CA2241381A1 - Blood-compatible and bacteria-repellent block copolymer - Google Patents
Blood-compatible and bacteria-repellent block copolymer Download PDFInfo
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- CA2241381A1 CA2241381A1 CA 2241381 CA2241381A CA2241381A1 CA 2241381 A1 CA2241381 A1 CA 2241381A1 CA 2241381 CA2241381 CA 2241381 CA 2241381 A CA2241381 A CA 2241381A CA 2241381 A1 CA2241381 A1 CA 2241381A1
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
- C08G81/027—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G containing polyester or polycarbonate sequences
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/62—Polymers of compounds having carbon-to-carbon double bonds
- C08G18/6287—Polymers of sulfur containing compounds having carbon-to-carbon double bonds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
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- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
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- General Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Materials For Medical Uses (AREA)
- Polyurethanes Or Polyureas (AREA)
- Paints Or Removers (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Application Of Or Painting With Fluid Materials (AREA)
- Coating Of Shaped Articles Made Of Macromolecular Substances (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
Disclosed are a block copolymer comprising a blocks A which carries sulfonate and carboxyl groups and a polyurethane or polyester block B, and a composition of this block copolymer and a further polymer. Also disclosed is a process for the preparation of the block copolymer in which a copolymer C having a hydroxyl group or amino group in addition to sulfonate and carboxyl groups is reacted with a polyurethane D having terminal isocyanate groups or a polyester D having terminal carboxylic acid chloride groups.
Further disclosed is a product which is coated entirely or partly with the block copolymer or is made entirely or partly of the block copolymer for medical, hygiene, industrial, foodstuffs or bioengineering purposes.
Further disclosed is a product which is coated entirely or partly with the block copolymer or is made entirely or partly of the block copolymer for medical, hygiene, industrial, foodstuffs or bioengineering purposes.
Description
BLOOD-COMPATIBLE AND BACTERIA-REPELLENT BLOCK COPOLYMER
Field of the Invention The invention relates to a blood-compatible and bacteria-repellent block copolymer which comprises blocks which carry sulfonate and carboxyl groups as well as polyurethane or polyester blocks. The invention furthermore relates to a process for the preparation of the block copolymer and to its use. Finally, the invention relates to products which are coated entirely or partly with the block copolymer according to the invention.
Prior Art The colonization and multiplication of bacteria on surfaces is as a rule an undesirable phenomenon which i8 often associated with adverse consequences. Thus, in the dr;nk;ng water and drinks industry, bacterial populations may lead to a reduction in quality to an extent that it may ~n~Anger health.
Bacteria on or in packaging often cause decay of foodstuffs or even cause infections in the consumer. In bioengineering plants which are to be operated under sterile conditions, bacteria foreign to the plant represent a considerable risk to the process. Such bacteria can be introduced with raw materials or remain in some or all components of the plant if sterilization is not complete. By adhesion, parts of the bacteria population can withdraw from the normal ~Yc~nge of liquid during rinsing and cle~n;ng, and multiply in the system.
It is known that bacterial colonie~ form in water treatment plants (for example for desalination through O.Z. 5177 i CA 02241381 1998-06-22 membranes) or else in containers which are filled with dissolved or liquid undiluted organic substances. Such microbial occupation can lead to blockage and/or corrosive destruction of the plant.
Protection against adhesion and spread of bacteria in food, care, and here in particular in care of the elderly, and in medicine is of particular importance. In mass catering or selling of drinks, considerable risks exist if disposable utensils are not used, in order to avoid waste, and reusable utensils are not cleaned adequately. The harmful spread of bacteria in hoses and pipes which carry foodstuffs is known, as in bacterial multiplication in storage containers and in textiles in a damp and warm environment, for example in baths.
Such areas are the preferred habitat of bacteria, as are certain surfaces in areas of high public use, as, for example, in public means of transport, hospitals, telephone booths, schools and, in particular, in public toilets.
In care of the elderly and sick, the often reduced defenses of those affected require careful measures against infections, in particular on intensive care wards and in home care.
The use of medical objects and equipment during medical examinations, treatments and operations requires particular attention, especially if such equipment or objects come into contact with living tissue or with body fluids. In the case of long-term or permanent contact, for example with implants, catheters, stents, heart valves and heart pacemakers, bacterial contamination can become a life-O.Z. 5177 , CA 02241381 1998-06-22 threatening risk to the patient.
