CA2241374A1

CA2241374A1 - Blood-compatible and bacteria-repellent copolymer

Info

Publication number: CA2241374A1
Application number: CA 2241374
Authority: CA
Inventors: Christine Anders
Original assignee: Huels AG
Current assignee: Huels AG
Priority date: 1997-06-24
Filing date: 1998-06-22
Publication date: 1998-12-24
Also published as: NO982930D0; DE19726738A1; NO982930L; EP0887363A1; JPH11124416A

Abstract

Disclosed is a copolymer having units of (a) at least one monomer containing a sulfonic acid or sulfonate group, (b) at least one monomer containing a carboxyl or carboxylate group and (c) at least one monomer containing an NCO-reactive group. The copolymer may have up to 70 mol%, based on the total of monomers (a), (b) and (c) of units of one or more other monomers having either a different functionality to that of the monomers mentioned or no functionality. The copolymer can be covalently bonded to a hydrophilic surface of a polymer substrate by reaction with a polyisocyanate. Also disclosed is an article having a surface modified in this way useful for medical, hygiene, industrial, foodstuffs or bioengineering purposes.

Description

Blood-Compatible and Bacterla-Repellent Copolymer FIELD OF THE INVENTION
The present inventlon relates to a blood-compatlble and bacterla-repellent copolymer, a process for lts preparatlon, a process for modlfylng a hydrophlllc surface wlth thls copolymer, and an artlcle havlng a surface modlfled ln thls way and lts use for varlous purposes descrlbed below, ln partlcular for medlcal purposes.
PRIOR ART
The colonlzatlon and multlpllcatlon of bacterla on surfaces ls as a rule an undeslrable phenomenon whlch ls often assoclated wlth adverse consequences. Thus, in the drinking water and drlnks lndustry, bacterlal populatlons may lead to a reductlon ln quality to an extent that lt may endanger health.
Bacterla on or in packaglng often cause decay of foodstuffs or even cause infectlons ln the consumer. In bloenglneerlng plants whlch are to be operated under sterlle condltions, bacterla forelgn to the plant represent a conslderable risk to the process. Such bacteria can be introduced with raw materlals or remaln ln some or all components of the plant lf sterlllzatlon ls not complete. By adheslon, parts of the bacterla populatlon can wlthdraw from the normal exchange of llquld durlng rlnslng and cleanlng, and multlply ln the system.
It ls known that bacterla colonles form ln water treatment plants (for example for desallnatlon through membranes) or else ln contalners whlch are fllled wlth O.Z. 5187 dissolved or liquld undlluted organlc substances. Such mlcroblal occupatlon can lead to a conslderable extent to blockage and/or corroslve destructlon of the plant.
Protectlon against adheslon and spread of bacterla ln food, in care, and here in particular in the care of the elderly, and in medlclne ls of partlcular lmportance. In mass caterlng or selllng of drlnks, conslderable risks exist if disposable utensils are not used, ln order to avold waste, and reusable utenslls are not cleaned adequately. The harmful spread of bacterla in hoses and plpes whlch carry foodstuffs ls known, as ls bacterial multiplicatlon ln storage contalners 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, such as, for example, in public means of transport, hospitals, telephone booths, schools and, in particular, in public toilets.
In the 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 ob~ects and equipment during medical examinations, treatments and operations requires particular attention, especially lf such equipment or obiects 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 life-threatening risk to the patlent.

