipped into sterile PBS solution again and then extracted in 10 ml of heated TRIS/EDTA (0.1 M trishydroxy-ethylaminomethane, 4 mM ethylenediaminetetraacetic acid, brought to pH 7.8 with HCl) in a boiling water bath for 2 minutes.
Small Eppendorf cups were filled with the extraction solution and were frozen immediately at -20~C until the adenosine triphosphate (ATP) extracted was determined by bioluminescence. The determination was carried out as follows: 100 ~l of reagent mix (bioluminescence test CLS II, BOEHRINGER MANNHEIM (GmbH) were introduced into a transparent tube of polycarbonate, and the light pulses were integrated over a period of 10 seconds in a LUMAT LB9501 light pulse measuring instrument (Laboratorien Prof. Berthold GmbH, 75323 Bad Wildbad, Germany). A 100 ~l sample was then added and measured again. The relative light units (RLU) were obtained by subtraction of the light pulses in the reagent mix from the number of light pulses measured in the complete batch. This value was related to the number of bacteria adhered to the film. The conversion factor between the RLU value and the bacterial count was determined by extracting an aliquot of 0.1 ml of the bacteria suspension with 108 cells/ml in 10 ml of *Trade-mark O.Z. 5178 hot TRIS/EDTA and then determining the ATP content.
The conditions for coating the various polymer substrates with the NCO-reactively modified copolymers and the results of the measurements of the primary bacterial adhesion are summarized in the following Table 2. It can be seen that the primary bacterial adhesion on the polymer substrates coated according to the invention is about one order of magnitude lower than that on the un-coated substrates.
- 17a -O.Z. 5178 . CA 02241380 1998-06-22 ~ o co C âe 8 ~ 8 ~e ~ 8 u, (o ~ ~ 0 0 . o , OO
cn ~r ~ ~~ O ~
z ~ ~r ~ ~'> ~ ~D ~
~ ~ ~u~ ~ ~ D ~ ~--D
_ _ ~o ~ 2 ~ ~ o c cn cn o o ~ ~
E c E~q~ ~ ~ ~ = D
~ F ~ ~ a ," ~ E q~ a~
O , _ ~ ~ ~, ~ ~ c ~
}- ~ 8C 5 ~ .8 ~ 7 ' 0 , ~a . 3 a . 3 .. .. ~ a~
., c - E
-- ~ -- o z z . ~~ . 8 L ~ . ~ ~ ~ ~
I I .
. o O O
' a ~ a c c ~_ , s , "~ s , ~ o c ~ ~
~~ E O
t ~ ~ Y ~ ~ E L
o o D ~ ~ ~ b ~ ~ ~ --~ = ~ ~ o ~
,. ~ .7 . ~ ~
O.Z. 5178
i xamples which may be ~l~erltioned are ethylene ~Iycol, propylene giycol, 3 0 1 ,4butanediol, 1 ,6~exanediol, ~ i, l ,etl ,ylolpropane, aminoell ,anol, N- methylaminoethanol, ethylenediamine, propylenediamine, O.Z. 5178 hexamethylenediamine and diethylenetriamine. As a result of the reaction, an NC0-reactively modified primary copolymer in which the NC0-reactive groups are located in side chains which are bonded via carboxylic ester or carboxamide groups to the skeleton of the primary copolymer consisting of carbon atoms is obtained.
The NCO-reactive groups render covalent fixing (or bonding) of the copolymer to the hydrophilic surface of the substrate possible by reaction with a linking polyisocyanate.
The proportion of NCO-reactive groups of the total functionality of the modified primary copolymer (i.e.
sulfonate, carboxyl and NC0-reactive groups) is preferably about 5 to 20 mol percent. Such a molar proportion renders possible and ensures firm bonding to hydrophilic surfaces with the aid of a polyisocyanate.
Since some carboxyl groups are consumed in the reaction of the primary copolymer with the polyfunctional NC0-reactive compound to give the NC0-reactive copolymer, as explained above, the molar proportion of carboxyl groups of the total functionality of the primary copolymer (ie.
sulfonate plus carboxyl groups) must be correspondingly higher if a certain ratio of carboxyl and sulfonate groups and a certain molar proportion of the NC0-reactive group of the total functionality of the NC0-reactive copolymer are specified. The amount of the polyfunctional NC0-reactive compound employed in this reaction depends on the functionality thereof (bi- or trifunctional), the molar proportion of carboxyl groups in the primary copolymer and the o.z. 5178 desired molar ratio of carboxyl and sulfonate groups in the NCO-reactively modified copolymer according to the invention.
