Description The present invention relates to a process for coating the surface of a substrate with a biocidal substance, to substrates and articles with biocidal surfaces obtainable by this process, and to the use of certain copolyamides in combination with an antimicrobial agent for an antimicrobial surface finishing as well as for the reduction of microbial, especially bacterial, growth on such a surface, especially on the surface of a medical article.

Providing articles which maintain a certain degree of antimicrobial activity throughout the full period of usage has been a long standing need. Surfaces showing an effective action against bacteria are desired especially in medicine, since infections by contami- nated surfaces are a rising concern. While various proposals have been made to incorporate antimicrobial agents into surfaces, e.g. those coming into direct contact with a patient such as hospital furniture or medical instruments, setbacks have been reported which relate to fast leaching (toxicity risk by fresh surface, and insufficient surface activity after aging), poor adherence of surface coating to its substrate, poor biocompati- bility etc. WO 98/58690 proposes a coating comprising a hydrogel polymer and a bio- active agent entrapped in a flexible stabilizing polymer, which is mainly selected from crosslinkable acrylics.

WO 03/066721 discloses certain polyamide coatings which may be loaded with aque- ous solutions of some antimicrobials such as cetyl pyridinium chloride.

It has now been found that certain copolyamides are especially suitable as a carrier for an antimicrobial agent, and may be applied as a coating providing a slow and efficient release of said antimicrobial agent.

The invention thus primarily pertains to a composition comprising a film-forming polyamide copolymer and an antimicrobial agent, characterized in that the copolymer (i.e. generally the phase formed by the copolymer) takes up at least 2% by weight of water, if in contact with an aqueous phase, and further characterized in that the antimicrobial agent is, at least partly, water soluble. The percentage of water uptake relates to the total weight of the swollen copolymer, the water content of which typically ranging from 2 to about 20% b.w.. Preferred copolyamides for use in the invention possess a capacity of water uptake, which is expressed by at least 3 % b.w. of water, more preferably at least 5 % b.w. of water, especially at least 8 % b.w. of water, the total water content of the swollen copolymer thus ranging e.g. from 3 to 18 % b.w., most especially from 10 to 15 % b.w. of water. Water uptake, in the sense as noted above, is generally detectable by comparison of the weight of the dried copolymer with the same copolymer equilibrated with purified water at room temperature (drying may be effected, for exam- pie, by heating to 60-100 °C in air and/or drying under reduced pressure, e.g. 1 -100 mbar, until no further weight loss detectable). Preferred copolymers are those, which are soluble in alcohol, or mixtures of alcohol containing up to 50% b.w. of water, and optionally up to 10% b.w. of further solvents. Examples are ethanol, propanol, especially in mixtures of lower (i.e. C1-C4-) alcohols in amounts of 70% b.w. or more, especially 80% b.w. or more, with water, a typical weight ratio being 8 : 2. Further solvents, may be selected e.g. from hydrocarbons such as toluene or especially non-aromatic hydrocarbons, they are preferably present in low amounts (e.g. up to 5, more preferably up to 2.5, especially up to 1 % b.w.), or not present at all. Examples for suitable polymers of this class, and solutions thereof, are given in WO 10/146054 or DE-A- 755617.

The invention further provides a coating formed by said composition, or an article comprising at least one surface covered with this coating.

Suitable polyamide copolymers are generally chosen from hydrophilic polyamides comprising a low ratio of (hydrophobic) methylene moieties CH2 to amide moieties CONH. Typical polyamides for use in the present invention comprise, or consist of, monomers selected from C2-C15 dioic acids combined with one or more C2-C15 diamines and/or C4-C8 aminoacids, C4-C8 lactams; the monomer components are preferably aliphatic and/or cycloaliphatic. Examples for dioic acids useful are aliphatic or cycloaliphatic ones like butane dioic acid, pentane dioic acid, hexane dioic acid, heptane dioic acid, octane dioic acid, cyclohexane dioic acid; preferred are straight-chain omega-dioic acids, or cyclohexane-1 ,4-dioic acid. Diamine moieties are often straight- chain aliphatic omega-diamines and/or cycloaliphatic omega-diamines, especially mixtures thereof. Examples for diamines useful are aliphatic diamines like butane diamine, pentane diamine, hexane diamine, heptane diamine, octane diamine, preferably straight-chain omega-diamines. Examples for cycloaliphatic diamines are cyclohexane diamine, amino-(aminocyclohexyl)-cyclohexane, di(aminocyclohexyl)methane, di(aminocyclohexyl)ethane, di(aminocyclohexyl)propane, and especially those of formula

wherein x is zero or 1 , A is Ci-C4alkylene, D is Ci-C4alkylene, -0-, -S-, -SO-, -SO2-; and wherein the residues Ax-Nh preferably are in the positions 4,4'. D is preferably alkylene, especially methylene. A is preferably zero. Preferred cycloaliphatic diamines , include cyclohexane-1 ,4-diamine, 1 -amino-4-(4-aminocyclohexyl)-cyclohexane, di(4- aminocyclohexyl)methane, 1 , 1 -di(4-aminocyclohexyl)ethane, 2,2-di(4- aminocyclohexyl)propane.

Examples for aminoacids useful are aminoacetic acid (glycin), 3-aminopropanoic acid, 6-aminohexanoic acid, 5-aminopentanoic acid, 4-aminobutanoic acid. Examples for lactams useful are those of 6-aminohexanoic acid, 5-aminopentanoic acid, 4-aminobutanoic acid.