O.Z. 5187 It has already been attempted ln varlous ways to suppress the colonlzatlon and spread of bacterla on surfaces.
In J. Mlcroblol. Chemoth. 31 (1993), 261-271, S.E. Tebbs and T.S.J. Elllott descrlbe palnt-llke coatlngs wlth quaternary ammonlum salts as components havlng an antlmlcroblal actlon.
It ls known that these salts are dlssolved out of the coatlng materlal by water, aqueous or other polar medla and by body flulds, and thelr actlon ls thus only of short duratlon. Thls equally applles to the lncorporatlon of sllver salts lnto coatlngs, as descrlbed ln WO 92/18098.
T. Ouchl and Y. Ohya descrlbe ln Progr.Polym.Scl. 20 (1995), 211 et seq. the lmmoblllzatlon of bacterlcldal actlve compounds on polymer surfaces by covalent bondlng or lonlc lnteractlons. In such cases, the germlcldal actlons are often slgnlflcantly reduced compared wlth the pure actlve compound.
Heteropolar bonds often prove to be not sufflclently stable.
Furthermore, the destructlon of the germs as a rule leads to undeslrable deposlts on the surfaces, whlch mask further bacterlcldal actlon and form the basls for a subsequent bacterla populatlon.
W. Kohnen et al. report ln ZBl. Bakt. Suppl. 26, Gustav Flscher Verlag, Stuttgart-Jena-New York, 1994, pages 408 to 410 that the adheslon of Staphylococcus epldermldls on a polyurethane fllm ls reduced lf the fllm ls pretreated by a glow dlscharge ln the presence of oxygen and then grafted wlth acryllc acld.
In the case of ob~ects for use for medlcal purposes, l.e. for examlnatlons, treatments and operatlons, as descrlbed O.Z. 5187 above, not only the bacterla-repellent propertles play a role, but also compatlbillty with blood, i.e. antithrombogenic propertles which are as pronounced as posslble, is also important. According to the international patent appllcation 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 llsted as one of the sultable plasma-formlng gases. J.-C. Lln et al. descrlbe ln Blomaterials 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-formlng gas. The authors report that the surfaces modlfied by SO2 plasma contalned sulfonate groups, were hlghly hydrophlllc and were thrombogenlc to a greater degree than the untreated surfaces.
The authors suspect that this is due to the combined action of surface chemlstry, that is to say of the sulfonatlon, and the hydrophillcity of the surfaces.
SUMMARY OF THE INVENTION
A principle ob~ect of the present invention ls to provide a durably blood-compatlble and bacterla-repellent polymer which can be flxed to a surface of a polymer substrate by a covalent chemlcal bond, and therefore permanently, without loss of actlon and whlch is not inactivated by bacteria which have been killed or by other deposits.
It has been found, surprisingly, that a partlcular copolymer ls effectlve to achleve thls ob~ect. The copolymer comprises monomer units of (a) at least one monomer containing O.Z. 5187 a sulfonic acld or sulfonate group, (b) at least one monomer contalnlng a carboxyl or carboxylate group and (c) at least one monomer contalnlng an NCO-reactlve group.
The lnventlon also relates to a process for the preparatlon of the copolymer, preferably lnltlated by free radlcals mentloned hereln, by polymerlzatlon of the monomers mentloned above.
In a partlcular embodlment of the process, the copolymer mentloned, whlch ls already NCO-reactlve because of lts content of monomer (c), ls reacted wlth a polyfunctlonal NCO-reactlve compound ln a polymer-analogous reactlon, as a result of whlch a further NCO-reactlve group is lntroduced.
The invention also relates to the copolymer with the further NCO-reactive group which is obtainable by this particular embodiment of the process.
The inventlon also relates to a process for the modlfication of a hydrophillc surface of a polymer substrate in which the copolymer according to the lnvention, which may have been reacted with a polyfunctional NCO-reactive compound as mentioned, is bonded covalently to the surface by reaction with a polyisocyanate.
Flnally, the lnventlon relates to a product (l.e., shaped artlcle) having a surface modlfled ln thls way, and to lts use for hyglene, industrial, foodstuffs and bioengineerlng purposes and, ln particular, for medical purposes.
The copolymer according to the lnvention reduces the adhesion and multlplication of bacteria to a high degree, even over a long period of tlme. Thls actlon ls not impaired by O.Z. 5187 the fixing to a polymer substrate via covalent bonds.
Bacterla affected by this action are, lnter alia, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyoqenes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Escherlchia coll. If it is important for the copolymer to be free from monomers or oligomers which are capable of migration, ln particular for medical uses, they can be removed by slow reprecipitation. For this purpose the copolymer is dissolved in water and the solution is stirred slowly into ethanol, as a result of which the copolymer is preclpitated. A fixed copolymer that is in oligomer- and monomer-free form can be obtained by extraction wlth water.
The physical and chemical properties of the substrate material remain virtually unchanged after the modification of the surface. Undesirable side effects due to exogenous substrates liberated or due to bacteria which have been kllled do not occur.
DESCRIPTION OF PREFERRED EMBODIMENTS
1. Copolymers according to the invention and their preparation The copol~ymers accordlng to the invention comprises units of monomers (a), (b) and (c), which are olefinically unsaturated and can be polymerlzed in a reaction initiated by free radicals to give the copolymer, i.e., a terpolymer.
Examples of suitable monomers (a) which may be mentioned are vinylsulfonic acid, methallylsulfonic acid, 2-acrylamido-2-methyl-l-propanesulfonic acid and, in particular, 4-styrene-sulfonic acld, as well as alkall metal salts thereof, in ~.Z. 5187 particular the sodlum salts.
Sultable monomers (b) are, for example, acrylic acld, methacrylic acid, 4-vlnylsalicyllc acld, ltaconic acid, vlnylacetlc acld, clnnamlc acld, 4-vlnylbenzolc acid, 2-vlnylbenzolc acld, crotonlc acld, isocrotonic acld, methylmalelc acld, dlhydroxymalelc acld, fumarlc acld, methylfumarlc acld, dimethylfumaric acid, allylacetlc acld and, ln partlcular, malelc acld, as well as alkall metal salts thereof, and agaln ln partlcular the sodlum salts.
Instead of sulfonlc acld or sulfonate groups, or carboxyl or carboxylate groups, the monomers (a) and (b) employed for the polymerlzatlon can lnltlally contaln groups derlved therefrom for example ester and amlde groups, and, where carboxyl groups are concerned, nltrlle or anhydrlde groups, whlch are converted lnto sulfonlc acld or carboxyl groups by hydrolysls ln the customary manner after the polymerization. Furthermore, monomers containing sulfonlc acld groups and/or carboxyl groups can be used as startlng substances ln the polymerlzation, and all or some of the acid groups can subsequently be neutrallzed, for example wlth sodium hydroxide. In the case of partlal neutrallzation, acid groups and salts thereof are present slde by slde.
Suitable monomers (c) include, in particular, those contalnlng a hydroxyl group, an epoxy group or a prlmary or secondary amlno group. These lnclude hydroxyalkyl acrylates and methacrylates, such as hydroxyethyl acrylate, the partlcularly preferred hydroxyethyl methacrylate (HEMA), 4-hydroxybutyl acrylate, 4-hydroxybutyl methacrylate, 3-O.Z. 5187 hydroxypropyl acrylate, 3-hydroxypropyl methacrylate polyalkylene glycol monoacrylates and monomethacrylates;
unsaturated alcohols or phenols, such as allyl alcohol, 2,3-butadien-l-ol, 2-butene-1,4-diol, 3-methylallyl alcohol and o-, m- and p-hydroxystyrene; and dihydroxymaleic acid, which at the same time is a monomer (b). Examples of monomers (c) containing an amino group which may be mentioned are, for example, 4-aminostyrene and diallylamine. Examples of monomers (c) containlng an epoxy group lnclude glycldyl acrylate and glycldyl methacrylate.
It ls of course posslble to employ corresponding mixtures instead of an indlvldual monomer (a), (b) or (c), for example a mixture of sodium styrenesulfonate and sodium vinylsulfonate, instead of sodlum styrenesulfonate by ltself.
In some cases, it ls possible and may be preferred to modlfy the biological and/or processing propertles of the copolymer by up to 70 mol%, based on the sum of monomers (a), (b) and (c), of monomers (d) havlng a dlfferent or no functionality, for example in order to increase the solubility in solvents other than water. Examples of such monomers which may be mentioned are vinyl esters, such as vinyl acetate and vlnyl propionate; vinyl ketones, such as vlnyl methyl ketone and vinyl butyl ketone; vinylaromatics, such as styrene and vinyltoluene; olefins, such as l-butene, l-hexene and 1-octene; and (meth)acrylates, such as methyl methacrylate, methyl acrylate and n-butyl acrylate.
Monomers (a), (b), (c) and optionally (d) may be present ln the copolymer as blocks or ln random distribution, O.Z. 5187 dependlng on the reactlon procedure. Of the three functlonal groups of the copolymer, the sulfonlc acld and~or sulfonate and the carboxyl and/or carboxylate groups together glve the deslred blood-compatlble and bacterla-repellent propertles, whlle the NCO-reactlve groups allow covalent flxlng (or bondlng) of the copolymer on the surface of the substrate.
The molar ratlos of the three functlonal groups can vary wlthln wlde llmlts. Carboxyl and/or carboxylate groups and sulfonlc acld and/or sulfonate groups are preferably present ln a molar ratlo of 0.1 to 10, more preferably 0.2 to 10, and ln partlcular 0.2 to 5. The NCO-reactlve groups are preferably present ln an amount of S to 30, ln partlcular 5 to 20 mol~, based on the sum of carboxyl, carboxylate, sulfonlc acld, sulfonate and NCO-functlonal groups.
The polymers may be prepared ln the customary manner by polymerlzatlon of monomers (a), (b), (c) and, optlonally, (d) lnltlated by free radlcals, preferably by a solutlon or emulslon polymerlzatlon. A partlcularly preferred solvent ls water, ln whlch the monomers and also the copolymer generally are readlly soluble. At low contents of monomer (c), the monomers and the copolymer are also at least partly soluble and otherwlse emulslflable ln strongly polar organlc solvents, such as dlmethylformamide, dlmethylacetamide and dlmethylsulfoxlde.
Sultable polymerlzatlon lnltlators are, for example, azonltrlles, alkyl peroxldes, acyl peroxldes, hydroperoxldes, peroxodlsulfates, peroxyketones, peroxyesters and percarbonates, as well as all the customary photolnltlators.