For the NCO-reactive modification, the primary copolymer can be reacted with an amino alcohol, for example ethanolamine, or a diamine, for example hexamethylenediamine, in an autoclave at elevated temperature under increased pressure. The course of the reaction can be monitored by means of potentiometric titration or NMR spectroscopy.
Alternatively, the modification can also be carried out under normal pressure by heating the primary copolymer and the modifying component in a high-boiling solvent, desirably in the presence of an entraining agent for water.
Use of the modified copolymer as a coating composition A solution or emulsion of the NCO-reactively modified copolymer can be used for modification of hydrophilic surfaces, in particular of hydrophilic surfaces of plastic.
In this case, the copolymer is fixed to the surface of the hydrophilic substrate by covalent bonds by means of a polyisocyanate, preferably a diisocyanate. Any known commercially available polyisocyanates are suitable for this, such as hexamethylene diisocyanate (HMDI), tolylene diisocyanate (TDI), methylene 4,4'-bis(phenyl isocyanate) (MDI), methylene 4,4'-bis(cyclohexyl isocyanate) (H-MDI) and isophorone diisocyanate (IPDI). The polyisocyanate reacts with the hydroxyl or amino groups of the copolymer and with hydroxyl or amino groups which are present on the hydrophilic surface of the substrate, to form urethane or urea bridges.
Some polyisocyanate molecules will of course react exclusively O.Z. 5178 with hydroxyl or amino groups of the NCO-reactively modified copolymer, with chain lengthening or linkage. At the abovementioned molar proportions of the NCO-reactive groups of the total functionality of the NCO-reactively modified copolymer according to the invention, however, the desired fixing to the substrate surface always takes place to an adequate extent.
Surprisingly, it has been found that the co-use of a chain-lengthen;ng agent during bonding of the NCO-reactively modified copolymer according to the invention leads to a higher concentration - detectable by means of ESCA - bioactive groups on the substrate and thus to an intensified action.
Chain-lengthening agents are compounds with as a rule terminal NCO-reactive groups, such as hydroxyl or amino groups.
Particularly suitable compounds are, for example, diamines, amino alcohols, and diols, in particular polyalkylene glycols having (where appropriate mean) molecular weights of about 100 to 3000.
If the NCO-reactively modified copolymer is present as a solution or emulsion in a aqueous medium or another medium which is reactive with NCO
- lOa -O.Z. 5178 CA 0224l380 l998-06-22 groups, the isocyanate groups of the polyisocyanate must first be blocked (or masked). This is effected in the customary manner with compounds which add onto the NCO groups at low temperatures, such as 20 to 60~C, and are split off again at higher temperatures. Such compounds are, for example, s methyl ethyl ketoxime and ~aprolactam. A particularly suitable polyisocyanate for use in aqueous systems is, for example, isophorone diisocyanate (IPDI) blocked with methyl ethyl ketoxime. If the copolymer is present as a solution or emulsion in a non-aqueous medium which is not reactive with NCO groups, for example in dimethylformamide, a non-blocked 10 polyisocyanate can be used, for example IPDI again, or hexamethylene diisocyanate (HDI), methylene 4,4'-~is(phenyl isocyanate, ~JlDI), methylene 4,4'-bis(cyclohexyl isocyanate) (H-MDI) or tolylene diisocyanate (TDI).
