CA2244049A1 - Bioactive coating with a low-friction surface - Google Patents

Abstract

Disclosed is a copolymer derived from monomers comprising: (A) maleic anhydride; (B) at least one vinyl alkyl ether having an alkyl radical of 1 to 6 carbon atoms; (C) at least one vinyl monomer containing a carboxyl or carboxylate group; and (D) at least one vinyl monomer containing a sulfuric acid, sulfate, sulfonic acid or sulfonate group. The copolymer is useful for the production of products for use in the fields of foodstuffs and tobacco, the water industry and bioengineering, hygiene provision and, in particular, medicine.

Description

Bioactive coatinq with a low-friction surface Field of the Invention The invention relates to polymers that may be used for coating substrates by covalent bonding. These polymers show certain bioactive properties on the basis of the presence of certain functional groups and furthermore are low-friction, i.e. have a remarkably low coefficient of friction when in a moistened (aqueous-moist) state. Important bioactive properties of polymers according to the invention are their bacteria-repellent properties and their good tolerability in contact with body fluids and tissue. Depending on the molar ratio of certain functional groups, the surfaces moreover are rendered cell proliferation-inhibiting or cell proliferation-promoting. The invention furthermore relates to articles having surfaces coated in this way.
Prior Art European Patent Publication 0 166 998 (corresponding to U.S. Patent No. 4,876,126) describes medical instruments and production thereof, in which, inter alia, a water-soluble copolymer (coating polymer) of maleic anhydride and vinyl methyl ether, or a derivative of such a copolymer, which may not be necessarily water-soluble, is bonded preferably covalently, but optionally also ionically or adsorptively, to a polymer substrate. The surfaces of the coating are said to show good sliding properties, that is to say have a low coefficient of friction, in the moistened (aqueous-moist) state. The copolymer, like the other coating polymers O.Z. 5238 mentioned in the publication, is said to contain a hydrophilic group and -OH, -CONH2, -COOH, -NH2, -COO~, -SO-3 and NR3 are expressly mentioned as the hydrophilic group. During covalent bonding, the copolymer is bonded covalently to the polymer substrate by means of reactive groups, such as isocyanate, amino, aldehyde and epoxide groups. When the substrate polymers originally contain no reactive groups, they are pretreated with compounds which contain such a group.
Polyisocyanates, polyamines, polyaldehydes and polyepoxides are mentioned as suitable compounds having reactive groups.
SummarY of the Invention It is an object of the invention to provide novel polymers which are suitable as coating compositions, and at the same time are bioactive and have a low-friction surface in the aqueous-moist state, the bioactivity and the low frictional resistance (or the good sliding properties) originating from the choice of certain functional groups, without further treatment being necessary.
Accordingly, the present invention provides a copolymer which is made of repeating units derived from monomers consisting essentially of:
(A) maleic anhydride (monomer A);
(B) at least one vinyl alkyl ether having an alkyl radical of 1 to 6 carbon atoms (monomer B);
(C) at least one vinyl monomer containing a carboxyl and/or carboxylate group (monomer C); and (D) at least one vinyl monomer containing a sulfuric o.z. 5238 acid, sulfate, sulfonic acid and/or sulfonate group (monomer D).
The polymer according to the invention contains acid groups (i.e., carboxyl and sulfuric or sulfonic groups) and/or anionic groups derived therefrom. Counterions for the anionic groups are preferably physiologically acceptable cations, such as alkali metal ions, in particular sodium ions, or ammonium ions, including quaternary ammonium ions. The molar ratio of the acid groups to the anionic groups may be varied, depending on the intended use of the polymer, by choice of corresponding monomers or can be modified subsequently by treatment with acids or bases. For example, as a rule no sulfuric acid or sulfonic acid groups should be present for medical uses, but this may be acceptable for uses in other technical fields.
The invention also relates to a process for the preparation of the polymer according to the invention, in which monomers A, B, C and D and where appropriate E, are subjected to free-radical polymerization.
The invention also relates to a process for coating substrates in which the copolymer is covalently bonded to the substrate.
The invention also relates to use of a polymer disclosed herein for production of a product for using the field of foodstuffs, tobacco, the water industry, bioengineering, hygiene provision, or medicine.
Finally, the invention relates to products (i.e.
articles) which are coated completely or partly with a polymer O.Z. 5238 disclosed herein and are suitable for use in the fields of foodstuffs and luxury foods, the water industry, bioengineering, hygiene provision and, in particular, medicine.
The polymers according to the invention show a remarkable combination of advantageous properties and therefore an outstanding physiological tolerability. They are readily compatible with blood and reduce the adhesion and multiplication of bacteria to a high degree, even over a relatively long time. This applies, inter alia, to the bacteria of the strains StaPhylococcus aureus, Sta~hylococcus e~idermis, Streptococcus pyo~enes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Esc~erichia coli. At the same time, the proliferation of cells, for example of umbilical cells, is usually also inhibited. The particular conditions under which a polymer is bacteria-repellent but cell proliferation-promoting are explained later. The surfaces of the polymers according to the invention are free from monomers and oligomers which are capable of migration and/or can be extracted. No undesirable side effects, for example by exogenous substances liberated or by bacteria which have been killed, are observed. At the same time, and last but not least, the novel polymers have a remarkably low frictional resistance in the aqueous-moist state.
~escri~tion of Preferred Embodiments 1. Monomer A
The usual industrial pure or highly pure maleic O.Z. 5238 anhydride as is commercially available in commercial quantities is used as monomer A.

2. Vinyl monomers B
The vinyl monomers B are vinyl alkyl ethers with alkyl radicals which have 1 to 6 carbon atoms, advantageously 1 to 4 carbon atoms. Vinyl ethyl ether and, in particular, vinyl methyl ether are preferred.

3. Monomers C
The monomer~ C are preferably ethylenically unsaturated mono-or dicarboxylic acids and their salts.
Preferred monomers C correspond to the general formula:
(CnH2n_q_x)(COOR )x (I) in which n in each case independently is an integer from 2 to 6;
x in each case independently is 1 or 2, preferably 1;
g in each case independently is 0 or 2; and R1 in each case independently is -H, an alkali metal ion or an ammonium ion of the formula N(R )4 , in which R5 in each case independently is hydrogen or an organic radical, preferably a hydrocarbon radical having 1 to 20 carbon atoms.
When _ is 1, the monomer~ C are unsaturated monocarboxylic acids. Example~ of suitable monomers C which may be mentioned are: acrylic acid, methacrylic acid, 4-vinylsalicylic acid, itaconic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic acid, sorbic acid, O.Z. 5238 caffeic acid, methylmaleic acid, crotonic acid, isocrotonic acid, fumaric acid, dimethlyfumaric acid, methylfumaric acid, dihydroxymaleic acid, allylacetic acid and the sodium salts and ammonium salts of these acids with the cation N(R5)4+.
Examples of this cation are ammonium, methylammonium, dimethylammonium, trimethylammonium, tetramethylammonium, dimethyl-l-n-octylammonium, dimethyl-l-n-octadecylammonium, dimethylbenzylammonium and dimethylanilinium.
Monomers C derived from benzene, of the general formula ( 6H6~b-c-d)[~cnH2n-l-q-x)(cOOR )x]bR c(OH)d (II) wherein Rl, n, ~ and _ are as defined above;
R3 in each case independently is Cl 4-alkyl, -NH2, -COOH, -SO3H, -OSO3H, -OPO(OH)2, -PO(OH)2, -OP(OH)2, -OPO(O-)OCH2-CH2 -N (CH3)3, -PO(O-)O-CH2-CH2 -N+ (CH3)3, -OP(O-)OCH2-CH2-N+(CH3)3 or a salt, in particular an alkali metal salt, of the - groups mentioned;