O.Z. 5187 They are as a rule used in amounts of 0.01 to 1.5 mol%, based on the sum of the monomers.
The polymerlzatlon may be inltlated by means of heat, for example by heatlng to 60 to 100~C, or by radlation of approprlate wavelength. It ls posslble, for example, to lnltlally lntroduce a portlon of monomers (a), (b), (c) and optlonally (d) lnto a reactor, to start the polymerization and to introduce the remainder of the monomers as a mlxture lnto the reactor, a temperature of 60 to 90~ preferably being maintained by cooling. A random copolymer is obtained in this manner. If a certain monomer or a proportion thereof is initially introduced into the reactor and the other monomers and, if appropriate, the remaining amount of monomer initially introduced are added in portions, in each case by themselves, a block copolymer is formed. These variants are of course ideally typical limit cases. In practice, merely as a result of the different rate of reaction of the monomers, in the first case, in addition to regions with random distribution, those with predominantly a block structure are also obtained, and in the second case, in addition to the blocks, transition zones with more or less uniform random distribution of the units are also obtained. The distribution of the monomers in the chain has no noticeable influence on the bioactivity of the copolymer.
When the polymerization has ended, a solution or emulsion of the copolymer having solids contents which may be, for example, 40 to 60% by weight is obtained, depending on the proportions of monomers (a), (b), (c) and optionally (d) and O.Z. 5187 on the solvent used. The solutlon or emulsion may be used dlrectly for modlflcatlon of hydrophlllc surfaces, in partlcular hydrophlllc surfaces of plastics. If the copolymer is to be isolated, for example, the solutlon may be poured lnto a solvent ln which the copolymer ls lnsoluble, for example lnto ethanol, and the copolymer may be separated off ln the customary manner.