Examples of particularly advantageous polyamides and copolyamides are linear ho- mopolyamides and copolyamides which are prepared in a known manner from the bi- functional carboxylic acids and diamines and/or from omega-amino acids, lactams or suitable derivatives of these compounds, such as a polyamide obtained from

metaxylylenediamine and adipic acid, or from trimethyl- or hexamethylenediamine or isophoronediamine and adipic acid; or a polyamide of epsilon-caprolactam/adipic acid/hexamethylenediamine/4,4-diaminodicyclohexylmethane, or of epsilon- caprolactam/adipic acid/hexamethylenediamine/polyethyleneglycoldiamine; or the N- methylol or N-alkoxymethyl derivatives of all these homopolyamides and copolyamides.

Since the present copolyamides essentially consist of the above monomer classes, the molar amount of dioic acid, in general, is roughly the same as the molar amounts of diamines (i.e. both components are present in equimolar amounts).

The present copolymer thus preferably consists essentially of monomer components

A, B and C, which add up to 100 % by weight in total, the monomer components being

5 to 60 % b.w. of lactames and/or amino acids (component A),

5 to 60 % b.w. of an equimolar mixture of dioic acid with one or more aliphatic diamines

(component B), and

10 to 70 % b.w. of an equimolar mixture of dioic acid with one or more cycloaliphatic diamines (component C). The lactame / amino acid monomers (component A) are preferably selected from 6- aminohexanoic acid, 5-aminopentanoic acid, 4-aminobutanoic acid and lactames thereof, especially epsilon-caprolactam.

The aliphatic diamine of component B is preferably selected from n-butane-1 ,4- diamine, n-pentane-1 ,5-diamine, n-hexane-1 ,6-diamine, n-heptane-1 ,7-diamine, n- octane-1 ,8-diamine, and most preferably is n-hexane-1 ,6-diamine (i.e. hexamethylenediamine).

The dioic acid components B and C is preferably selected from succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid; most preferably, the dioic acid monomer is adipic acid.

The cycloaliphatic diamine of component C preferably is of the formula

with definitions and preferences as noted above; most preferably, the cycloaliphatic diamine monomer is 4,4'-diamino-dicyclohexylmethane. Preferred are copolymers comprising the following monomer composition:

• 15 to 40 % b.w., especially 20 to 40 % b.w., of lactames and/or amino acids (component A),

• 20 to 45 % b.w., especially 20 to 40 % b.w., of an equimolar mixture of dioic acid with one or more aliphatic diamines (component B), and

• 25 to 60 % b.w., especially 30 to 60 % b.w., of an equimolar mixture of dioic acid with one or more cycloaliphatic diamines (component C)

with percentages of components A, B and C adding up to 100%. Examples for especially well suitable copolymers in the present compositions are those containing 20-30 % b.w. of component A, 20-30 % b.w. of component B and 40-60 % b.w. of component C; furthermore preferred are those containing 20-30 % b.w. of component A, 20-27.5 % b.w. of component B and 45-55 % b.w. of component C; for example those containing 25 % b.w. of component A, 25 % b.w. of component B and 50 % b.w. of component C wherein each quantity may vary by +-20%, especially by +-

10%, most especially by +-5%; again with percentages of components A, B and C adding up to 100% in each case. Especially preferred are copolymers essentially consisting of

30 to 40 % b.w. of lactames and/or amino acids (component A),

30 to 40 % b.w. of an equimolar mixture of dioic acid with one or more aliphatic diamines (component B), and

30 to 40 % b.w. of an equimolar mixture of dioic acid with one or more cycloaliphatic diamines (component C),

for example those containing about one third by weight of each of components A, B and C, wherein each quantity may vary e.g. by +-5%.

The molecular weight (Mn, as determined e.g. by GPC) of the polyamide copolymer is preferably from the range 5000 to 50000, especially 10000 to 30000. The polydisper- sity of the polyamide copolymer is preferably <5, especially <4.5, especially <4.

Especially useful copolyamides for the purpose of the invention include those of CA- Reg. Nos. 25053-13-8, 74083-22-0, 150747-01 -6, 25053-13-8, 73561 -43-0,

An especially preferred copolyamide is the one essentially consisting of the monomer units hexanedioic acid, hexahydro-2H-azepin-2-one, 1 ,6-hexanediamine and 4,4'- methylenebis[cyclohexanamine] in the ratio as defined above (CA-Reg. No. 25053-13- 8).

The above swellable copolyamides are suitable for systems based on water soluble antimicrobial actives. The present copolyamides, especially CA-Reg. No. 25053-13-8, are film-forming polyamides which form flexible, scratch-resistant coatings or tough, resilient, abrasion-resistant coverings on plastics, films, nonwovens, fabrics, leather, paper, wood, or metal. Most importantly, these materials are able to take up water (see above), which forms a liquid phase. It has been the finding of the present invention, that water-soluble actives can migrate within this phase to the polymer surface, thus leading to a water triggered release of the active component. Proper migration leads to bactericidal concentrations at the surface that efficiently kill adhering microorganisms.

It has been the finding of the present invention that, surprisingly, proper migration inside a polymer matrix and high antimicrobial functionality can be achieved when the antimicrobial active is dissolved, or partly dissolved, in the liquid phase (plasticizer). In this case, the antimicrobial active is sufficiently mobile in the liquid plasticizer phase within the solid polymer. By using this system (e.g. consisting of the polyamide of CA- Reg. No. 25053-13-8as a polymer matrix, which contains the antimicrobial active such as P18 antimicrobial peptide and/or PHMB) microorganisms are killed efficiently.

Polyamides useful in the present invention are known compounds, many of them are items of commerce.