The substrates of plastic, the surfaces of which are modified with the copolymer accordin~ to the invention, can be homo- or copolymefs which are 15 h~dlopl,ilicorhyd,opl,ilized in nature, as explained below, i.e. carry hydroxyl groups and/or amino groups on the surface. Hydrophilic and hydrophilized (co)polymers are desiynated here in com",on as hydrophilic. The base (co)palymers which are sl ~it~h!e in principle include, for example, polyolefins, such as polyethylene, polypropylene, polyisobutylene, polybutadiene, 20 palyisoprene, naturally occurring rubbers and polyethylene~o~ropylene;
halogen~ontaining polymers, such as polyvinyl chloride, polyvinylidene ~lol ide, poly~ ropre,~e, polytetrafluoroethylene and polyvinylidene fluoride; polymers and copolymers of vinylaromatic monomers, such as polystyrene, polyvinyltoluene, polystyrene~o-vinyltoluene, polystyrene-co-2 5 acrylonitrile, and polystyrene~obl ~t~iene-co-acrylonitrile; polycondensates, for example polyesters, such as palyethylene terephthalate and polybutylene tefe~.htl,alale; poly~l,idPs, such as polycaprolactam, polylaurolactam and the polyconde"sala of adipic acid and he~ca,l,aU ,~lenediamine; polyether-~lock amides, for example of laurolactam or caprolactam and polyethylene glycoi 3 o having on average 8, 12 or 16 ethoxy groups; and furthermore poly~ tl,anesl polyethers, polyc~,~o"ales, polysulfones, polyether-ketones, polyester-amides and-imides, polyacrylonitrile and polyacrylates and Illethdcrylates.
-- 1 1 _ O.Z. 5178 If the polymers or copolymers are not sufficiently hydrophilic, they must be hydrophilized. This is the case if the contact angle of water at 25~C, measured by the method of R.J. Good et al., Techniques of Measuring Contact Angles in Surface and Colloid Sciences, Volume 11, Plenum Press New York, N.Y., 1979, is ~30~. Even if this condition is met, an additional hydrophilization improves the adhesion of the NCO-reactive polymer applied.
A whole range of methods are available for the hydrophilization. Thus, monomers containing hydroxyl sroups, such as hydroxyethyl (meth)acrylate or hydroxybutyl (meth)acrylate, can be grafted onto a polymeric substrate surface ~y a radiation-induced reaction . Instead of using nDna~rs, a c~olyrer ~taining ~ly~xyl groll~s can also ~e ryldLLe~ anto the dl~ surfaoe.
Such copolymers can further~,ore be applied to the substrate surface in the customary manner, for example by spraying, dipping or spin coating with soiutions of the copolymers. Polymers or copolymers ~hich are not s~fficiently hydrophilic can furthermore be hydrophilized by treatment with argon plasma or irradiation with UV rays of 100 to 400 nm. Treatment with a~"."o"ia ~las",a achieves not only hydrophilization but, by introduction of amino groups, additional bonding possibilities and physiological effects.
2 o Finally, e~c~ ,;ng with strong acids, such as sulfuric acid, hydrochloric acid and nitric acid, or bases, such as alkali metal hydroxides, also leads to an adequate hydrophilization of hydrophobic polymers or cop~lymers.
The hydrophilic or hydrophilized substrate surfaces are coated in the clJslollld~ c~ " ,er, for e~a"~le by cli~p;"g, spraying or spin coating, with the solution or emulsion of the NC0-reactively modified copolymer accordi,lg to the invention, which comprises a polyisocyanate, which is blocked if apyro~rhte. After evaporali,lg the solvent and, if approp, iate, splitting off the blocl<ing agent, fixing of the copolymer to the sul~ ate surface takes place at 120 to 150~C. This temperature is expediently maintained for 10 seconds to 5 minutes, to give a ~e"~ically bonded coating which not infrequently fails more cohesively (i.e. in itself) than adhesiveiy (i.e. at the interfaces). The coating cannot be detached selectively from the substrate of plastic using sclvents, which corresponds to covalent bondiny to the surface .hereof.
O.Z. 5178 In one variant of the coating process, the hydrophilic or hydrophilized substrate surface is first treated with the polyisocyanate, which is blocked if appropriate, in order to fix the polyisocyanate to the surface by means of one of its NCO groups, and the solution or emulsion of the NCO-reactively s modified copolymer is then applied to the pretreated area, the hydroxyl or amino groups of said copolymer reac~ing with the remaining NCO groups of the polyisocyanate.
6. Products according to the invention Products, such as devices, equipment and other objects, having surfaces 10 co"~, ,lateiy or partly modified according to the invention are suitable for many uses in which it is important to avoid or suppress adhesion and growth of bacteria. ~hey are thus suitable, inter alia"'or hygiene, industrial, foodstuffsand bioengineering purposes, such as have been described by way of example above. The objects are preferably s~litable for medical uses, 15 especially if bacteria-repellent properties and compatibility with blood are simultaneously ir~ o~lan~. However, the advantageous properties of the objects according to the invention also manifest themselves in contact with body fluids other than blood, such as Iymph, or with tissue. Medical uses are, for exa""~le, those as Iymph drainages, wound dressings, tubes, stents, 20 heart valves, membranes, blood bags or as catheters, for example for peritoneal dialysis.