k iS 1, 2 or 3;
c is 0, 1, 2 or 3; and _ is 0, 1, 2 or 3;
with the provision that b + c + _ 5 6, advantageously 5 4, can also be contained in the polymer according to the invention.
4. Monomers D
The monomers D are ethylenically unsaturated organic mono- or disulfuric acids or mono- or disulfonic acids and their salts.

O.Z. 5238 Preferred monomers D containing sulfonic acid and/or sulfonate groups correspond to the general formula (CnH2n_q_x)(S03R )x (III) in which _, x, ~ and Rl have the meaning given for the formula I.
Suitable monomers D of the formula III containing sulfonic acid and/or sulfonate groups are, inter alia, sodium allylsulfonate, sodium methallylsulfonate, sodium vinylsulfonic acid, sodium vinylsulfonate, 4-styrenesulfonic acid, 2-styrenesulfonic acid, sodium 2-styrenesulfonate, sodium 4-styrenesulfonate, sodium vinyltoluenesulfonate, dimethyl-l-n-octylammonium 4-styrenesulfonate and dimethyl-l-n-octylammonium-2-styrenesulfonate.
Monomers containing sulfonic acid and/or sulfonate groups and derived from benzene, of the general formula (C6H6b-c-d)[(cnH2n-l-q-x)(so3Rl)x]bR3c(OH)d (IV) in which Rl, n, ~ and x and R3, b, c and d are as defined above, are also suitable as monomers D.
Other suitable monomers D contain sulfuric acid and/or sulfate groups. Of these, sodium allyl sulfate and sodium methallyl sulfate may be mentioned as examples.
A preferred group of monomers D containing sulfate groups are of the general formula:

O.Z. 5238 (H-l-R3- R4)n H- f - R3-R4 H

in which:
R1 is a hydrogen atom or a methyl radical, R2 is a divalent organic radical, preferably an aliphatic, cycloaliphatic or aromatic hydrocarbon radical having up to 10 carbon atoms, or a single bond, R3 is -O- or -NH-, R4 is hydrogen, the radical -S03-Na+ or the radical -So3-N(R5)4+, in which R5 has the meaning given in formula I, and n is 4 or 5;
with the proviso that at least one of the substituents R4 is a radical -S03-Na+ or -So3-N(R5)4+.
In preferred monomers D of the formula V, R1 is hydrogen, R2 is an alkylene radical having 1 to 4 carbon atoms, a phenylene radical or a single bond, R3 is -O- or -NH-, R4 is hydrogen or the radical -S03-Na+ and n is 4.
The monomers D of the formula V contain modified sugar residues which are preferably derived from pentoses, and in particular from arabinose. The sugar residues contain at o.z. 5238 least one of the radicals -O-S03-Na+ ("O-sulfate") or -NH-SO3-Na+ ("N-sulfate"), preferably adjacent to the radical R2.
They preferably contain 1 to 4 of these radicals. O-sulfate and N-sulfate radicals can be present simultaneously in a sugar residue, in which case the N-sulfate radical is then preferably positioned adjacent to the radical R2.
Alternatively, however, the sugar residue can also contain exclusively one type of these radicals, for example only O-sulfate radicals. Each of the species mentioned ~radicals containing only O-sulfate and N-sulfate-containing radicals) is suitable by itself or together with the other species as monomer D of the formula V. The ratio of the mixture is thus 0:100 to 100:0.
The preparation of monomers D of the formula V is described below 4.1 Monomers of formula V derived from pentitols The preparation of monomers of formula V is described by means of a special case starting from D-glucono-1,5-lactone 1 and resulting in a monomer of formula V which is derived from a pentose, namely D-arabinose. However, the skilled worker will be able to apply the process without difficulty to other suitable precursors.
In a first stage, the hydroxyl groups of the lactone 1 are protected by acetalization, for example with acetone, and, at the same time, the (cyclic) lactone is transesterified with methanol to give the (open-chain) methyl ester. An isomer mixture consisting of methyl 3,4j5,6-di-O-O. Z. 5238 isopropylidene-D-gluconate 2 and methyl 2,3j5,6-di-O-isopropylidene-D-gluconate 3 is obtained. This mixture is reduced in a second stage, for example with lithium aluminum hydride, whereby the carboxylic ester functionality becomes a carbinol functionality. Once again, a mixture of isomers is obtained, namely 3,4jS,6-di-O-isopropylidene-D-sorbitol 4 and 2,3;5,6-di-O-isopropylidene-D-sorbitol 5. In a third stage, this mixture of isomers is oxidized with an oxidizing agent such as sodium periodate with cleavage of the carbon chain to give a single product, the arabinose aldehyde 2,3;4,5-di-O-isopropylidenealdehydo-~-arabinose 6. In the subsequent fourth stage, a vinyl functionality is introduced, for example by a Grignard reaction with 4-vinylphenylmagnesium chloride.
A partly protected 4-vinylphenylpentanepentaol, 2,3;4,5-di-O-isopropylidene-l-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 7 is obtained and is referred to as arasty for brevity hereinafter.
This sequence of stages 1 to 4 is illustrated by the following reaction scheme.