Examples for medical devices comprising the present composition are especially catheters, vascular shunts. Further, the present composition may be included in filter materials, dressing materials, syringes, suture materials, gloves, mattresses, packag- ing materials (for food, drugs, medical devices, cosmetics, e.g. in the form of boxes or films comprising paper, cardboard and/or plastics coated with the composition of the invention), hospital furniture and equipment, fabrics and water purification equipment.

Catheter associated urinary infections are among the most common and costly hospi- tal-acquired infections. Very often, these infections originate from biofilms that form on the abiotic catheter surfaces. To avoid or delay biofilm formation catheters with antimicrobial functionalities are required. Antimicrobial functionalities can be achieved by (i) permanently immobilizing antimicrobial actives on the catheter's surface or by (ii) compounding the antimicrobial actives into the polymer matrix or into a coating aiming at slow release. Surfaces with permanently immobilized actives are prone to inactivation by surface alterations such as protein film formation, adsorption of dead bacteria and aging. In contrast, antimicrobial surface functionalities based on the slow release of actives are more resistant to these processes since their activity is not solely dependent on the properties of the outermost layer. However, slow release approaches often suffer from poor migration of the antimicrobial actives. Generally, poor migration leads to low and often sub-lethal concentrations of antimicrobial actives on the surfaces. Sublethal concentrations lead to incomplete inactivation of microorganisms and promote the formation of resistances. Thus, an antimicrobial coating is required that efficiently kills adhering microorganisms by ensuring proper migration of the antimicrobial active.

The antimicrobial agent (antimicrobial active) contained in the present composition generally is water soluble, at least to an extent necessary to provide the desired antim- icrobial effect. The antimicrobial agent may be selected from suitable biocides, antibiotics and/or complexing agents.

Complexing agents are usually selected from suitable mono- or especially multidentate components (also denoted as chelators) containing bonding sites e.g. selected from sulfur, oxygen, aminic nitrogen, hydroxamate, carboxylate, examples are polycarbox- ylic acids and hydroxy acids including their salts like citrate, lactate, maleate, ethyl- enediaminetetraacetate (EDTA), ethyleneglycol-bis^-aminoethylether)-N ,N ,N',N'- tetraacetate (EGTA), diethylene triamine pentaacetate (DTPA), N ,N'-ethylene-bis-(o- hydroxyphenyl-glycine) (EH PG), deferasirox, deferiprone (3-hydroxy-1 ,2- dimethylpyridin-4(1 H)-one); amino acids and their salts; polythiocarboxylic acids and their salts like dimercaptosuccinic acid; peptides and proteins such as transferrine; polyhydroxamic acids and their salts like deferoxamine; especially preferred is ethyl- enediaminetetraacetate (EDTA). These agents possess an own antimicrobial effect, which is believed to be the result of a depletion of ions necessary for bacterial proliferation (see Issam I . Raad, Xiang Fang, Xavier M . Keutgen, Ying Jiang, Robert Sherertz and Ray Hachem: The role of chelators is preventing biofilms formation and catheter- related bloodstream infections; Current Opinion in Infectious Diseases 2008; 2Λ_, 385- 392), and are well suitable for storage in, and slow release from the present plasticizer phase.

Biocides for use as the water soluble antimicrobial active are, for example, antimicrobial oligomers or polymers, such as oligomers or polymers comprising quaternary ammonium moieties or guanidine moieties, or are antimicrobial peptides or proteins with antimicrobial effect.

Preferred agents of this class are polyhexamethylene biguanide (PH M B)

Γ N H N H ~~|

N H— — N H— ( C H 2 ) 6

as well as salts and adducts thereof such as hydrochlorides, (hydro) phosphates etc., or the antimicrobial peptide P18 (see: Structure and fungicidal activity of a synthetic antimicrobial peptide, P18, and its truncated peptides, Lee, Biotechnology Letters 26: 337-341 , 2004).

PH M B, and properties when applied in aqueous environment, is disclosed e.g. in US- 4758595; see especially col. 3, line 12, to column 4, line 50, whose contents is hereby incorporated by reference. In many living organisms, antimicrobial peptides are the first line of defense against pathogenic microorganisms that try to attack mucous membranes. Antimicrobial peptides are synthesized by mucous membranes and secreted to the surface. The peptides kill pathogenic bacteria before they can attach and colonize the surface. PH M B belongs to the large class of cationic/hydrophobic antimicrobials (like quaternary ammonium compounds). Antimicrobial peptides and cati- onic/hydrophobic antimicrobials kill bacteria by interacting with the poly- anionic/hydrophobic bacterial envelope (cell wall and plasma membrane). The interaction with the cell envelope leads to the disruption of membrane gradients and finally to the death of the microorganisms.

Other antimicrobial peptides useful in combination with the present copolymer in the present invention are disclosed, for example, at http://aps.unmc.edu/AP/main.php; Wang et al., Nucleic Acids Res. 2004 January 1 ; 32(Database issue): D590-D592.