The following examples are intended to illustrate the invention further, but not to limit its scope as presented in the patent claims.
Examples 1 to 4 25 Preparation of the primary copolymer 200 ml of a 1 M solution of maleic acid in water were mi~d with 200 ml of a 1 M solution of sodium styrene sulroi,ate in water. rhe reaction mixture ~as provided with 1 mol~/O, based on the total amount of monomers, of potassium ~IUAi~ ff~'' as an initiator, and nitrogen ~s passed U~ for 15 minutes.
O,Z. 5178 CA 0224l380 l998-06-22 The batch was heated to 60~C and stirred under a nitrogen a~-~sphere for 4 hours. The reacticn nixture WRS then stirred into eth~n~l, the oopolymEr precipitating out.
Polymer-analogous conversion of the primary copolymer into NCO-5 reactive copolymers (i) With ethanolamine in an autoc~ave (Examples 1 to 3) In each case 60 9 of the primary copolymer were L~a~ed with the ccn4~nl~lLs shown in Table 1 and under the conditions shown there in a 200 ml autoclave. The conversion was determined by potentiometric determination lo of the residual acid.
O,Z, 5178 Table 1 Example 1 Example 2 Example 3 Acid units of the 2.768 2.768 2.768 copolymer (mmol) NaOH (mmol) 1.384 - -Ethanolamine (mmol) 1.384 2.768 2.768 Water (g) 29.9 38.0 36.0 Reaction time (hours) 10 10 10 Temperature (~C) 140 180 180 Pressure (bar) 3.7 9.9 9.9 Conversion (%) 29.8 79.4 92.2 (ii) With ethylene glycol under normal pressure (Example 4) 60 g of the copolymer were dissolved in 600 ml of ethylene glycol and 600 ml of ethanol (as an entraining agent for the water of reaction). The mixture was heated at 100~C
for 6 hours, while stirring. After in each case 0.5 hour, the ethanol/water mixture which had distilled off was replaced with ethanol (250 ml in total). The volatile portions were then distilled off under reduced pressure (20 mbar) at a temperature up to 120~C. The residue was washed twice with acetone and dried. The conversion, according to Karl-Fischer titration, was 85%.
Modification of hydrophilic polymer surfaces with NCO-reactive copolymers by means of polyisocyanates To fix the NCO-reactive copolymers from Examples 1 to 4 on various polymer substrates, the polyisocyanate components and the NCO-reactive copolymers were dissolved in a suitable solvent and applied to the surface of the polymer substrate by dipping. The solvent was then evaporated and the o.z. 5178 NC0-reactive copolymer was fixed to the polymer substrate by heating. To remove residual monomers and oligomers, the coated substrate was washed with water with a temperature of 60~C.
The coating was detected by means of ESCA
measurements. It was detectable with the aid of the changed elemental composition compared with the non-coated polymer substrates, and in particular by the sulfur added.
Determination of the Primary bacterial adhesion under static conditions An overnight culture of the bacteria strain Klebsiella pneumoniae in yeast extract-peptone-glucose nutrient medium (1%+1%+1%) was centrifuged off and take up again in phosphate-buffered saline (=PBS; 0.05 M KH2P04, pH
7.2 + 0.9% NaCl). The mixture was diluted to a cell concentration of 108 cells/ml with PBS buffer. The suspended bacteria were brought into contact for 3 hours with the piece of film to be investigated. For this, circular pieces of film coated on both sides and having a diameter of 1.6 cm (=4.02 cm2) were pricked onto a dissecting needle and shaken with the cell suspension. Films coated on one side were clamped in the form of a circular, flat disk of 4.5 cm diameter with a supporting membrane of flexible PVC 2-3 cm thick into a membrane filter apparatus. The cell suspension was poured onto the side facing upwards, with the coating to be tested, and the system was shaken for 3 hours. The membrane filter apparatus must be tight, i.e. no cell O.Z. 5178 suspension must flow out through leaking cells.