O. Z. 5238 CH20H CC~X~H3 ~ COOCH3 H ~ CH30H;
--O~ --O~
_o \ --~~\
2 3 ~
- OH ~ - OH ~ ~d - OH - O CHO T
~ 4-c~o- CHOH
o ~ O N~O4 ~ ~ ~y~

- oX --OX - oX - ~X
- O

__ _ _ The sequence of reactions in stages 1 to 3 (that is to say up to compound 6) has been described by H. Regeling et al., Recl. Trav. Chim. Pays-Bas 1987, (106) 461 and D.Y.
Jackson, Synth. Commun. 1988 (18) 337. Stage 4 (to compound 7) was published for the first time by G. Wulff et al., Macromol. Chem. Phys. 1996 (197) 1285.
To prepare a compound corresponding to arasty 7 with an amino group in position 1 it is possible, in a first stage, to oxidize arasty to the corresponding ketone, 2,3j4,5-di-O-isopropylidene-D-arabino 4-vinylphenyl ketone 8. This is converted by reduction in a second stage to 1-amino-1-deoxy-2,3;4,5-di-O-isopropylidene-1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 9. This sequence of reactions is illustrated by the following formula diagram:

o.z. 5238 0 ~ DMSO/(cOcl)2 O ~ NaCNBH2 O

--O --O --O
--O~ '--O / --O
_0/\ _o~ _OX

_ 8 9 In the first stage, arasty 7 can be oxidized for example with oxalyl chloride and dimethyl sulfoxide at a temperature <-50~C in an inert solvent. The reductive amination in the second stage is advantageously achieved with sodium cyanoborohydride as reducing agent in the presence of ammonium acetate in a solvent with exclusion of water at room temperature.
Heparin contains unprotected hydroxyl groups and is O-sulfated and N-sulfated. Compounds 7 and 9 are therefore deprotected (deacetalized) in a first stage and 0- and/or N-sulfated in a second stage so that the polymer prepared from them is as far as possible analogous to heparin. The deprotection takes place in acidic medium in which ketals are unstable. The protected compounds are heated, for example, with dilute mineral acid or an acidic ion exchanger to obtain from 7 1-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 10 and from 9 l-amino-l-deoxy-l-(4-vinylphenyl)-D-gluco(D-manno)-pentit o. z. 5238 11. The deprotection and the subsequent sulfation are depicted in the following formula diagram:

CHOH ~mh~lit~ ~120 CHOH ~a~on CHOR
H+form HO- RO --OH -OR
-OH -OR
_O X OH -OR

7 1o 12 R~HorSO3-Na+

1 ~2 \-~ \ ~
o ~ a.1NH~CHNH2 ~a~on CHNHR
HO- RO--OH -OR
_O X OH -OR
-OH -OR

R=HorSO3-Na+

The two compounds 10 and 11 are sulfated, expediently using a sulfur trioxide/pyridine complex. Because of the preceding deacetalization, the sulfation does not result in a single product with one or more sulfate groups in defined positions. However, the primary hydroxyl groups and the amino groups ought to be preferentially sulfated. The degree of sulfation can be controlled by choice of a suitable * Trade-mark o.z. 5238 molar ratio of sulfur trioxide to hydroxyl and amino groups.
It is advantageous for more than one sulfate group to be introduced on average per molecule, because heparin contains about 2.7 sulfate groups per disaccharide unit (equivalent to 1.35 sulfate groups per molecule of monomer I). Sulfation of the deprotected amine compound 11 results in both O-sulfate and N-sulfate groups in the molecule, which is desired in the light of the intended analogy to heparin.
The sulfation is advantageously carried out at room temperature in order to avoid premature polymerization. It is nevertheless possible, by a relatively long reaction time, for example up to 100 hours, for the reaction to be continued until all the OH and NH2 groups have reacted completely. It is possible to use as solvent for example excess pyridine or an ether such as tetrahydrofuran. Since the sulfate groups in the reaction products are unstable to acid, it is advisable to add a dehydrating agent, for example molecular sieves, to the precursor solution before adding the sulfur trioxide/pyridine complex. For the same reason it is advisable, after completion of the reaction, to hydrolyze the reaction mixture first by adding water and shortly thereafter a base (which keeps the pH in the alkaline range). An example of a suitable base is a saturated barium hydroxide solution, which also precipitates sulfate ions. Excess barium ions can be precipitated, for example, by passing in carbon dioxide, where appropriate after cautious concentration to remove solvent.
The barium carbonate is filtered off and the filtrate is O.Z. 5238 passed through an ion exchange column in the Na+ form, or treated with the ion exchanger in another way, in order to replace the barium ions by sodium ions. The products, O-sulfated l-hydroxy-l-deoxy-l-(4-vinylphenyl)-D-gluco(D-manno)-pentitol 12 and N- and O-sulfated l-amino(4-vinylphenyl)-D-gluco(D-manno)-pentitol 13 can be isolated, in each case in the form of the sodium salt, as solid powders by freeze drying the solution which has been concentrated further.
4.2 Monomers of formula V derlved from hexitols The preparation of these monomers is described by means of another special case which starts once again from D-glucono-1,5-lactone 1 and results in two monomers which are formally derived from a hexose, namely D-glucose. However, the skilled worker will be able without difficulty to apply the process to other suitable precursors and prepare other monomers according to the invention.
D-Glucono-1,5-lactone 1 is first converted in a one-pot reaction with a secondary amine and acetone in acidic medium into a mixture of the regioisomers 3,4;5,6-di-O-isopropylidene-D-gluconic acid diethylamide 14 and 2,3j5,6-di-O-isopropylidene-D-gluconic acid diethylamide 15. A mixture of the isomers 3,4;5,6-di-O-isopropylidene-1-(4-vinylphenyl)-keto-D-glucose 16 and 2,3;5,6-di-O-isopropylidene-1-(4-vinylphenyl)-keto-D-glucose 17 is obtainable from this mixture by a Grignard reaction with phenylmagnesium chloride.
The mixture of isomers 16, 17 is hydrogenated ~or reduced), for example with sodium borohydride or lithium o.z. 5238 aluminum hydride, resulting in two pairs of regioisomeric diastereomers 3,4;5,6-di-0-isopropylidene-1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol and 2,3;5,6-di-O-isopropylidene-1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol 20 (not depicted in the following formula diagram). These can be deprotected in acidic medium, resulting in 1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol 21. Sulfation, for example with the sulfur trioxide/pyridine complex as described thereof, results in the sulfation product 22, which is a monomer of formula V.
Alternatively, the mixture of isomers 16, 17 can be reductively aminated, for example with sodium cyanoborohydride and an ammonium salt. This results in two pairs of regioisomeric diastereomers 1-amino-1-deoxy-3,4;5,6-di-O-isopropylidene-1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol and 1-amino-1-deoxy-2,3;5,6-di-O-isopropylidene-1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol 23 (not depicted in the following formula diagram). These can in turn be deprotected in acidic medium, resulting in 1-amino-1-deoxy-1-(4-vinylphenyl)-D-glycero-D-gulo(D-ido)-hexitol 24. This is sulfated as described to give the sulfation product 25, which is likewise a monomer of formula V.
It is possible in both variants to reverse the sequence of hydrogenation or reductive amination and deprotection.
The described reaction sequence is depicted by the following formula diagram, intermediates 20 and 23 not being o.z. 5238 depicted:
~OH
~0 ~=0 HO OH