Besides PH MB and antimicrobial peptides, any other antimicrobial active belonging to the large class of cationic antimicrobials can be used such as:

Cationic detergents and quarternary ammonium compounds

Quarternary ammonium compounds,

Benzyl-C12-18- alkyldimethyl-, Chloride

Quarternary ammonium compounds,

Benzyl-C12-16-alkyldimethyl-, Chloride

Quarternary ammonium compounds,

Di-C8-10-alkyldimethyl-,Chloride

Quarternary ammonium compounds,

C12-14- Alkyl[(ethylphenyl)methyl]dimethyl-, Chloride

Quarternary ammonium compounds (Benzylalkyldimethyl (Alkyl from C8- C22, saturated and non-saturated, coco- and soy alkylic) chloride, bromide or hydroxide) Quarternary ammonium compounds (Benzylalkyldimethyl (Alkyl from C8- C22, saturated and non-saturated, coco- and soy alkylic) chloride, bromide oder methylsulphate) Quarternary ammonium compounds (Alkyltri methyl (Alkyl

from C8-C18, , saturated and non-saturated, coco- and soy alkylic) chloride, bromide oder methylsulphate)

Benzalkonium chloride (Alkyl-dimethyl-benzyl-ammoniumchloride)

Alkyl-didecyl-polyoxethyl-ammoniumpropionate, Alkyl-dimethyl- compounds alkylbenzyl-ammoniumchlorid, Alkyl-dimethyl-ethyl-ammoniumchloride,

Alkyl-didecyl-polyoxethyl-ammoniumpropionate

Alkyl-dimethyl-alkylbenzyl-ammoniumchloride

Alkyl-dimethyl-ethyl-ammoniumchloride

Alkyl-dimethyl-ethylbenzyl-ammoniumchloride

Benzalkoniumpropionate

Cocos-dimethylbenzyl-ammoniumchloride Cocos-dimethylbenzyl-ammoniumchloride,

Lauryl-dimethyl-benzyl-ammoniumchloride

Myristyldimethyl-benzyl-ammoniumchloride

Benzethoniumchloride

Benzyl-di-hydroxyethyl-cocosalkyl-ammoniumchloride

Cocosdimethyl-benzyl-ammoniumchloride

Dialkyl-dimethyl-ammoniumchloride

Didecylmethyloxyethylammoniumpropionate

Mecetroniumethylsulfate

Methylbenzethoniumchloride

n-Octyl-dimethyl-benzyl-ammoniumchloride

Undecylamidopropyltrimoniummethosulfate

Oleyltrimethylammoniumchloride

Dioctyldimethylammoniumchloride

Didecyldimethylammoniumchloride

Dicocodimethylammoniumchloride

Cocosbenzyldimethylammoniumchloride

Cocosalkylbenzyldimethylammoniumchloride Amphiphilic detergents

Alkyloligoamincarbonic acid

Cocamidopropyl betain

Alkyl Dimethyl betain

Cocoamidopropyl hydroxysultain

Dipalmitoyllecithin

Alkylbetaines

Talgamphopolycarboxyglycinate

Cocoamphopolycarboxyglycinate

Coco fatty acid iminopropionate

Octyliminodipropionate

Cocoiminoglycinatee

Alkylamines und amine derivatives

Alkylamine

Bis(3-aminopropyl)dodecylamine

n-Cocospropylendiammoniumborate Dodecylaminsulfamate

n-3-Dodecylaminopropylglycine

n-Dodecyl-n-(3-aminopropyl)1 ,3-propandiamine

Glucoprotamine

Cocospropylendiamine

Cocosaminacetate

Polymers

Dodecyldipropylentriamine

Polylysine

Chitosane

Polyhexamethylenbiguanid

Polyethylenimin

polymere, quarternary ammonium compounds

polymere guanides

polymere biguanides

Polynorbornene

Arylamide oligomeric

Phenylen ethynylene

Kenawy et al., 2007 (The Chemistry and Applications of Antimicrobial Polymers: A State-of-the-Art Review) und darin zitierte Literatur

Polymethacrylate

Polymeric quarternary pyridinium compounds

Acyl-Lysine oligomers

N-alkyl polyethylenimines

Peptidomimetika

Aminosteroles

Amphiphilic, cationic-hydrophobic compounds

Quarternary phosphonium compounds

trihexyl(tetradecyl)phosphonium chloride

trihexyl(tetradecyl)phosphonium bromide

trihexyl(tetradecyl)phosponium decanoate

tetradecyl(trihexyl)phosphonium bis-(2,4,4-trimethylpentyl)phosphinate tetradecyl(trihexy) phosphonium dicyanamide triisobutyl(methyl) phosphonium tosylate

tributyl(methyl)phosphonium methylsulfate

tetradecyl(trihexyl) phosphonium bistriflamide

tetradecyl(trihexyl) phosphonium hexafluorophosphate

tetradecyl(trihexyl) phosphonium tetrafluoroborate

hexadecyl(tributyl) phosphonium bromide

tetrabutylphosphonium bromide

tetrabutylphosphonium chloride

tetra-n-octylphosphonium bromide

tetradecyl(tributyl) phosphonium chloride

ethyl(tributyl)phosphoniurr) diethylphosphate

tetradecyl(tributyl)phosphoniurr) dodecylbenzenesulfonate

tetradecyl(trihexyl)phosphonium dodecylbenzenesulfonate

tetrabutylphosphonium acetate

tetrabutylphosphonium bromide

tetrabutylphosphonium chloride

tetra-n-octylphosphonium bromide

tetradecyl(tributyl)phosphoniurr) chloride

tetradecyl(trihexyl)phosphoniurr) chloride

octadecyl(trioctyl)phosphoniurr) iodide

Of some specific interest is the inclusion of oligodynamic metals, or their compounds, especially particles containing silver: Zeolite supported silver is disclosed in U.S. Pat. Nos. 4,775,585; 4,91 1 ,898; 4,91 1 ,899, 6,071 ,542, U.S. Pat. No. 6,585,989. Glass supported silver is disclosed for example in published U.S. app. No. 2005/0233888. Antibacterial micro- or nanosilver is disclosed inter alia in US-6720006, US-6822034, US-2006-018943, US-2010-136073, US-2008-306183, and literature cited therein. Also useful as biocidal agents are silver compounds like silver chloride, silver oxides, silver carboxylates like silver citrate.