At the end of the contact period, the bacteria suspension was sucked off with a water pump and, for washing, the pieces of film were shaken with 20 ml of sterile PBS
solution in a 100 ml glass beaker for 2 minutes. The piece of film was dipped into sterile PBS solution again and then extracted in 10 ml of heated TRIS/EDTA (0.1 M trishydroxy-ethylaminomethane, 4 mM ethylenediaminetetraacetic acid, brought to pH 7.8 with HCl) in a boiling water bath for 2 minutes.
Small Eppendorf cups were filled with the extraction solution and were frozen immediately at -20~C until the adenosine triphosphate (ATP) extracted was determined by bioluminescence. The determination was carried out as follows: 100 ~l of reagent mix (bioluminescence test CLS II, BOEHRINGER MANNHEIM (GmbH) were introduced into a transparent tube of polycarbonate, and the light pulses were integrated over a period of 10 seconds in a LUMAT LB9501 light pulse measuring instrument (Laboratorien Prof. Berthold GmbH, 75323 Bad Wildbad, Germany). A 100 ~l sample was then added and measured again. The relative light units (RLU) were obtained by subtraction of the light pulses in the reagent mix from the number of light pulses measured in the complete batch. This value was related to the number of bacteria adhered to the film. The conversion factor between the RLU value and the bacterial count was determined by extracting an aliquot of 0.1 ml of the bacteria suspension with 108 cells/ml in 10 ml of *Trade-mark O.Z. 5178 hot TRIS/EDTA and then determining the ATP content.
The conditions for coating the various polymer substrates with the NCO-reactively modified copolymers and the results of the measurements of the primary bacterial adhesion are summarized in the following Table 2. It can be seen that the primary bacterial adhesion on the polymer substrates coated according to the invention is about one order of magnitude lower than that on the un-coated substrates.
- 17a -O.Z. 5178 . CA 02241380 1998-06-22 ~ o co C âe 8 ~ 8 ~e ~ 8 u, (o ~ ~ 0 0 . o , OO
cn ~r ~ ~~ O ~
z ~ ~r ~ ~'> ~ ~D ~
~ ~ ~u~ ~ ~ D ~ ~--D
_ _ ~o ~ 2 ~ ~ o c cn cn o o ~ ~
E c E~q~ ~ ~ ~ = D
~ F ~ ~ a ," ~ E q~ a~
O , _ ~ ~ ~, ~ ~ c ~
}- ~ 8C 5 ~ .8 ~ 7 ' 0 , ~a . 3 a . 3 .. .. ~ a~
., c - E
-- ~ -- o z z . ~~ . 8 L ~ . ~ ~ ~ ~
I I .
. o O O
' a ~ a c c ~_ , s , "~ s , ~ o c ~ ~
~~ E O
t ~ ~ Y ~ ~ E L
o o D ~ ~ ~ b ~ ~ ~ --~ = ~ ~ o ~
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O.Z. 5178
Claims (25)
1. An NCO-reactively modified copolymer which comprises (a) at least one monomer containing sulfonate groups, (b) at least one monomer containing carboxyl groups and (c) at least one type of NCO-reactive group introduced after the copolymerization.
2. The NCO-reactively modified copolymer according to claim 1, wherein monomer (a) is vinylsulfonic acid, styrenesulfonic acid or methallylsulfonic acid, or a salt thereof.
3. The NCO-reactively modified copolymer according to claim 2, wherein the monomer (a) is sodium styrenesulfonate or sodium vinylsulfonate.
4. The NCO-reactively modified copolymer according to claim 1, 2 or 3, wherein monomer (b) is selected from the group consisting of acrylic acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, methylmaleic acid, dihydroxymaleic acid, crotonic acid, isocrotonic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid, methyl(meth)acrylate, ethyl(meth)acrylate, (meth)acrylonitrile and (meth)acryamide.
5. The NCO-reactively modified copolymer according to claim 4, wherein the monomer (b) is acrylic acid, methacrylic acid or maleic acid.
6. The NCO-reactively modified copolymer according to any one of claims 1 to 5, which comprises, in addition to monomers (a) and (b), at least one further monomer (d) selected from the group consisting of a vinyl ketone, a vinylaromatic monomer, an olefin, a diolefin, a vinyl ester and N-vinylpyrrolidone, at an amount up to 30 percent by weight, based on the sum of monomers (a), (b) and (d).