It has already been attempted in various ways to suppress the colonization and spread of bacteria on surfaces.
In J. Microbiol. Chemoth. 31 (1993), 261-271, S.E. Tebbs and T.S.J. Elliott describe paint-like coatings with quaternary onium salts as components having an antimicrobial action.
It i8 known that these salts are dissolved out of the coating material by water, aqueous or other polar media and by body fluids, and their action is thus only of short duration. This equally applies to the incorporation of silver salts into coatings, as described in WO 92/18098.
T. Ouchi and Y. Ohya describe in Progr.Polym.Sci. 20 (1995), 211 et seq. the immobilization of bactericidal active compounds on polymer surfaces by covalent bo~; ng or ionic interactions. In such cases, the germicidal actions are often significantly reduced compared with the pure active compound.
Heteropolar bonds often prove to be not sufficiently stable. Furthermore, the destruction of the germs as a rule leads to undesirable deposits on the surfaces, which mask further bactericidal action and form the basis for a subsequent bacteria population.
W. ~ohn~n et al. report in ZBI. Bakt. Suppl. 26, Gustav Fischer Verlag, Stuttgart-Jena-New York, 1994, pages 408 to 410 that the adhesion of StaPhylococcus ePidermidis on a polyurethane film is reduced if the film is pretreated by a glow discharge in the presence of oxygen and then grafted with acrylic acid.
In the case of objects for use for medical purposes, O.Z. 5177 i.e. for examinations, treatments and operations, as described above, not only the bacteria-repellent properties play a role, but also compatibility with blood, i.e. antithrombogenic properties which are as pronounced as possible, is also important. According to the international patent application WO 94/17904, membranes for medical purposes can be modified by treatment with a low pressure plasma such that, inter alia, their thrombogenic properties are reduced compared with untreated m~mhranes. Sulfur dioxide is also listed as one of the suitable plasma-forming gases. J.-C. Lin et al. describe in Biomaterials 16 (1995), 1017-1023, the plasma treatment of the inner surface of LDPE pipes, it being possible again to employ sulfur dioxide as the plasma-forming gas. The authors report that the surfaces modified by SO2 plasma contained sulfonate groups, were highly hydrophilic and were thrombogenic to a greater degree than the untreated surfaces.
The authors suggest that this is due to the combined action of surface chemistry, that is to say of the sulfonation, and the hydrophilicity of the surfaces.
A primary object of the present invention i8 to provide an enduringly blood-compatible and bacteria-repellent block copolymer which can be fixed to the surface of substrates, in particular substrates of plastic, permanently without 1088 of action and which is not inactivated by either bacteria which have been killed or by other deposits.
Summary of The Invention Thus, the preRent invention provides a block copolymer which comprises a block A which carries ~ulfonate O.Z. 5177 and carboxyl groups, as well as a polyurethane or polyester block B.
The molar ratio of the carboxyl group to the sulfonate group which, by interaction, results in the desired blood-compatible and bacteria-repellent properties of the block copolymer is preferably 0.1 to 10, more preferably 0.2 to 10, in particular 0.2 to 5. The sulfonate group means a salt of a sulfonic acid group (-S03H), preferably a physiologically acceptable salt such as an alkali metal salt.
The invention also provides a process for the preparation of this block copolymer, in which a copolymer C
containing a hydroxyl group and/or an amino group, as well as at least one monomer contA;n;ng a sulfonate group and at least one monomer contA;n;ng a carboxyl group, is reacted with a polyurethane D having terminal isocyanate groups or a polyester D having terminal carboxylic acid chloride groups or equivalent thereof.
In a particular embodiment of this process, the polyurethane D is produced ln situ, that is to say in the presence of the copolymer C, and then reacted with this.
The invention also provides a process for coating polymer substrates, in which the block copolymer is applied to a surface thereof.
In a particular embodiment of this process, the block copolymer is applied to a polyurethane substrate, when block B is a polyurethane block, and to a polyester substrate, when block B is a polyester block.