1. HNEt 2 2. Acetone / H

O~C,N~t 2 O~C,NEt2 --OH
O~ + O
--O --OH
- ~X - ~X
--O --O

1. CH3CH 2MgBr 2. ~MgCI

3. H20/H

o. z . 5238 C=O =O
-OH -O
O-- ~< ' O
-O -OH
_oX _oX
1~ 1 17 1. N~B~ 1 1. NH~OAclN~H3CN
2. ~-120 ~ ~ . ~-l~

-OH -OH
HC~- HO--OH -OH
-OH -OH
-OH -OH

S031P~l so31pyl O.Z. 5238 CHOR CHNHR
--OR --OR
RO-- RO----OR --OR
--OR --OR
--OR --OR

4.3 Monomers with acetalized or aminalized carbonyl functionality Preferred monomers of this type correspond to formula V:

( H--C--R3--R4)n (V) H

in which R1, R2, R3, R4 and n have the meanings stated above for formula V, including the preferred meanings; with the proviso that (1) at least once, advantageously once or twice, per molecule, substituents H and -R3-R4 on the same carbon atom o.z. 5238 form with this carbon atom a carbonyl functionality C=O which has undergone intramolecular acetalization or aminalization by a hydroxyl or amino functionality in position 3 relative to the carbonyl functionality to form a tetrahydrofuran or pyrrolidine ring or by a hydroxyl or amino functionality in position 4 relative to the carbonyl functionality to form a pyran or pentamethyleneimine ring, and that (2) at least one of the substituents R4 is a radical SO ~Na+
An acetalized or aminalized monomer of formula V can be prepared, for example, by first proceeding as described under 4.2, but preparing from the mixture of isomers 16, 17, by deprotection in acidic medium, a single product, namely 1-(4-vinylphenyl)-keto-D-glucose 18. This is converted in its acetal form by sulfation, once again for example with sulfur trioxide/pyridine, into the sulfated compound 19, which is a monomer of formula V. The sequence of stages is depicted by the following formula diagram O.Z. 5238 C -O C O IR-120 < o ~~ ~
~ - OH OR
O ~ O HO -_ O - OH - OH
--~ / --~~ ~' --OH
_ O~ O'~~ - OH 19 6 17 18 R- H or SO3Na Other monomers of formula V of the invention can be prepared starting from monomers which are initially still protected by intermolecular acetalization (with acetone) and are free of sulfate groups. The preparation of an unprotected monomer which is free of sulfate groups and is derived from a ketohexose will be described taking the example of 1-(4-vinylphenyl)-D-manno(D-gluco)-hexulo-2,6-pyranose 27. This starts from the acetone-protected 2,3;4,5-di-0-isopropylidene-1-(4-vinylphenyl)-D-manno(D-gluco)-hexulo-2,6-pyranose 26, whose preparation has been described by G. Wulff, J. Schmidt, T.P. Venhoff in Macrom. Chem. Phys., 197, 1285 (1996). An example for the preparation of a monomer which is free of sulfate groups and is derived from an aldohexose is the synthesis of 6-(4-vinylphenyl)-D-glycerol(L-glycero)-~-D-galactopyranose 30. The starting material in this case is 1,2;3,4-di-0-isopropylidene-6-(4-vinylphenyl)-D-glycero(L-glycero)-~-D-galactopyranose 29, whose preparation has o.z. 523823443-649 likewise been described by G. Wulff, J. Schmidt, T.P. Venhoff loc. cit. Deprotection of the hydroxyl groups takes place in both cases using an acidic ionic exchanger in an inert solvent, for example an alcohol, at moderately elevated temperature, such as 50 to 100~C, expediently in an inert gas atmosphere and in the presence of an oxidation inhibitor.
It is possible to prepare by sulfation of monomers 27 and 30 which are free of sulfate groups (R4 = H in each case) their completely or partly sulfated (R = SO3~Na+) derivatives. Once again a sulfur trioxide/pyridine complex, for example, is used, expediently at room temperature in order to avoid premature polymerization. The reaction is nevertheless complete after a relatively long time. The degree of sulfation can be determined by choice of a suitable molar ratio of sulfur trioxide to hydroxyl groups.

r O ~ IR - 120 ~ H~ SO3~ ~ ~ oO~OR

OH ~ ~ OR

R-H ~ SO3Na Preparation of monomers IV 28 and 31 is described by the following formula diagram:

o.Z. 5238 ~0 1R-I2~ ~ S

O ~ ~ OH ~ OR

29 30 R-H ~ SO3Na 5. Certain combination~ of monomers C and D
Instead of two monomers C and D having the formulae II and III, the polymer according to the invention can also comprise only one monomer (C+D) which contains the various characteristic groups of monomers C and D in the same molecule. It is also possible to employ two or more monomers C instead of only one monomer C, and two or more monomers D
instead of only one monomer D. It is thus possible to use a mixture of acrylic acid and sodium acrylate instead of acrylic acid by itself, and a mixture of sodium 4-styrenesulfonate and 4-styrene-sulfuric acid instead of sodium 4-styrenesulfonate.
A combination of monomer~ C and D which contains both of carboxyl and/or carboxylate groups and sulfonic acid and/or sulfonate groups has proven suitable for the polymers according to the invention. From the standpoint of compatibility, there are three possible two-component combinations of the groups mentioned, that is to say carboxyl and sulfonic acid groups, carboxyl and sulfonate groups and O.Z. 5238 carboxylate and sulfonate groups, and furthermore two three-component combinations, that is to say carboxyl, carboxylate and sulfonate groups and carboxyl, sulfonic acid and sulfonate groups. All these combinations characterize usable representatives of the polymers according to the invention.
The polymers can of course also comprise monomers which are formed by subsequent modification of functional groups after the polymerization. Thus, for example, the acrylamide unit can subsequently be converted into the acrylic acid unit by hydrolysis in an acid medium. Furthermore, carboxyl and sulfonic acid groups can be converted by neutralization (for example in phosphate buffers) and carboxylic ester and sulfonic acid ester groups can be converted by hydrolysis into carboxylate and sulfonate groups respectively.
In the combination of monomers C and D mentioned, the molar ratio of carboxyl and/or carboxylate groups to sulfonic acid and/or sulfonate groups can vary within wide limits. However, it is preferred in the range from 0.1 to 10.
At such a ratio, the polymers show pronounced bacteria-repellent properties. Particularly pronounced cellproliferation-inhibiting properties are additionally achieved if the ratio mentioned is 0.2 to 3, more preferably 0.4 to 3, and in particular 0.4 to 2. The coated surfaces remarkably show bacteria-repellent but cell proliferation-promoting properties if the molar ratio is 2 to 10, preferably 3 to 10, and in particular 3 to 5. A polymer is cell proliferation-promoting in the context of the invention if the adhesion and o.z. 5238 multiplication of mammalian cells is improved or at any rate less severely impaired than the adhesion and multiplication of bacteria.