2. Reactlon of the copolymers accordlng to the inventlon with polyfunctional NC0-reactive compounds As mentioned above, in a particular embodlment of the process, the copolymer according to the lnventlon, whlch ls already NC0-reactive because its proportlon of monomer (c), ls reacted wlth a polyfunctlonal NC0-reactlve compound ln a polymer-analogous reactlon. As a result of thls reactlon a further NC0-reactlve group, partlcularly preferably a hydroxyl or prlmary or secondary amlno group, ls lntroduced. The llnklng denslty durlng subsequent covalent flxlng of the copolymer to a hydrophllic polymer substrate ls lncreased ln thls manner. Copolymers contalnlng carboxyl and sulfonate groups are preferable, above all, for the reactlon. After the reaction, the sulfonate group may be converted into a sulfonic acld group by treatment wlth an acld and an unreacted part of a carboxyl group may be converted lnto a carboxylate group wlth a base, if thls ls deslred.
Sultable polyfunctlonal NC0-reactlve compounds are preferably polyols, such as diols or trlols; amlno alcohols, such as amlno- or N-alkylamlnoalkanols; and polyamlnes, such as dlamines and triamines. Examples which may be mentioned O.Z. 5187 are: ethylene glycol, propylene glycol, 1,4-butanedlol, polyalkylene glycol, 1,6-hexanedlol, trimethylolpropane, amlnoethanol, N-methylamlnoethanol, ethylenedlamlne, propylenedlamlne, hexamethylenedlamlne and dlethylenetrlamlne.
The NCO-reactlve groups are at the same tlme carboxyl-reactlve and react durlng the reactlon wlth carboxyl groups of the copolymer accordlng to the lnventlon to form ester groups or carboxamlde groups, wlth lntroductlon of further NCO-reactlve groups.
Since carboxyl groups are consumed in the modlflcatlon of the copolymer accordlng to the lnventlon by reactlon wlth the polyfunctlonal NCO-reactlve compound, the molar proportlon of the carboxyl group ln the total functlonallty of the non-modlfied copolymer must be correspondlngly hlgher lf a certaln ratlo of a carboxyl or carboxylate group to a sulfonic acid or sulfonate group and a certaln molar proportlon of an NCO-reactlon group ln the total functlonallty of the modlfled copolymer ls lntended. The amount of the polyfunctlonal NCO-reactlve compound employed ln thls reactlon depends on the functlonallty thereof (bl- or trlfunctlonal), the molar proportlon of a carboxyl group ln the non-modlfled copolymer and the desired molar ratio of a carboxyl or carboxylate group to a sulfonlc acld or sulfonate group ln the modlfled copolymer. The proportion of the NCO-reactive group ln the total functlonallty of the modlfled copolymer (l.e. sulfonate, carboxyl and NCO-reactlve groups) ls hlgher than in the case of the non-modifled copolymer and ls preferably about 10 to 50, ln partlcular about 10 to 30 mol O.Z. 5187 percent.
For the NC0-reactlve modlflcatlon, the copolymer according to the invention can be reacted with an amlno alcohol, for example ethanolamlne, or a polyamine, for example hexamethylenedlamlne, in an autoclave at elevated temperature under increased pressure. The course of the reactlon can be monltored by means of potentlometrlc tltratlon or NMR
spectroscopy. Alternatively, the modification can also be carrled out under atmospheric pressure by heating the primary copolymer and a polyol, for example a polyethylene glycol, ln a high-boillng solvent, expediently in the presence of an entralnlng agent for water.