The invention also provides a composition of at O.Z. 5177 least one block copolymer according to the invention and at least one other polymer. The other polymer is preferably a polyurethane when block B is a polyurethane block, and a polyester when block B is a polyester block.
The block copolymer according to the invention, and coatings or compositionn thereof, are compatible with blood over a long period of time and act like heparin. At the same time, they reduce the adhesion and multiplication of bacteria to a high degree, even over a long period of time. Bacteria which are affected by this action are, inter alia, Staphylococcus aureus, StaPhYlococcus ePidermidis, StrePtococcus pyoqenes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Escherichia coli. If it is important, for medical uses in particular, that the block copolymer or a coating thereof is free from monomers or oligomers which are capable of migration, these can be extracted with nuitable solvents, such as ethanol. The physical and chemical properties of the substrate material r~m~in virtually llnc~nged after the coating. Undesirable side effects due to exogenous substrates liberated or due to bacteria which have been killed do not occur.
Description of Preferred Embodiments 1 Copolymer C and blocks A
Blocks A of the block copolymer are derived from copolymer C of the preparation process. The statements regarding copolymer C therefore apply mutatis mutandis also to blocks A, and vice versa. Because they are formed by a polymerization reaction initiated by free radicals, copolymers O.Z. 5177 C have a carbon skeleton. Of the various polymers C having a hydroxyl and/or an amino group (for l;nk;ng with polyurethane or polyeater B) and at leaat one monomer contA;n;ng a sulfonate group and at least one monomer contA;n;ng a carboxyl group, copolymer C1, C2 and C3 are described in more detail below.
1.1 Copolymer C1 Copolymer C1 is built up from monomera (a), (b) and (c), which are olefinically unsaturated and can be polymerized to a terpolymer in a reaction initiated by free radicala.
Monomer (a) i~ an olefinically unaaturated monomer contA;n;ng a Rulfonate group. Examples which may be mentioned are vinylRulfonates and styrenesulfonateR, such as sodium vinylaulfonate and, in particular, aodium atyrenesulfonate (o-and p-isomers), aR well aa sodium methallylaulfonate. The correapQn~;ng olefinically un~aturated sulfonic acids can also be employed as monomers for the copolymerization, and a copolymer with Rulfonic acid groups is then obtained. Such copolymers and block copolymers prepared therefrom also belong to the scope of the present invention. If the ~ulfonic acid groups are subsequently neutralized, for example with aodium hydroxide, products which correapond to thoRe prepared with olefinically unsaturated ~ulfonate monomera from the beg;nn;ng are obtained.
Monomer (b) is an olefinically unsaturated monomer containing a carboxyl group. Examples of theRe are, inter alia, acrylic acid, methacrylic acid, 4-vinylsalicylic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-O.Z. 5177 vinylbenzoic acid, crotonic acid, isocrotonic acid, methylmaleic acid, dihydroxymaleic acid, fumaric acid, methyl$umaric acid, dimethylfumaric acid, allylacetic acid and, in particular, maleic acid. Instead of the carboxyl groups, the monomers employed for the polymerization can initially contain groups derived therefrom, for example ester, amide, nitrile or anhydride groups (e.g. maleic anhydride), which can be converted into carboxyl groups in the customary manner after the polymerization. The carboxyl group in the terpolymer can furthermore also be present entirely or partly in the form of carboxylate groups. This can be achieved by neutralizing the carboxyl groups, for example by sodium hydroxide, or by employing in the copolymerization the correspo~;ng compounds cont~;n;ng carboxylate groups, instead of or in addition to the monomers mentioned which contain carboxyl groups. Such copolymers cont~; n; ng carboxylate groups and the block copolymers resulting therefrom belong to the scope of the present invention.
Monomer (c) is an olefinically unsaturated monomer cont~; n; ng a hydroxyl or amino group. Monomers cont~; n; ng a hydroxyl group, include, inter alia, a hydroxy(C2-C10)alkyl (meth)acrylates, such as hydroxyethyl acrylate, hydroxyethyl methacrylate (HEMA), which is particularly preferred, 4-hydroxybutyl acrylate and 4-hydroxybutyl methacrylate. A
particularly preferred monomer containing an amino group is, for example, 4-aminostyrene.