6. Further monomer~ (monomers E) In addition to monomers A to D, the polymers according to the invention can comprise one or more further olefinically unsaturated monomers (monomers E), which are free from carboxyl, carboxylate, sulfuric acid, sulfate, sulfonic acid, sulfonate and acid anhydride groups. Whether the polymer is water-soluble or only swellable depends on their nature and amount of the monomers including the monomer E. If the polymer is to be applied as a coating composition from an aqueous medium, the co-use of hydrophilic monomers, for example containing hydroxyl groups, is easily possible.
Monomers E containing hydroxyl groups or amino groups are also beneficial for the covalent bonding of the polymer according to the invention to substrates. It is easy to determine by preliminary experiments which monomers E the polymer according to the invention can comprise in what amounts so that it meets the particular requirements imposed, for example in respect of its mechanical properties.
Monomers E which can be used are, for example ~meth)acrylic acid derivatives, preferably alkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aminoalkyl, N,N-dialkylaminoalkyl esters having 1 to 10 carbon atoms in each alkyl or alkoxy moiety. Examples include ethyl acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl o.z. 5238 acrylate, 2-(2'-hydroxyethoxy)ethyl acrylate, 2-hydroxy-1-methylethyl acrylate, 2-N,N-dimethylaminoethyl acrylate, n-propyl methacrylate, 2-hydroxyethyl methacrylate, 2-(2'-hydroxyethoxy)ethyl methacrylate, 2-hydroxy-1-methylethyl methacrylate, 2-N,N-dimethylaminoethyl methacrylate, diethylene glycol monomethacrylate, (meth)acrylamide and (meth)acrylonitrile. Another group of the monomers E may be olefinically unsaturated amine5, such as vinylamine and allylamine: vinyl ketones, such as vinyl ethyl ketone;
olefins, such as 1-butene, l-hexene and 1-octene;
vinylaromatics, such as styrene, ~-methylstyrene and vinyltoluene; and vinylsiloxanes.

7. Preparation of the polymers accordinq to the invention The polymers may be prepared in the customary manner by polymerization initiated by free radicals, preferably by solution or emulsion polymerization. Suitable solvents are, for example, ketones, such as acetone, methyl ethyl ketone and cyclohexanone; ethers, such as diethyl ether, tetrahydrofuran and dioxane; alcohols, such as methanol, ethanol, n- and iso-propanol, n- and iso-butanol and cyclohexanol; strongly polar solvents, such as dimethylformamide, dimethylacetamide and dimethylsulfoxide; hydrocarbons, such as heptane, cyclohexane, benzene and toluene; halogenated hydrocarbons, such as methylene chloride and chloroform; esters, such as ethyl acetate, propyl acetate and amyl acetate; and nitriles, such as acetonitrile; or mixtures of these solvents.
Suitable polymerization initiators are, for example, o.Z. 5238 azonitriles, alkyl peroxides, acyl peroxides, hydroperoxides, peroxyketones, peroxyesters and percarbonates, and all the customary photoinitiators. The polymerization is initiated by means of heat, for example by heating to 60 to 100~C, or by exposure to radiation of an appropriate wavelength. When the exothermic polymerization reaction has ended, the polymer is separated off from the solvent in the customary manner, for example by precipitation by means of n-hexane. Monomeric or oligomeric constituents can be removed by extraction with a suitable solvent, for example with water or aqueous alcohol.
Instead of monomers C and D, it is also possible to employ monomers having functional groups which may be converted into the functional groups characteristic of monomers C and D after the polymerization. Thus, carboxylic ester groups can be converted into carboxylate groups by treatment with aqueous or aqueous-alcoholic alkali, or carboxylic ester, carboxamide or nitrile groups can be converted into carboxyl groups by hydrolysis in an acid medium. As already mentioned, the ratio of carboxyl to carboxylate groups or of sulfonic acid to sulfonate groups or sulfuric acid to sulfate groups can furthermore be modified in the desired manner with alkaline or acid reagents after the polymerization.
The ratio of the amounts in which monomers A to D
are employed can vary within wide limits. Advantageously, the proportion of monomer A, maleic anhydride, is 15 to 50 mol~, preferably 35 to 50 mol~; the proportion of monomer B is O.Z. 5238 likewise 15 to 50 mol%, preferably 35 to 50 mol%; the proportion of monomer C is 0.5 to 30 mol~, preferably 0.5 to 15 mol%; and the proportion of monomer D is likewise 0.5 to 30 mol~, preferably 0.5 to 15 mol~. If the polymer according to the invention comprises further monomers E, the proportion thereof is as a rule 0.5 to 69 mol~, preferably 0.5 to 30 mol%.
It is preferred that conditions of the preparation of the copolymers are chosen such that the units of maleic anhydride in the resulting copolymers are in a carboxylic acid anhydride form, for example, by minimizing use of water.

8. Coating of ~ubstrate~ with polymers according to the invention The invention furthermore relates to a process for coating substrates, in particular polymer substrates, in which the polymer according to the invention is bonded covalently to the substrate, for which reactive groups both in the polymer according to the invention and on the polymer substrate are required. The invention furthermore relates to products of polymer materials, ceramic or metal coated completely or partly with the polymers according to the invention.
The most diverse polymer substrates can be coated with the polymer according to the invention. Suitable polymers are, for example, polyamides, such as polyamide-6, polyamide-12, polyamide-6,6 and polyamide 6,12; polyurethanes of the most diverse diisocyanates and polyols and polyether-and polyester-polyols; polyether-block amides; polyester-block o.Z. 5238 amides; polyether-ester-amides; polyesters of aromatic dicarboxylic acids and varlous aliphatic or cycloaliphatic diols; and furthermore polyvinyl chloride, polystyrene, polyacrylates, polymethacrylates, polyethers, polycarbonates, polyolefins, silicones and polytetrafluoroethylene.
The polymer substrates mentioned often contain groups, such as carboxyl, amino or hydroxyl groups, which are helpful for covalent bonding of the coating polymer.
Alternatively, such groups can be generated on the surface of the polymer, for which a large number of known methods are available. Thus, o.z. 5238 corresponding monomers can be copolymerized or standard polymers can be modified, for example by treatment with acids or bases; irradiation with UV light, electron beams or x-rays; treatment with high-frequency or micro-wave plasma; or flaming. Primers with reacting groups can furthermore s also be applied to poiymers which do not originally contribute reactive groups and have not been subjected to any of the treatments mentioned or similar treatrnents. Suitable primers are, for example, polyisocyanates, such as tolylene diisocyanate, hexamethylene diisocyanate, diphenyl-methane 4,4'-diisocyanate, dicycloxymethane 4,4'~iisocyanate and iso-10 phorone diisocyanate; polyamines, such as ethy~enediamine, triethylene-diamine, 1,3-propylenediamine, 1,4-butylenediamine and 1,6-hexamethyle-nediamine; polyaldehydes, such as su¢cinaldehyde, adipaldehyde and terephthalaldehyde; and polyepoxides, such as ethylene glycol diglycidyl ether and 1,3-propylene glycol diglycidyl ether 15 A pretreatment with a suitab~e primer also allows covalent bonding of the coating polymer according to the invention to inorganic substrates, such as ceramic or metal, for example to highgade steel.