3. Modlfication of hydrophilic surfaces with copolymers according to 1. and 2.
The lnventlon also relates to a process for modlfication of a hydrophilic surface of a polymer substrate, ln whlch a copolymer accordlng to the lnvention, with or without subsequent modificatlon by reactlon wlth a polyfunctional NC0-reactive compound, is bonded covalently to the surface by reaction wlth a polylsocyanate.
In this procedure, the copolymer is fixed to the surface of the hydrophllic substrate by covalent bonds. The polyisocyanate reacts with the NC0-reactlve group of the copolymer and with a hydroxyl group present on the surface of the substrate to form urethane bonds. Urea bridges may be formed in a correspondlng manner from an amlno group on the surface of the substrate. Some of the polyisocyanate molecules of course react exclusively with a hydroxyl group of O.Z. 5187 the copolymer wlth chain lengthenlng or linklng or crossllnklng. Nevertheless, at the stated molar proportions of 5 to 50 mol% of the NC0-reactive group, permanent and flrm bonding of the copolymer to the polymer substrate is achleved.
If the copolymer is present in aqueous solution or emulsion or in another medium which is reactive with NC0 groups, the isocyanate groups of the polyisocyanate must initially be protected (or blocked or masked). This may be done in the customary manner wlth compounds which add onto the NC0 groups at low temperatures, such as 20 to 60~C, and are split off again at higher temperatures. Such blocking compounds are well known in the art and are for example, methyl ethyl ketoxime, acetone oxlme, ~-caprolactam, ethyl acetoacetate, malonlc acid esters, butyl glycolate, diisopropylamine, 3,5-dimethylpyrazole and 1,2,4-triazine. A
partlcularly preferred polyisocyanate for use in a~ueous systems is, for example, isophorone diisocyanate (IPDI) blocked with methyl ethyl ketoxime. If the copolymer is obtained as solutions or emulsions in organic solvents whlch are inert toward NC0 groups, for example in dimethylformamide, a non-blocked polyisocyanate may be used, for example again IPDI or hexamethylene diisocyanate (HDI), 4,4'-methylene-di(phenyl isocyanate) (MDI), the hydrogenation product thereof (H-MDI) or toluene diisocyanate (TDI).
Surprisingly, it has been found that the co-use of a chain-lengthenlng agent durlng bondlng of an NC0-reactlve copolymer according to the invention leads to a higher concentration-detectable by means of ESCA- of bioactive groups O.Z. 5187 on the substrate and thus to an lntenslfled action. Chain-lengthening agents are compounds wlth as a rule termlnal NCO-reactlve groups, such as hydroxyl or amlno groups.
Particularly suitable compounds are, for example, diamlnes, amlno alcohols and dlols, ln partlcular polyalkylene glycols (such as polyethylene glycol) havlng (where appropriate mean) molecular weights of about 100 to 3000, ln amounts of, for example, 10 to 100% by weight, based on the copolymer.

4. Modiflable polymer substrates The polymers of which the surface ls modlfled accordlng to the lnventlon can be homo- or copolymers which are hydrophllic or hydrophlllzed in nature, as explalned below, l.e. carry hydroxyl groups and/or amino groups on the surface. Hydrophilic and hydrophilized (co)polymers are designated here iointly as hydrophilic. The base (co)polymers whlch are suitable in principle include, for example, polyolefins, such as polyethylene, polypropylene, polyisobutylene, polybutadiene, polyisoprene, naturally occurring rubbers and polyethylene-co-propylene; halogen-containing polymers, such as polyvinyl chloride, polyvinylidene chloride, polychloroprene, polytetrafluoro-ethylene and polyvinylidene fluoride; polymers and copolymers of vinylaromatic monomers, such as polystyrene, polyvinyltoluene, polystyrene-co-vinyl-toluene, polystyrene-co-acrylonitrile, and polystyrene-co-butadiene-co-acrylonitrile; polycondensates, for example polyesters, such as polyethylene terephthalate and polybutylene terephthalate;
polyamides, such as polycaprolactam, polyaurolactam and the O.Z. 5187 polycondensate of adipic acid and hexamethylenediamine;
polyether block amides, for example of laurolactam or caprolactam and polyethylene glycol having on average 8, 12 or 16 ethoxy groups; and furthermore polyurethanes, polyethers, polycarbonates, polysulfones, polyether-ketones, polyester-amides and -imides, polyacrylonitrile and polyacrylates and -methacrylates.
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., techni~ues of Measuring Contact Angles in Surface and Colloid Sciences, Volume 11, Plenum Press New York, N.Y., 1979, is ~36~. A whole range of methods are available for the hydrophilization. Thus, monomers containing hydroxyl groups, such as hydroxyethyl (meth)acrylate or hydroxybutyl (meth)acrylate, can be grafted onto a polymeric substrate surface by a radiation-induced reaction. Instead of using monomers, a copolymer containing hydroxyl groups can also be grafted onto the substrate surface. Such copolymers can furthermore be applied to the substrate surface in the customary manner, for example by spraying, dipping or spin coating with solutions of the copolymers. Polymers or copolymers which are not sufflciently hydrophlllc can furthermore be hydrophilized by treatment with argon plasma or irradiation with UV rays of 100 to 400 nm. Other known hydrophilization methods are flaming and corona and ozone treatment. Treatment with ammonla plasma achieves not only hydrophilization but, by introduction of amino groups, O.Z. 5187 additional bonding possibilities and physiological effects.
Finally, etchlng with strong acids, such as sulfurlc acid, hydrochloric acid and nltric acid, or bases, such as alkali metal hydroxides, also leads to an adequate hydrophllizatlon of hydrophobic polymers or copolymers.
The hydrophllc or hydrophilized substrate surfaces are coated in the customary manner, for example by dipping, spraying or spin coating, with the solution or emulsion of the copolymer, which comprises a polyisocyanate, whlch is blocked if appropriate. After evaporatlng the solvent and, lf approprlate, splltting off the blocking agent, fixing of the copolymer to the substrate surface takes place at 120 to 200~C, in particular 160 to 190~C. This temperature is expediently maintalned for 5 seconds to 30 minutes, advantageously 10 seconds to 5 minutes, and a covalently bonded coating which is very resistant to abrasion is then obtained.
In one variant of the coating process, the hydrophlllc or hydrophilized substrate surface is first treated wlth the polyisocyanate, whlch ls blocked lf approprlate, in order to fix the polylsocyanate to the surface by means of one of its NCO groups, and the solution or emulsion of the copolymer is then applied to the pretreated area, the NCO-reactive groups of said copolymer reacting with the remaining NCO groups of the polyisocyanate.