7. The NCO-reactively modified copolymer according to claim 6, wherein monomer (d) is selected from the group consisting of vinyl methyl ketone, vinyl butyl ketone, styrene, .alpha.-methylstyrene, vinyltoluene, ethylene propylene, 1-butene, 1-octene, butadiene, isoprene, vinyl acetate, vinyl propionate and N-vinylpyrrolidone.
8. The NCO-reactively modified copolymer according to any one of claims 1 to 7, wherein the NCO-reactive groups are hydroxyl or primary or secondary amino groups.
9. The NCO-reactively modified copolymer according to claim 8, wherein the NCO-reactive group is introduced into the copolymer by reaction with a polyol, an amino alcohol or a polyamine.
10. The NCO-reactively modified copolymer according to claim 9, wherein the polyol, amino alcohol or polyamine is selected from the group consisting of ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, trimethylolpropane, aminoethanol, N-methylaminoethanol, ethylenediamine, propylenediamine, hexamethylenediamine and diethylenetriamine.
11. The NCO-reactively modified copolymer according to any one of claims 1 to 9, wherein the molar ratio of carboxyl groups to sulfonate groups is 0.1 to 10.
12. The NCO-reactively modified copolymer according to any one of claims 1 to 11, wherein the proportion of NCO-reactive groups of the total functionality of the NCO-reactively modified copolymer is 5 to 20 mol%.
13. The NCO-reactively modified copolymer according to any one of claims 1 to 12, which comprises maleic acid, sodium styrenesulfonate and ethanolamine or ethylene glycol.
14. A process for the preparation of an NCO-reactively modified copolymer as claimed in any one of claims 1 to 13, which comprises polymerizing at least one monomer (a) containing sulfonate groups as defined in any one of claims 1 to 3, and at least one monomer (b) containing carboxyl groups as defined in any one of claims 1 to 5 under free-radical initiation to give a primary copolymer and reacting this with a polyfunctional NCO-reactive compound as defined in claim 8, 9, and 10 to give an NCO-reactively modified copolymer.
15. A process for the modification of a hydrophilic surface in which an NCO-reactively modified copolymer according to any one of claims 1 to 13 is bonded covalently to the surface by reaction with a polyisocyanate.
16. The process according to claim 15, wherein the reaction takes place in an aqueous medium and the polyisocyanate is a blocked polyisocyanate.
17. The process according to claim 16, wherein the blocked polyisocyanate comprises a residue of methyl ethyl ketoxime or .epsilon.-caprolactam.
18. The process according to claim 15, 16, or 17, wherein the polyisocyanate or blocked polyisocyanate comprises isophorone diisocyanate, hexamethylene diisocyanate, methylene 4,4'-bis(phenyl isocyanate), methylene 4,4'-bis (cyclohexyl isocyanate) or tolylene diisocyanate, or a residue thereof, respectively.
19. The process according to any one of claims 15 to 18, wherein the reaction takes place in a non-aqueous medium which is not reactive with NCO groups and the polyisocyanate is a non-blocked polyisocyanate.
20. The process according to any one of claims 15 to 19, wherein the hydrophilic surface is produced on a plastic substrate by a treatment selected from the group consisting of argon plasma treatments, irradiation with UV rays of 100 to 400 nm, ammonia plasma treatment, and etching with a strong acid or a strong base.
21. A product comprising a surface completely or partly modified by a process as defined in any one of claims 15 to 20 for medical use.
22. A product according to claim 21, which is a lymph drainage, wound dressing, tube, stent, heart valve, membrane, blood bag or catheter.
23. An NCO-reactively modified copolymer, which comprises:
a primary copolymer portion produced by a free radical copolymerization and comprising units of:
(a) at least one olefinically unsaturated monomer having a sulfonate group, (b) at least one olefinically unsaturated monomer having a carboxyl group, and (d) at least one olefinically unsaturated monomer having no functional group or a functional group effective to modify bioactivity, processing properties or compatibility with a substrate of the NCO-reactively modified polymer in an amount of 0 to 30% by weight based on the total amount of the monomers (a), (b) and (d), and a portion introduced by reacting a part of the carboxyl groups of the primary copolymer portion with a polyfunctional NCO-reactive compound having at least two carboxyl-reactive and NCO-reactive groups selected from the class consisting of a hydroxyl group, a primary amino group and a secondary amino group to form a carboxylic ester or carboxamide group and to introduce at least one NCO-reactive group selected from the class mentioned above in a side chain bonded via the carboxylic ester or carboxyamide group to a carbon skeleton of the primary copolymer portion, wherein the NCO-reactively modified copolymer has a molar ratio of the sulfonate group to the carboxyl group of 0.1 to 10.