Moreover, any other water soluble antimicrobial active, biocide, antibiotic, can be used with this system: such other biocides include, for example, benzoic acid, its salts and esters; propionic acid and its salts; salicylic acid and its salts; sorbic acid and its salts; formaldehyde; paraformaldehyde; o-phenylphenol and its salts; inorganic sulphites and hydrogen sulphites; sodium iodate; chlorobutanol; 4-hydroxybenzoic acid and its salts and esters; 3-acetyl-6-methylpyran-2,4 (3H)-dione; formic acid; sodium formiate; di- bromohexamidine and its salts; undec-10-enoic acid and salts; hexetidine; 5-bromo-5- nitro-1 ,3-dioxane; bronopol; 2,4-dichlorobenzyl alcohol; triclocarban; 2.4.4'-trichloro-2'- hydroxy-diphenylether (Triclosan); 4-chloro-3,5-xylenol; imidazolidinyl urea; poly(1 - hexamethylenebiguanide hydrochloride); 2-phenoxyethanol; hexamethylenetetramine; methenamine 3-chloroallylochloride; 1 -(4-chlorophenoxy)-1 -(imidazol-1 -yl)-3,3- dimethylbutan-2-one; 1 ,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine-2,4-dione; benzyl alcohol; 1 -hydroxy-4-methyl-6(2,4,4-trimethylpentyl)-2-pyridon or its monoetha- nolamine salt; methyldibromoglutaronitrile; bromochlorophen; 4-isopropyl-m-cresol; mixture of 5-Chloro-2-methyl-isothiazol-3(2H)-one and 2-methylisothiazol-3(2H)-one with magnesium chloride and magnesium nitrate; clorophene; 2-chloroacetamide; chlorhexidine and its digluconate, diacetate and/or dihydrochloride; 1 -phenoxypropan- 2-ol; alkyl (C12-C22) trimethyl ammonium bromide and/or chloride; 4,4-dimethyl-1 ,3- oxizalidine; N-(hydroxymethyl)-N-(dihydroxymethyl-1 ,3-dioxo-2,5-imidazolidinyl-4)-N'- (hydroxymethyl)urea; bismuth dimercaprol; hexamidine and its salts; glutaraldehyde; chlorphenesin; sodium hydroxymethylglycinate; benzethonium chloride; benzalkonium chloride, bromide and/or saccharinate; benzylhemiformal, listerine, alexidine, and essential oils including thymol, geraniol, carvacrol, citral, hinokitiol, eucalyptol, eugenol, menthol, catechol, lactic acid, lactates, 1 ,2-pentanediol.

Antibiotics include: Aminoglycosides (Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin), Ansamycins (Geldanamycin, )Herbimy-cin), Carbacephem (Loracarbef), Carbapenems (Ertapenem, Doripenem, Imipe- nem/Cilastatin, Meropenem), Cephalosporins (Cefadroxil, Cefazolin, Cefalotin or Cefa- lothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime), Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Cef-tazidime, Ceftibu- ten, Ceftizoxime, Ceftriaxone, Cefepime), Ceftobiprole), Glycopep-tides (Teicoplanin, Vancomycin, Telavancin), Lincosamides (Clindamycin, Clinda-mycin), Lipopeptide (Daptomycin), Macrolides (Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin), Monobactams (Az- treonam), Nitrofurans (Furazolidone, Nitrofuran-toin), Penicillins (Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Di-cloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin

Ticarcillin), Penicillin combinations (Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, Ticarcillin/clavulanate), Polypeptides (Bacitracin, Colistin, Polymyxin B), Quinolones (Ciprofloxacin, Enoxacin, Gatifloxacin, Levofloxacin, Lomeflox- acin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin), Sulfonamides (Mafenide, Sulfonami-dochrysoidine, Sulfacetamide,! Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole, Sul- fanilimide , Sulfasalazine, Sulfisoxazole, Trimethoprim, Tri-methoprim-

Sulfamethoxazole), Tetracyclines (Demeclocycline, Doxycycline, Mino-cycline, Oxytet- racycline, Tetracycline), Others (Arsphenamine, Chloramphenicol, Fosfomycin, Fusidic acid, Linezolid, Metronidazole, Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Ri- faximin, Thiamphenicol, Tinidazole).

The use of the is antimicrobial surface functionality is not limited to catheters but can be applied for all applications that require antimicrobial surface functionality. Using compositions of the invention, antimicrobial coatings on plastics, films, nonwovens, fabrics, leather, paper, wood, ceramics or metal can be achieved. The substrate can be a two-dimensional object such as a sheet or a film, or any three dimensional object; it can be transparent or opaque. Examples for plastics or films are polymers such as acrylic polymers, styrene polymers and hydrogenated products thereof, vinyl polymers and derivatives thereof, polyolefins and hydrogenated or epoxidized products thereof, aldehyde polymers, epoxide polymers, polyamides, polyesters, polyurethanes, polycarbonates, silicones, sulfone-based polymers and natural polymers and derivatives thereof.