5 . Art icles according to the invent ion Shaped articles having surfaces modifled accordlng to the lnventlon are sultable for O.Z. 5187 , ~ CA 02241374 1998-06-22 many uses for which it is i" ,po, l~t to avoid or suppress adhesion and growth of bacteria. lhey are thus suitable, inter alia, for hygiene, industrial, foodstuffs and bioenyi,~eering purposes, such as have been described by way of example abo\~e. The objects are preferably suitable for medical uses, s especially if bacteria~epellent properties and compatibility with blood are simultaneously importan~ However, the advantageous properties of the objects acoordi"~ to the invention also ",a"irest themselves in contact with body fluids other than blood, such as Iymph, or with tissue. Medical uses are, for ex~",~ l~, those as catheters, Iymph drainages, wound dressings, tubes, 10 stents, heart valves or as hoses 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 The following rllOnOIll~(S were employed:
15 Table 1 - so,- n~G,.~
na."er Abbrcvidlion Sodium 4-styrenesulfonate S1 Sodium methallylsulfonate S2 Sadium vinylsuHonate S3 20 Table 2 - Ct~OH ~--o~ ers :
Nl~no",er Abbrevi~lion Aaylic acid C1 Maleic acid C2 Fumaric acid C3 1~ .1,ac.. ylic acid C4 ~abl~ 3 - OH monomers nG",er I Abbrevidlion il O.~, 5187 Hydroxyethyl " ,eU ,a~ylate H1 Polyethylene glycol 1000-monon~etl,~/l ether H2 ",onol"etl,~c ylate - Glycldyl ,netl,a~yla~e H3 Hydroxyethyl acrylate H4 The copolymers ac~r~i"y to the invention listed in Table 4 were prepared by solution polyme, icdliol ~ under the conditions stated therein. Whether or the extent to which the polymerization had taken place was investigated by means of thin layer ~ .,nalography. The polymers were ~.r~i~ilaled by 10 stirring the poly",eri~dlion mixture into elt,a.,ol washed with ethanol and ~ried.

_ 19 _ O.Z. 51~7 Determination of the primary bacterial adhesion under static conditions An overnight a~lture of the bacteria strain Klebsiella pneumoniae in yeast extract-peptone-glucose nutrient medium (1% + 1% + 1 %) is centrifuged off and taken up again in ~hos,.~l ,ale-buffered saline (=PBS; 0.05 M KH2PO4 pH
7.2 ~ 0.9% NaCI). The mixture is diluted to a cell c~, ~ce~ dlion of 1 o8 cells/ml with PBS bu~er. The sus~,ended baole, ia are brought into c~ntact for 3 hours with the piecs of film to be investigated. For thisl circular pieces of film coated on both sides and having a diameter of 1.6 crn (=4.02 cm2) are pricked onto a ~ liss~lil ,~ needle and shaken with the cell suspension. Films coated on one side are clamped in the form of a circular flat disk of 4.5 aT
diameter with a supporting membrane of flexible PVC 2-3 cm thick into a membrane filter appar~l~Js. The cell suspension is poured onto the side facing upward with the codlil ~y to be te~sted and the system is shaken for 3 hours. The mel,lbrane filter apparal~s must be tight i.e. no cPII suspension must flow out through leaking c811s.

At the end of the col~ l period the bacteria susp~,~sion is suctioned off with a wate~et pump and for washing the pieces of film are sl ,aken with 20 ml of sterile PBS solution in a 100 ml glass beal<er for 2 minutes. The piece of film is dipped into sterile PBS solution again and then e~l,a~led in 10 ml of lledt~d TRIS/El:)TA (0.1 M trishydroxyethy~a",;.,o",eU,~"e 4 mM
ethylenedia",i"etetraacPlic acid brought to pH 7.8 with HCI) in a boiling water bath for 2 minutes.