There are numerous possibilities for covalent bonding of the coating polymer to a polymer substrate or a primer. Thus, carboxylic acid an-2 o hydride groups of the co~ti ~y polymer ¢an react with amino groups on thesurface of the polymer substrate, which can have been generated, for example, (i) by NH3 plasma, (ii) by treatment of a polyamide or polyuretha-ne with alkali, (iii) by hydrolysis of copol~",efi~ed NCO groups or NCO
groups introduc~d by priming with a polyisocyanate or (iv) by priming with 25 an alkylenediamine. Alternatively, for e~.a"lplE, NCO groups on the sub-strate polymer which are excess NCO groups from the synthesis of a polyurethane or formed by treatment of a polymer substrate having hydroxyl or amino groups on the surface with a polyisocyanate (if appropriate in blocked form) as a primer, can react with hydroxyl groups in 30 the coating polymer, which have been introduced into the molecule, for example, by copolymeri~a~i~" of a mon~mer E c~ntaining hydroxyl groups.

O. Z 5238 A third variant comprises linking a polymer substrate having hydroxyl or amino groups onto the surface with a coating polymer which contains copolymerized amino or hydroxyl groups with the aid of a diepoxide. Furthermore, dicarboxylic acid dihalides can be employed as primers if the polymer substrate and coating polymers contain COCI-reactive groups. All these reactions are known per se and further linking mechanisms will readily become apparent to a person skilled in the art, depending on the nature of the functionality of the reactive groups on the polymer substrate, in the coating polymer and, where appropriate, in the primer.
The primer and coating polymer are expediently applied in solution to the polymer substrate. Suitable solvents are, for example, water; alcohols, such as methanol, ethanol and n-butanol; ketones, such as acetone, butanone (methyl ethyl ketone) and cyclohexanone; esters, such as methyl acetate, methyl propionate, ethyl acetate and n-butyl acetate; ethers, such as ethylene glycol diethyl ether and tetrahydrofuran; and aromatic hydrocarbons, such as toluene and xylene. The choice of solvent depends on the nature of the polymer substrate, which must not be dissolved, but should certainly be swollen. If water or alcohols are employed as the solvent, the NCO groups must be protected in the customary manner, for example with methyl ethyl ketoxime, from polyisocyanates envisaged as the primer.
If a polymer substrate is treated with a primer before being coated, the solution thereof is expediently o. z. 5238 allowed to act on the substrate for some time, for example 5 minutes to 2 hours, if appropriate at elevated temperature, for example up to 60~C, and the solvent is then evaporated, if appropriate in vacuo and/or at elevated temperature.
The known processes, such as dipping, spraying, brushing, knife-coating and spin-coating, are suitable for coating the polymer substrate. After the coating operations, the solvent is in turn evaporated. For covalent linking of the coating polymer with the substrate, the coated substrate is expediently kept at elevated temperature, for example at 50 to 90~C, for some time, for example 5 minutes to 2 hours. If a blocked isocyanate is to effect the linking, correspondingly higher temperatures may be necessary.
Coating with the polymers according to the invention renders it possible to further use known and proven materials and production processes. This is particularly important if the mechanical properties of the materials are of great importance, or the production plants for the existing production processes require high investments.

9. Products according to the invention The polymers according to the invention offer particular advantages in the case of shaped articles which are moved along against sensitive surfaces. This is the case, for example, with catheters and tubes according to the invention, which subject the internal walls of vessels, such as veins and arteries, to minimal stress as a result of low frictional resistance.

O.z. 523~3 The shaped articles produced according to the invention are intended in particular for use in the fields of foodstuffs and tobacco, the water industry, bioengineering, hygiene provision and, in particular, medicine. For example, the polymers described herein can be used for the production of textiles, apparatus, pipes and tubes, condoms, packagings and medical articles coated with a polymer according to the invention on plastic, ceramic or metal as the substrate.
Medical articles are, for example, implants or aids, such as drainage, guide wires, cannulas, intraocular lenses, contact lenses, stents, vascular prostheses, joint prostheses, dialysis membranes and suture materials. Preferred products are catheters or tubes for medical use.
The following examples are intended to illustrate the invention further, but not to limit its scope as described in the patent claims.
Examples Measurement of the adhe~ion of bacteria to coated stan~rd films via ATP (static) After adsorption of microbe cells on a standard film having a coating of a particular polymer according to the invention, the non-adhering bacteria are rinsed off with sterile PBS buffer solution. The bacteria constituent adenosine triphosphate (ATP is extracted in the customary manner from the bacteria adhering to the film and determined in a bioluminometric 0. Z. 5238 assay using a commercJally available test combination. The number of ~ Iight pulses measured is proportional to the number of adhering bacteria. A
non-coated standard film serves as the reference sample. For example, if a polyamide 12 film is coated with a polymer according to the invention, a non-coated polyamide 12 film serves as the referencs sample. To calcula-te the inhibition of the adhe$ion of bacteria, the adsorption on the referen-ce film is set at 100. The inhibition is the difference between the adsorption on the coated and that on the non~oated standard fllm.

Measurement of the frictional resistance A non~oated standard film is glued onto a pane of glass, the angle of inclination of which to the horizontal is infinitely adjustable and can be measured. A piece of the coated standard film is clamped with the coated side facing outward in the clamping device of a rectangular test weight (6 cm x 4 cm, weight 100 9). The coated and the non-coated standard film are moistened to dripping wet, and the test weight is placsd on the glass plate glued with the standard film. The angle of inclination of the glass plate is increased, continu~sly and without jerking, at about 20 Glminute, sta, li"~ at 0~, until the weight mounted on it moves. The angle established at this point in time is recorded. Its tang~nt is the coefficient of adhesive 2 0 friction.