Acrylic polymers can be polymers formed from at least one acrylic monomer or from at least one acrylic monomer and at least one other ethylenically unsaturated monomer such as a styrene monomer, vinyl monomer, olefin monomer or maleic monomer. Examples of acrylic monomers are (meth)acrylic acid, (meth)acrylamide,

(meth)acrylonitrile, ethyl (meth)acrylate, butyl (meth)acrylate, hexyl (meth)acrylate, 2- ethylhexyl (meth)acrylate, glycidyl methacrylate, acetoacetoxyethyl methacrylate, di- methylaminoethyl acrylate and diethylaminoethyl acrylate. Examples of styrene monomers are styrene, 4-methylstyrene and 4-vinylbiphenyl. Examples of vinyl monomers are vinyl alcohol, vinyl chloride, vinylidene chloride, vinyl isobutyl ether and vinyl acetate. Examples of olefin monomers are ethylene, propylene, butadiene and isoprene and chlorinated or fluorinated derivatives thereof such as tetrafluroethylene. Examples of maleic monomers are maleic acid, maleic anhydride and maleimide. Examples of acrylic polymers are poly(methyl methacrylate) (PMMA), poly(butyl methacrylate), polyacrylonitrile (PAN), polyacrylic acid, styrene/2-ethylhexyl acrylate copolymer, styrene/acrylic acid copolymer.

Styrene polymers can be polymers formed from at least one styrene monomer or from at least one styrene monomer and at least one vinyl monomer, olefin monomer and/or maleic monomer. Examples of styrene polymers are polystyrene (PS), styrene butadiene styrene block polymers, styrene ethylene butadiene block polymers, styrene ethylene propylene styrene block polymers and styrene-maleic anhydride copolymers. Vinyl polymers can be polymers formed from at least one vinyl monomer or from at least one vinyl monomer and at least one olefin monomer or maleic monomer. Examples of vinyl polymers are polyvinyl chloride (PVC), polyvinylidenfluoride (PVDF), poly- vinylalcohol, polyvinylacetate, partially hydrolysed polyvinyl acetate and methyl vinyl ether-maleic anhydride copolymers. Examples of derivatives thereof are carboxy- modified polyvinyl alcohol, acetoacetyl-modified polyvinyl alcohol, diacetone-modified polyvinyl alcohol and silicon-modified polyvinyl alcohol.

Polyolefins can be polymers formed from at least one olefin monomer or from at least one olefin monomer and maleic monomer. Examples of polyolefines are low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP), biaxially orientated polypropylene (BOPP), polybutadiene, polytetrafluoroethylene (Teflon- PTFE), chlorinated polyethylene and isopropylene-maleic anhydride copolymer.

Aldehyde polymers can be polymers formed from at least one aldehyde monomer or polymer and at least one alcohol monomer or polymer, amine monomer or polymer and/or urea monomer or polymer. Examples of aldehyde monomers are formaldehyde, furfural and butyral. Examples of alcohol monomers are phenol, cresol, resorcinol and xylenol. An example of a polyalcohol is polyvinyl alcohol. Examples of amine monomers are aniline and melamine. Examples of urea monomers are urea, thiurea and dicyandiamide.

An example of an aldehyde polymer is polyvinyl butyral formed from butyral and polyvi- nylalcohol.

Epoxide polymers can be polymers formed from at least one epoxide monomer and at least one alcohol monomer and/or amine monomer. Examples of epoxide monomers are epichlorohydrine and glycidol. Examples of alcohol monomers are phenol, cresol, resorcinol, xylenol, bisphenol A and glycol. An example of epoxide polymer is phenoxy resin, which is formed from epichlorihydrin and bisphenol A. Polyamides can be polymers formed from at least one monomer having an amide group or an amino as well as a carboxy group or from at least one monomer having two amino groups and at least one monomer having two carboxy groups. An example of a monomer having an amide group is caprolactam. An example of a diamine is 1 ,6- diaminohexane. Examples of dicarboxylic acids are adipic acid, terephthalic acid, isophthalic acid and 1 ,4-naphthalenedicarboxylic acid. Examples of polyamides are polyhexamethylene adipamide and polycaprolactam.

Polyesters can be polymers formed from at least one monomer having a hydroxy as well as a carboxy group or from at least one monomer having two hydroxy groups and at least one monomer having two carboxy groups or a lactone group. An example of a monomer having a hydroxy as well as a carboxy group is adipic acid. An example of a diol is ethylene glycol. An example of a monomer having a lactone group is carprolac- tone. Examples of dicarboxylic acids are terephthalic acid, isophthalic acid and 1 ,4- naphthalenedicarboxylic acid. An example of a polyester is polyethylene terephthalate (PET). So-called alkyd resins are also regarded to belong to polyester polymers.

Polyurethane can be polymers formed from at least one diisocyanate monomer and at least one polyol monomer and/or polyamine monomer. Examples of diisocyanate monomers are hexamethylene diisocyanate, toluene diisiocyanate, isophorone diisocyanate and diphenylmethane diisocyanate.

Examples of polycarbonates are poly(aromatic carbonates) and poly(aliphatic carbonates). Poly(aliphatic carbonates) can be formed from carbon dioxide and at least one epoxide.

Examples of sulfone-based polymers are polyarylsulfone, polyethersulfone (PES), poly- phenylsulfone (PPS) and polysulfone (PSF). Polysulfone (PSF) is a polymer formed from 4,4-dichlorodiphenyl sulfone and bisphenol A.

Examples of natural polymers are starch, cellulose, gelatine, caesin and natural rubber. Examples of derivatives are oxidised starch, starch-vinyl acetate graft copolymers, hy- droxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, nitryl cellulose, ethyl cellulose, carboxymethyl cellulose and acetyl cellulose.

Fabrics can be made from natural fibres such as fibres from animal or plant origin, or from synthetic fibres. Examples of natural fibres from animal origin are wool and silk. Examples of natural fibres from plant origin are cotton, flax and jute. Examples of synthetic textiles are polyester, polyacrylamide, polyolefins such as polyethylene and poly- propylene and polyamides such as nylon and lycra.