Small ~ ,e"do, r cups are filled with the e~l(a~ l solution and are frozen i"""edialely at -20~~ until the ade.~osi"e lli~JhosçJh~te (ATP~ e~.;ted is 2s d~t~lll;.l~ by biolu",;.,esc nce. nle dete,,,,i,)~liu., is cal~ied out as follows:
100 ul of reaye, lL mix (biolu, ~ esce,)ce test CLS ll BOEHRINGER
MANNHEIM GmbH) are in~oduc~ into a lr~ ~a~are, ll tube of polyca, I,onate and the light pulses are i"(~ylated over a period of 10 se~nds in a LUMAT
L89501 light pulse measuring instrument (Lal~l dtL~I ie~ l Prof. 8erthold GmbH
~o 75323 Bad Wild~.a~ Germany). A 100 ,ul sa."~l~ is then added and * Trade -mark - 2 0 O.Z. 5~87 measured again. The relative llght unlts ~RLU) are obtalned by subtractlon of llght pulses ln the reagent mix from the number of llght pulses measured in the complete batch. This value is related to the number of bacterla adhered to the film. The conversion factor between the RLU value and the bacterial count is determined by extracting an allquot of 0.1 ml of the bacteria suspension wlth 108 cells/ml ln 10 ml of hot TRIS/EDTA and then determlning the ATP content.
The conditions for coating the varlous polymer substrates with the copolymers according to the invention, as well as the elemental composltion on the modifled surface, and the results of the measurements of the prlmary bacterlal adhesion are summarized in the following Table 5.

~.Z. 5187 _ 5 ~ ~

U U
C s C - s .0 ~ E ~ ~ E E
.
-- ~ - a 0 E E E~ ~ E E
o o ~ o o ~DQ ~ 3 j S 3 E i i U~
E

~ o o o o o ~ o E _ ~ ~~. ~ ~
_ o S ~ ~ ~ ~, _ o _ _ ~ _ _ _ o o o o o ~ ~E ~ n u~

. .

,_, a.z. 5187 C O
~ Y ~ o ~ ,_ .. .. ..
C Z ' ,~ ~
,oo U~ o ~ X
UJ ~ o ~ o ~_ ~

0~ ~ 0~ ~ -7 E o E o o o E o o c o ~ o ' E ~~ ~ o o E ~o ' E o E ~

~ ~ ~ o _ ~ o o ~ ~ o o o ~

s 1 ~
~ e ~ ~

~ O ~ O x J ~ x .

u~ E . ~ ~ ~ ~ 1. E~

O.Z. 5187

Claims

1. A copolymer comprising units of (a) at least one monomer containing sulfonic acid or sulfonate groups, (b) at least one monomer containing carboxyl or carboxylate groups and (c) at least one monomer containing an NCO-reactive group.

2. The copolymer according to claim 1, which comprises at least 30 mol%, of monomers (a), (b) and (c) based on the sum of monomers.

3. The copolymer according to claim 1 or 2, wherein monomer (a) is selected from the group consisting of vinyl sulfonic acid, methallysulfonic acid, 2-acrylamido-2-methyl-1-propanesulfonic acid, or an alkali metal salt thereof.

4. The copolymer according to claim 3, wherein monomer (a) is sodium p-styrenesulfonate.

5. The copolymer according to any one of claims 1 to 4, 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, crotonic acid, isocrotonic acid, methylmaleic acid, dihydroxymaleic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid and maleic acid, or an alkali metal salt thereof.

6. The copolymer according to claim 5, wherein monomer (b) is maleic acid.

7. The copolymer according to claims 1 to 6, wherein monomer (c) is selected from the group consisting of hydroxyethyl acrylate, hydroxyethyl methacrylate, 4-hydroxybutylacrylate, 4-hydroxybutylmethacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropylmethacrylate, allylalcohol, 2,3-butadlen-1-ol, 2-butene-1,4-diol, 3-methylallyl alcohol, o-, m- and p-hydroxystyrene and dihydroxymaleic acid.

8. The copolymer according to claim 7, wherein monomer (c) is hydroxyethyl methacrylate.

9. The copolymer according to any one of claims 1 to 8, which further comprises up to 70 mol%, based on the sum of monomers (a), (b) and (c), of a monomer (d) selected from the group consisting of vinyl acetate, vinyl propionate, vinyl methyl ketone, vinyl butyl ketone, styrene, vinyltoluene, 1-butene, 1-hexene, 1-octene, methylmethacrylate, methyl acrylate and n-butyl acrylate.

10. The copolymer according to any one of claims 1 to 8, wherein the molar ratio of the carboxyl and/or carboxylate groups to the sulfonic acid and/or sulfonate groups is 0.1 to 10.

11. The copolymer according to claim 10, wherein the ratio is 0.2 to 5.

12. The copolymer according to any one of claims 1 to 11, which additionally comprises NCO-reactive groups introduced by reaction with a polyfunctional NCO-reactive compound.

13. The copolymer according to claim 12, wherein the polyfunctional NCO-reactive compound 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.