Example 1 100 ml of dimethyl sulfoxido (DMS0) are introduced under an inert gas (nitrogen) into a 1 1 five-nedced flask provided with a stirrer, refluxed condenser and four dropping funnels. A solution (feed 1 ) is prepared from 100 ml of DMS0 and 70 g of maleic anhydride (MA) and is introduced into dropping funnel 1. Dropping funnel 2 is fllled with 6Z ml of vinyl methyl ether (VME; feed 2). Dropping funnel 3 contains a solution (feed 3) of 7.2 ml of acrylic acid (M), 19.ô g of sodium styrenesulfonate (NaSS) and 70 mJ of DMS0. 1.5 9 of azoisobutyronitrile in 20 ml of DMS0 (feed 4) are O. Z. 5238 introduced into dropping funnel 4. 8 ml of feed 1 from dropping funnel 1 and in each case S ml of feed 2, 3 and 4 from dropping funnels 2, 3 and 4 are metered into the flasl~. Thereafter, the mixture is heated to 70~C. After a further 10 minutes, feed t, 2 and 3 are metered in over a period of 3.5 s hours, while feed 4 is metered in over a period of 4 hours. When the addition has ended, the reaction solution is kept at 70CC for a further 4 hours. The quaternary polymer is precipitated out by stirring into 2 1 of n-hexane and washed with water. NMR analysis of the quatemary polymer shows a composition of MA 43.2 mol%
VME 45.1 mol%
M 6.6 mol%
NaSS 5.1 mol%

The molar ratio of COOH or COO- to SO3- iS 1.3.

l 5 To measure the adhesion of h3Ctl~ ia, a polyamide 12 film is coated with the quatemary polymer. For this, a solution of the quatemary polymer in dimethylsulfoxide (20 g/l) is prepared. This solution is sprayed onto the polyamide 12 film and the solvent is allowed to evaporate. Measurement of bacterial adso" tion with Kl~bsiella Dneu~or~ showed a reduction by 92% compared with the non~oated polyamide 12 film.

To measure the coefficient of fnction, the film coated with the quaternary polymer, as described, was glued to the test weight. Measurement of the fricSional resistance with respect to a non-coated polyamide 12 film gave a cGerri~ien~ of adhesive friction of 0.05. The coefficient of adhesive friction of two non~oated polyamide 12 films is 0.42.

Example 2 The procedure is as in Example l, but feed 3 is a solution of 9 ml of acrvlic O, Z. 5238 ~44~-ha9 acid (M) 14.4 9 of sodium styrenesulfonate (Na~) an~ f~J ml Ot L~M~U.
NMR analysis of the quaternary polymer gives a composition of MA 42.9 mol%
VME 44.~ mol%
M 7.5 mol%
NaSS 4.7 mol%

The molar ratio of COOI I or COO- to S O3-is 1.6.

Measurement of the adhesion of bacteria with Klebsiella Pneumoniae gives a reduction by 95% compared with a non-coated polyamide 12 film.

The coe~cient of adhesive friction is 0.06.

Example 3 A polyamide 12 film (~ cm x 6 cm) is immersed in a 1% strength by weight solution of diphenylme~harle diisocyanat~ in ethyl methyl ketone at room temperature under an inert gas (argon) for 1 hour. The film is removed and dried in a drying cabinet at 60~C for a period of 30 minutes. The dried film is then i"""ersed in a 2% strength by weight solution of the polymer from Exa,nple 1 in dimethyl sulfoxide at room temperature for 4 seconds. The film is then dried first in a drying cabinet at 60~C for 1 hour and then at 70~ v under a pressure of 1 Mbar for 5 hours. Thereafter the film is 2 0 placed in water at 25 C for 3 hours and dried at 6C~ C for 24 hours.

The inhibition of the adsor~,ti~" of Klebsiella pneumoniae. Iike that of the other abovementioned strains of bacteria is > 92%. The coefficient of adhesive friction is 0.05.

Similar results are achieved if the polymer of Example 2 is bonded cova-2 5 lently to a polyamide 12 film in an analogous manner.

O, Z. 5238 23443-64g

Claims (31)

1. A copolymer which is made of repeating units derived from monomers consisting essentially of:
(A) maleic anhydride;
(B) at least one vinyl alkyl ether having an alkyl radical of 1 to 6 carbon atoms;
(C) at least one vinyl monomer containing a carboxyl or carboxylate group; and (D) at least one vinyl monomer containing a sulfuric acid, sulfate, sulfonic acid or sulfonate group, wherein the monomers (C) and (D) may be replaced by at least one vinyl monomer containing both (i) a carboxyl or carboxylate group and (ii) a sulfuric acid sulfate, sulfonic acid or sulfonate group.

2. The copolymer according to claim 1, which contains sulfate or sulfonate groups and carboxyl or carboxylate groups.

3. The copolymer according to claim 2, in which the carboxylate and sulfonate groups when contained, have a sodium or ammonium ion as their counterion.

4. The copolymer according to any one of claims 1 to 3, in which monomer B is vinyl methyl ether.

5. The copolymer according to any one of claims 1 to 4, in which monomer C has the general formula:

(C n H2n-q-x)(COOR1)x (I) in which:
n is an integer of from 2 to 5;
x is 1 or 2;
q is 0 or 2; and R1 in each case independently is -H, an alkali metal ion or an ammonium ion of the formula N(R5)4+ in which R5 independently is a hydrogen atom or a hydrocarbon radical having 1 to 20 carbon atoms.

6. The polymer according to any one of claims 1 to 4, in which monomer C has the general formula:

(C6H6-b-c-d)[(C n H2n-1-q-x)(COOR1)x]b R3c(OH)d (II) (in which:
n is an integer of from 2 to 5;
x is 1 or 2;
q is 0 or 2;
R1 in each case independently is -H, an alkali metal ion or an ammonium ion of the formula N(R5)4+ in which R5 independently is a hydrogen atom or a hydrocarbon radical having 1 to 20 carbon atoms ;
b is 1, 2 or 3;
c is 0, 1, 2 or 3;
d is 0, 1, 2 or 3; and R3 in each case independently is C1-4-alkyl, -NH2, -COOH, -SO3H, -OSO3H, -OPO(OH)2, -PO(OH)2, -OP(OH)2-OPO(O-)OCH2-CH2-N+(CH3)3, -PO(O-)O-CH2-CH2-N+(CH3)3, -OP(O-)OCH2-CH2-N+(CH3)3 or a salt thereof;
with the proviso that the total of a, c and d is not more than 6.

7. The polymer according to any one of claims 1 to 6, in which monomer D has the general formula:
(C n H2n-q-x)(SO3R1)x, (III) (in which:
n is an integer of from 2 to 5;
x is 1 or 2;
q is 0 or 2; and R1 in each case independently is -H, an alkali metal ion or an ammonium ion of the formula N(R5)4+ in which R5 independently is a hydrogen atom or a hydrocarbon radical having 1 to 20 carbon atoms).

8. The polymer according to any one of claims 1 to 6, in which monomer D has the general formula:

(C6H6-b-c-d)[(C n H2n-1-q-x)(SO3R1)x]b R3c(OH)d (IV) in which:
n is an integer of from 2 to 5;
x is 1 or 2;
q is 0 or 2;
R1 in each case independently is -H, an alkali metal ion or an ammonium ion of the formula N(R5)4+ in which R5 independently is a hydrogen atom or a hydrocarbon radical having 1 to 20 carbon atoms .