Examples of ceramics are products made primarily from clay, for example bricks, tiles and porcelain, as well as technical ceramics. Technical ceramics can be oxides such as aluminium oxide, zirconium dioxide, titanium oxide and barium titanate, carbides such as sodium, silicon or boron carbide, borides such as titanium boride, nitrides such as titanium or boron nitride and silicides such as sodium or titanium silicide.

Examples of metals are iron, nickel, palladium platin, copper, silver, gold, zinc and aluminium and alloys such as steel, brass, bronze and duralumin.

The invention further pertains to a process for applying an antimicrobial coating, and to the use of the composition of the invention for achieving an antimicrobial, preserving and/or sterilizing effect, especially on the surface of an article, such as a medical article, like those described above. Thus, the invention opens a way to provide an article equipped with an antimicrobial surface by carrying out the following steps: i) preparing a solution or dispersion of a polyamide copolymer as described above and the antimicrobial agent as described above, in a suitable solvent,

ii) applying the solution to the surface of the article, and

iii) drying the obtained coating.

The solvent in step (i) is preferably selected from aliphatic C1 -C6 alcohols, phenols, benzyl alcohol, and mixtures thereof with up to 50% b.w. of water; especially selected from methanol, ethanol, propanol and mixtures thereof with water. The composition can be applied, for example, using a wire bar or by dipping or spraying. Drying (step iii) may be effected, for example, by heating to 60-100 °C in air and/or drying under reduced pressure, e.g. 1 -100 mbar. The dry coating layer can have a thickness in the range of from 0.1 to 1000 μΐη, preferably from 1 to 100 μΐη. The amount of antimicrobial agent usually ranges from 1 to 100 parts by weight, relative to 100 parts by weight of the educt polyamide copolymer. The solution or dispersion of step (i) may comprise one or more quarternary ammonium compounds, other biocides and/or additional components such as surfactants, de-foamers.

Examples of biocides are 5-chloro-2-(2,4-dichlorophenoxy)phenol, which is sold, for example, under the tradename Ciba® Irgasan® DP300, N'-ferf-butyl-N-cyclopropyl- 6-(methylthio)-1 ,3,5-triazine-2,4-diamine, which is sold under the tradename Ciba® Irgarol® 1051 , 2-thiazol-4-yl-1 H-benzoimidazole, which is sold under the tradename Ciba® Irgaguard® F3000, chlorhexidine, gallic acid, mucobromic acid, itaconic acid and 3-iodo-2-propynyl butyl carbamate, which is sold under the tradename Ma- guard™ 1-100.

Examples of surfactants are anionic surfactants such as sodium dodecyl sulfate or ammonium lauryl sulfate, cationic surfactants such as cetyl trimethylammonium bromide or cetyl pyridinium chloride, amphoteric surfactants such as dodecyl betaine and nonionic surfactants such as copolymers of poly(ethylene oxide) and poly(propylene oxide).

Examples of defoamers are mineral oil preparations such as the defoamer sold under the tradename Ciba® EFKA® 2526 and polyether functionalzed polysiloxanes such as the defoamer sold under the tradename Ciba® EFKA® 2550

The composition can comprise 0 to 50% by weight of the additional components based on the weight of the composition. Preferably, it comprises 0.001 to 10% by weight of additional components and more preferably 0.01 to 5% by weight. The antimicrobial article of the invention thus comprises a substrate material having at least one surface formed by plastics, films, nonwovens, fabrics, leather, paper, wood, glass or metal, which is covered by the antimicrobial composition described above. The antimicrobial article preferably is a medical device, a filter pad, a dressing, a syringe, a suture, a glove, a mattress, especially a catheter or a vascular shunt.

Further examples of medical articles are wound care bandages, catheters, implants, artificial organs, artificial joints, artificial blood vessels and medicinal devices such as medical instruments and tools, stethoscopes, tubes, syringes and needles.

The following examples illustrate the invention. Unless indicated otherwise, percentages refer to percent by weight (b.w.), room temperature denotes a temperature from the range 20-24°C. Abbreviations used in the examples or elsewhere:

CA Chemical Abstracts

OD optical density

TSBY growth medium for bacteria: Peptone from casein 17.0 g , peptone from soymeal 3.0 g, D(+)-Glucose 2.5 g, NaCI 5.0 g , K2HP04 2.5 g, distilled water 1000.0 ml , adjust pH to 7.3)

Example 1 - Compounding of PHMB and P18 Antimicrobial Peptide

A copolyamide (CA-Reg. No. 25053-13-8) consisting of equal amounts by weight of the monomer components epsilon-caprolactam (component A), equimolar mixture of hexamethylenediamine and adipic acid (component B), and equimolar mixture of 4,4'- diamino-dicyclohexylmethane and adipic acid (component C), together with an antimicrobial agent (P18 or PHMB), is dissolved in a mixture of n-propanol (80%) and water (20%). PHM B is supplied by Arch Chemicals, P18 is supplied by custom peptide synthesis, Bachem (Switzerland). Silicone rubber discs are coated using the resulting vis- cous solution. After evaporation of the solvents, the films are washed to mimic leaching of the antimicrobials in a continuous-flow of a urinary catheter. In detail, the antimicrobials are added to 1.5 ml of a mixture of 80% n-propanol and 20% water to a final concentration of 10% relative to the copolyamide. The mixture is heated to 85°C and stirred until the antimicrobials are completely dissolved and a homogenous, viscous and clear solution is obtained. The viscous and clear solution is used to cast films on silicone rubber discs.