14. The copolymer according to any one of claims 1 to 13, wherein the molar proportion of NCO-reactive groups, based on the sum of the molar proportions of sulfonic acid, sulfonate, carboxyl, carboxylate and NCO-reactive groups, is 5 to 50%.

15. A process for the preparation of a copolymer as defined in any one of claims 1 to 14 comprising (a) at least one monomer containing sulfonic acid or sulfonate groups, (b) at least one monomer containing carboxyl or carboxylate groups and (c) at least one monomer with an NCO-reactive group, which process comprises subjecting the monomers to polymerization.

16. The process as claimed in claim 15, wherein the polymerization is initiated by free radicals.

17. The process as claimed in claim 15 or 16, wherein the polymerization is a solution polymerization with water as the solvent.

18. The process according to claim 17, wherein the molar proportion of NCO-reactive groups, based on the sum of the molar proportions of sulfonic acid, sulfonate, carboxyl, carboxylate and NCO-reactive groups, is 5 to 50%.

19. A process for the modification of a hydrophilic surface of a polymer substrate, which comprises covalently bonding a copolymer as defined in any one of claims 1 to 14 to the surface by reaction with a polyisocyanate.

20. The process according to claim 18 or 19, wherein the reaction is carried out in an aqueous medium and the polyisocyanate is a masked polyisocyanate.

21. The process according to claim 20, wherein the marked polyisocyanate comprises a residue of a compound selected from the group consisting of methyl ethyl ketoxime, acetone ketoxime, a residue of .epsilon.-caprolactam, ethyl acetoacetate, malonic acid esters, butyl glycolate, diisopropylamine, 3,5-dimethylpyrazole and 1,2,4-triazine.

22. The process according to claim 19, 20 or 21, wherein the hydrophilic surface is produced on a plastic substrate by a treatment selected from the group consisting of argon plasma treatment, irradiation with UV rays of 100 to 400 nm, flaming corona treatment, ozone treatment, ammonia plasma treatment and etching with a strong acid or a strong base.

23. The process according to any one of claims 19 to 22, wherein the polyisocyanate or blocked polyisocyanate comprises isophorone diisocyanate, hexamethylene diisocyanate, 4,4'-methylene-di(phenylisocyanate) or the hydrogenated product thereof or toluene diisocyanate; or a residue thereof, respectively.

24. A product having a surface modified by a process as defined in any one of claims 19 to 23.

25. A product as claimed in claim 24, which is a catheter, hose, membrane, blood bag, wound dressing, tube, stent or heart valve.

26. The use of a product as claimed in claim 25 for hygiene, industrial, foodstuffs or bioengineering purposes.

27. The use of a product as defined in claim 24 or 25 for medical purposes.

28. A copolymer composed essentially of units of:
(a) at least one ethylenically unsaturated monomer containing a sulfonic acid or sulfonate group, (b) at least one ethylenically unsaturated monomer containing a carboxyl or carboxylate group, (c) at least one ethylenically unsaturated monomer containing an NCO-reactive group selected from the class consisting of hydroxyl, epoxy, primary amino and secondary amino groups, and (d) at least one ethylenically unsaturated monomer containing no or a different functionality from those of the monomers (a), (b) and (c) to modify biological or processing properties of the copolymer, wherein the units of the monomers (a) and (b) are contained at a molar ratio of the carboxyl or carboxylate group to the sulfonic acid or sulfonate group of 0.1 to 10, the units of the monomer (c) are contained such that the amount of the NCO-reactive group is 5 to 30 mol% based on the total of the carboxyl, carboxylate, sulfonic acid, sulfonate and NCO-reactive groups and the units of the monomer (d) are contained in an amount of 0 to 70 mol% based on the units of the monomers (a), (b) and (c).

29. A modified copolymer produced by reacting a carboxyl group in a copolymer with at least one polyfunctional NCO-reactive compound selected from the class consisting of a polyol, an amino alcohol and a polyamine, wherein the copolymer is as defined in claim 28 and has a sulfonate group and a carboxyl group when reacted with the polyfunctional NCO-reactive compound, an unreacted part of the carboxyl group being optionally converted to a carboxyl group and the sulfonate group being optionally converted to a sulfonic acid group after the reaction; and wherein the modified copolymer contains an NCO-reactive group selected from the class consisting of hydroxyl and primary amino and secondary amino groups in an amount of 10 to 50 mol% based on the total of the carboxyl, carboxylate, suflonic acid, sulfonate and NCO-reactive groups.

30. The modified copolymer as claimed in claim 29, wherein the polyfunctional NCO-reactive compound is a polyalkylene glycol having a molecular weight of about 100 to 3,000.

31. A shaped article made essentially of a polymer having a modified surface which, prior to modification, carries a hydroxyl or amino group and has been modified with polyisocyanate and the copolymer of claim 28 or the modified copolymer of claim 29 or 30 such that the copolymer or modified copolymer is covalently bonded through the polyisocyanate to the surface using the hydroxyl or amino group.