9. The polymer according to any one of claims 1 to 6, in which monomer D has the general formula:

(in which R1 is a hydrogen atom or a methyl radical, R2 is a divalent organic radical, or a single bond, R3 is -O- or -NH-, R4 is hydrogen, -SO3-Na+ or -SO3-N(R5)4+, in which the radicals R5 in each case independently are a hydrogen atom or an organic radical, and n is 4 or 5;
with the proviso that at least one of the substituents R4 is -SO3-Na+ or -SO3-N(R5)4+).

10. The polymer according to any one of claims 1 to 8, which contains both (i) a carboxyl or carboxylate group and (ii) a sulfonic acid or sulfonate group.

11. The polymer according to claim 10, in which a molar ratio of the carboxyl or carboxylate group to the sulfonic acid or sulfonate group is 0.1 to 10.

12. The polymer according to claim 10, in which the molar ratio of the carboxyl or carboxylate group to the sulfonic acid or sulfonate group is 0.2 to 3.

13. The polymer according to claim 10, in which the molar ratio of the carboxyl or carboxylate group to the sulfonic acid or sulfonate group is 2 to 10.

14. The polymer according to claim 1, which consists essentially of repeating units derived from:
(A) maleic anhydride;
(B) vinyl methyl ether;
(C) at least one unsaturated carboxylic acid 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, sorbic acid, caffeic acid, methylmaleic acid, crotonic acid, isocrotonic acid, fumaric acid, dimethylfumaric acid, methylfumaric acid, dihydroxymaleic acid, and allylacetic acid, or a salt thereof selected from the group consisting of sodium, ammonium, methylammonium, dimethylammonium, trimethylammonium, tetramethylammonium, dimethyl-1-n-octylammonium, dimethyl-1-n-octadecylammonium, dimethylbenzylammonium and dimethylanilinium salts; and (D) at least one monomer selected from the group consisting of sodium allylsulfonate, sodium methallylsulfonate, vinylsulfonic acid, sodium vinylsulfonate, 4-styrenesulfonic acid, 2-styrenesulfonic acid, sodium 2-styrenesulfonate, sodium 4-styrenesulfonate, sodium vinyltoluenesulfonate, dimethyl-1-n-octylammonium-4-styrenesulfonate, dimethyl-1-n-octylammonium-2-styrenesulfonate, sodium allyl sulfate and sodium methallyl sulfate.

15. The polymer according to claim 14, which comprises, as copolymerized monomers, maleic anhydride, vinyl methyl ether, acrylic acid and sodium 2- or 4-styrenesulfonate.

16. The polymer according to claim 14 or 15, which comprises an additional monomer (E) selected from the group consisting of ethylacrylate, isobutyl acrylate, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, 2-(2'-hydroxyethoxy)ethyl acrylate, 2-hydroxy-1-methylethyl acrylate, 2-N,N-dimethylaminoethyl acrylate, n-propyl methacrylate, 2-hydroxyethyl methacrylate, 2-(2'-hydroxyethoxy)ethyl methacrylate, 2-hydroxy-1-methylethyl methacrylate, 2-N,N- dimethylaminoethyl methacrylate, diethylene glycol monomethacrylate, (meth)acrylamide, (meth)acrylonitrile, vinylamine, allylamine, vinyl ethyl ketone, 1-butene, 1-hexene, 1-octene, styrene, .alpha.-methylstyrene and vinyltoluene.

17. A copolymer composed of repeating units of:
(A) 15 - 50 mol% of maleic anhydride;
(B) 15 - 50 mol% of at least one vinyl alkyl ether having an alkyl radical of 1 to 6 carbon atoms;
(C) 0.5 - 30 mol% of at least one ethylenically unsaturated mono- or dicarboxylic acid or a physiologically acceptable salt thereof;
(D) 0.5 - 30 mol% of at least one ethylenically unsaturated organic mono- or disulfuric acid or mono- or disulfonic acid or a physiologically acceptable salt thereof;
and (E) 0 or 0.5 - 69 mol% of at least one olefinically unsaturated monomer which is free from carboxyl, carboxylate, sulfuric acid, sulfate, sulfonic acid, sulfonate and acid anhydride groups, wherein the units of (C) and (D) may be replaced by units of at least one ethylenically unsaturated monomer (C + D) containing both (i) a carboxyl group or a physiologically acceptable salt thereof and (ii) a sulfuric or sulfonic acid group or a physiologically acceptable salt thereof, and wherein the units (A) of maleic anhydride are present in a carboxylic acid anhydride form in the copolymer.

18. The copolymer of claim 17, lacking repeating units of the monomer (E).

19. The copolymer of claim 17 or 18, wherein the units (D) are of a physiologically acceptable salt of an ethylenically unsaturated organic monosulfonic acid; and the units (C) are of an ethylenically unsaturated monocarboxylic acid.

20. The copolymer of claim 17, 18 or 19, which has a molar ratio of the units (C) to the units (D) of 0.1 to 10.

21. A process for the preparation of a polymer according to any one of claims 1 to 20, which comprises subjecting monomers A, B, C and D, and optionally E, to free-radical polymerization.

22. The process according to claim 21, which comprises solution or emulsion polymerization of the monomers in the presence of azoisobutyronitrile.

23. The process according to claim 22, wherein DMSO is a solvent for solution polymerization.

24. The process according to claim 23, which comprises reacting maleic anhydride, vinyl methyl ether acrylic acid and sodium 2- or 4-styrenesulfonate.

25. A process for coating a substrate, which comprises covalently bonding a polymer as claimed in any one of claims 1 to 20 to the substrate by means of reactive groups both in the polymer and on the substrate.

26. The process according to claim 25, wherein the reactive groups are provided on the substrate by treatment with a primer having reactive groups.

27. The process according to claim 26, wherein the primer is selected from the group consisting of tolylene diisocyanate, hexamethylene diisocyanate, diphenylmethane 4,4'-diisocyanate, dicycloxymethane 4,4'-diisocyanate, isophorone diisocyanate, ethylenediamine, triethylenediamine, 1,3-propylenediamine, 1,4-butylenediamine, 1,6-hexamethylenediamine, succinaldehyde, adipaldehyde, terephthalaldehyde, ethylene glycol diglycidyl ether and 1,3-propylene glycol diglycidyl ether.

28. The use of a polymer according to any one of claims 1 to 20 for production of a product for use in the field of foodstuffs, tobacco, water industry, bioengineering, hygiene provision or medicine.

29. The use according to claim 28, wherein the product is a catheter or tube for medical use.

30. A shaped article which is coated completely or partly with a polymer as claimed in any one of claims 1 to 20, for use in the field of foodstuffs, luxury foods, water industry, bioengineering, hygiene provision or medicine.

31. The article as claimed in claim 30, which is a catheter or tube for medical use.