Example 2 - Release of PHMB

PHMB is compounded into the copolyamide of CA-Reg. No. 25053-13-8 (example 1 ) and films are casted as described in example 1 on PVC foil (backing film). The PHMB content is 10% (w/w) relative to the copolymer. To analyze migration and release of PHMB, the coated films are incubated in 100 ml of ultra-pure water. Every 60 min the film is transferred into a new container with 100 ml of water. The PHMB content in the water is analyzed by competition with Nioxime for NiCI2. Nioxime forms a red complex with NiCI2. PHMB forms a more stable and colorless complex with NiCI2. The increase in PHMB is determined by the decrease in red color using a calibration curve. In detail, 0,2 ml of NiCI2-solution (3.37 mM) and 0.2 ml of Nioxime solution (28.14 mM) are added to 5 ml of the aqueous solution containing an unknown concentration of PHM B. After adding ultra-pure water to a total volume of 50 ml, the sample is sonicated for 5 min and incubated for 1 h. The red color intensity is determined by measuring the ab- sorption at 550 nm.

Figure 1 shows rapid and substantial release of PH MB within the first 10 h. The release rate decreases with increasing time and decreasing concentration of PH MB within the polymer. Still, within 190 h more than 85% of the PHM B is released, arguing for proper migration of PHM B inside the water phase of the present coating.

Example 3 - Analysis of Antimicrobial Activity A static biofilm assay in 24-well plates is developed for Staphylococcus epidermidis, Escherichia coli and Proteus mirabilis. The biofilm is grown on silicone rubber discs that are reversibly attached to the bottom of the wells. Surface colonization and biofilm formation are analyzed 1 h and 24h after addition of the bacteria. The surfaces are removed from the plate, rinsed and the attached bacteria are removed by sonication. The resulting suspensions are diluted and plated on agar plates. The number of living bacteria on the silicone rubber surface is determined by counting the colonies after overnight incubation of the agar plates. In detail, biofilm formation is triggered by adding 105 colony forming units (cfu, number living bacteria) at high salinity to each well. A pre-culture in a 100 ml shake-flask is started from an overnight culture by diluting into TSBY medium to yield a final optical density (OD 600 nm) of 0.1 . The pre-culture is shaken at 37°C until the logarithmic growth phase with an OD 600 nm of ~ 3 is reached. Next, the pre-culture is diluted to a final concentration of ~ 10E5 cfu/ml (OD 600 nm of ~ 0.0004) in 5% TSBY in saline (0,9% NaCI in water). 1 ml of the cell suspension is added to the silicone rubber discs (15 mm diameter) that are fixed to the bottom of 24-well plates using vacuum grease. After 1 h and 24h at gentle agitation and 37°C, the silicone rubber discs are removed. The silicone rubber discs are rinsed with saline and transferred to 50 ml Falcon tubes containing 2 ml of saline. The attached cells are removed from the surfaces by sonication for 5 min. Sonication has been shown not to harm the cells. The resulting bacterial cell suspensions are mixed, diluted and plated on agar plates. After overnight incubation at 37°C the colony forming units (cfu) are counted. Example 4 - Antimicrobial Activity of Copolyamide Coating Containing PHMB

PHMB is compounded into the copolyamide of CA-Reg. No. 25053-13-8 as described in example 1 . The anti-biofilm activity of the coated silicone rubber discs is analyzed against S. epidermidis, E. coli and P. mirabilis as in example 3. To mimic the continuous-flow situation of a urinary catheter and to analyze the permanence of the antimicrobial surface functionality, the surfaces are washed prior to the biofilm assay. The protocols include repeated washing cycles with 1 ml of saline (10x) and incubation in large volumes of saline for 1 h and 24h.

As a result, a strong activity against biofilms of all three organisms is observed even after extensive washing demonstrating the effectiveness of the antimicrobial coating as novel antimicrobial surface functionality (figure 2).

Example 5 - Antimicrobial Activity of Coating Containing the Antimicrobial Peptide P18

To demonstrate the general applicability, the antimicrobial peptide P18 is used as antimicrobial active. P18 is compounded into the copolyamide of CA-Reg. No. 25053-13- 8 as described in example 1. The anti-biofilm activity of the coated silicone rubber discs is analyzed against S. epidermidis, E. coli and P. mirabilis as in example 3. To mimic the continuous-flow situation of a urinary catheter and to analyze the permanence of the antimicrobial surface functionality, the surfaces are washed prior to the biofilm assay. The protocols include repeated washing cycles with 1 ml of saline (10x) and incubation in large volumes of saline for 1 h and 24h.

A strong activity against biofilms of S. epidermidis and E. coli is observed even after extensive washing (E. coli after 10 washing cycles and 24 h incubation (cfu/cm ² ): 2x10 ² (invention) vs. 2x10 ⁶ (control). The lack of activity against P. mirabilis biofilms reflects the activity spectrum of the antimicrobial peptide P18 which is not active against this organism. The strong anti-biofilm activity against the susceptible organisms E. coli and S. epidermidis demonstrate the effectiveness of the present coating as novel antim- icrobial surface functionality.

Brief description of Figures:

Figure 1 shows the release of PHMB from the copolyamide as of example 1 (backing film/ultrapure water; cumulated release of PHMB in percent as a function of time).

Figure 2 shows the anti-biofilm activity of silicone rubber surfaces after coating according to example 4; Control (C, silicone rubber without antimicrobial surface functionaliza- tion), and Silicone rubber with coating containing 10 % PHM B after 10x washes and 24h in saline (A, B).