a primary copolymer portion produced by a free radical copolymerization and comprising units of:
(a) at least one olefinically unsaturated monomer having a sulfonate group, (b) at least one olefinically unsaturated monomer having a carboxyl group, and (d) at least one olefinically unsaturated monomer having no functional group or a functional group effective to modify bioactivity, processing properties or compatibility with a substrate of the NCO-reactively modified polymer in an amount of 0 to 30% by weight based on the total amount of the monomers (a), (b) and (d), and a portion introduced by reacting a part of the carboxyl groups of the primary copolymer portion with a polyfunctional NCO-reactive compound having at least two carboxyl-reactive and NCO-reactive groups selected from the class consisting of a hydroxyl group, a primary amino group and a secondary amino group to form a carboxylic ester or carboxamide group and to introduce at least one NCO-reactive group selected from the class mentioned above in a side chain bonded via the carboxylic ester or carboxyamide group to a carbon skeleton of the primary copolymer portion, wherein the NCO-reactively modified copolymer has a molar ratio of the sulfonate group to the carboxyl group of 0.1 to 10.
24. The copolymer according to claim 23, which contains the NCO-reactive group in an amount of 5 to 20 mol percent based on the total amount of the sulfonate group, the carboxyl group and the NCO-reactive group.
25. A plastic article having a surface which, before being coated, has a hydroxyl or amino group and has been coated with the copolymer as defined in claim 23 or 24 such that the copolymer is fixed by covalent bonds by means of a polyisocyanate to the surface.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1997126737 DE19726737A1 (en) | 1997-06-24 | 1997-06-24 | Blood-compatible and bacteria-repellent NCO-reactive modified copolymer |
| DE19726737.8 | 1997-06-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2241380A1 true CA2241380A1 (en) | 1998-12-24 |
Family
ID=7833463
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2241380 Abandoned CA2241380A1 (en) | 1997-06-24 | 1998-06-22 | Blood-compatible and bacteria-repellent nco-reactively modified copolymer |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0887356A1 (en) |
| JP (1) | JPH11124406A (en) |
| CA (1) | CA2241380A1 (en) |
| DE (1) | DE19726737A1 (en) |
| NO (1) | NO982931L (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11871745B2 (en) | 2021-03-08 | 2024-01-16 | Ka Shui Plastic Technology Co. Ltd. | Bacteria repellant polymer composites |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2002227202A1 (en) * | 2000-12-05 | 2002-06-18 | Quest Medicine, Inc. | The use of polymers for inactivating pathogens |
| CN115607750B (en) * | 2021-07-16 | 2024-02-23 | 中国科学院宁波材料技术与工程研究所 | In-situ anticoagulation modified medical PVC material, and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3917573A (en) * | 1972-09-28 | 1975-11-04 | American Cyanamid Co | Process for the preparation of water emulsifiable anionic resins and the resins thus produced |
| JPH0639495B2 (en) * | 1989-07-31 | 1994-05-25 | 東洋製罐株式会社 | Process for producing antibacterial polymer and use thereof |
-
1997
- 1997-06-24 DE DE1997126737 patent/DE19726737A1/en not_active Withdrawn
-
1998
- 1998-05-05 EP EP98108162A patent/EP0887356A1/en not_active Withdrawn
- 1998-06-22 CA CA 2241380 patent/CA2241380A1/en not_active Abandoned
- 1998-06-23 NO NO982931A patent/NO982931L/en not_active Application Discontinuation
- 1998-06-24 JP JP10177393A patent/JPH11124406A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11871745B2 (en) | 2021-03-08 | 2024-01-16 | Ka Shui Plastic Technology Co. Ltd. | Bacteria repellant polymer composites |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH11124406A (en) | 1999-05-11 |
| NO982931D0 (en) | 1998-06-23 |
| DE19726737A1 (en) | 1999-01-07 |
| EP0887356A1 (en) | 1998-12-30 |
| NO982931L (en) | 1998-12-28 |
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