It is of course possible to employ correspo~; ng mixtures instead of an individual monomer (a), (b) or (c), for O.Z. 5177 example a mixture of sodium p-styrenesulfonate and sodium p-vinylsulfonate in~tead of ~odium p-styrenesulfonate alone.
The monomers mentioned can furthermore contain further functional groups in addition to the olefinic double bond and the sulfonate or carboxyl group if they do not interfere with the reactions and do not impair the desired biological actions.
Copolymer C1 may consist exclusively of monomers (a), (b) and (c). In some cases, it is possible and expedient to co-use minor amount~, for example up to 30 mol percent, based on the sum of monomers (a), (b) and (c), of further ethylenically unsaturated monomers (d) with a different or no functional group during the preparation of copolymer C1 for modification of the biological and/or processing properties of the block copolymer according to the invention. Examples which may be mentioned of such monomers are vinyl ketones, such as vinyl methyl ketone or vinyl butyl ketone;
vinylaromatic monomers, such as styrene, ~-methylstyrene or vinyltoluene; vinyl esters, such as vinyl acetate or vinyl propionate; olefins, such as ethylene, propylene, 1-butene and 1-octene; diolefins, such as 1,3-butadiene and isoprene; and N-vinylpyrrolidone. Block copolymers with low proportions of such monomers are also block copolymers according to the invention.
Monomers (a), (b), (c) and, optionally, (d) can be present in copolymer C1 as blocks or in random distribution, dep~n~; ng on the reaction procedure in the polymerization.
Copolymer C1 is prepared in the customary manner by O.Z. 5177 polymerization of the monomers-(a), (b), (c) and, if appropriate, (d), initiated by free radicals, advantageously by ~olution or emulsion polymerization. A particularly suitable solvent is water, in which the monomers and also the copolymer are usually readily soluble. Strongly polar organic solvents, such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, are also particularly suitable. The other suitable solvents include tetrahydrofuran and acetone. A
suitable ~olvent for a given combination of monomers can easily be determined by orientating experiments.
Suitable polymerization initiators are, inter alia, azonitriles, alkyl peroxides, acyl peroxides, hydroperoxides, peroxyketones, peroxyesters and percarbonates, as well as all the customary photoinitiators.
The polymerization may be initiated by heat, e.g. by heating to 60 to 100~C, or by radiation of correspo~; ng wavelength. For example, it is possible to introduce initially a portion of the monomers (a), (b) and (c) and, if appropriate, (d) into the reactor, to start the polymerization and to introduce the remainder of the monomers into the reactor as a mixture, a temperature of 60 to 100~C expediently being maintained by cooling. A random copolymer C1 may be obt~;ne~ in this manner. If a certain monomer or a proportion thereof is initially introduced into the reactor and the other monomers and, if appropriate, the remaining amount of the monomer initially introduced are added in each case by themselves in portions, a block copolymer C1 is formed. These variants are of course ideally typical limit casen. In O.Z. 5177 practice, merely as a result of the different rate of reaction of the various monomers (a), (b) and (c), in addition to regions of largely random distribution, those with a predominantly block structure are obtained, and in the ~econd case, in addition to the blocks, transition zones with random distribution of the units are also obtained.
When the polymerization has ended, dep~n~; ng on the proportions of monomers (a), (b) and (c) and, if appropriate, (d) and the solvent used, a solution or emulsion of the copolymer C1 with solids contents which can be, for example, 5 to 20% by weight in the case of solution polymerization and 40 to 60% by weight in the case of emulsion polymerization i8 obtained.
1.2 Copolymer C2 Copolymer C2 i8 prepared in a two-stage reaction. A
primary copolymer is first prepared from the monomers (a) and (b) mentioned above with respect to copolymer C1, and is modified after the polymerization, as explained below. The explanations regarding monomers (a) and (b), regarding further functional groups contained therein, if appropriate, regarding the further monomers (d) of different or without functionality which may optionally be co-used, and regarding the polymerization process given in connection with copolymer C1 apply accordingly.
After the polymerization, the primary copolymer is reacted with at least one compound having two or more groups which are reactive with an NCO or COCl group. This reaction i~ conducted in a polymer-analogous manner as a second O.Z. 5177 reaction step to give copolymer C2. As a result, at least one type of a group which is reactive with an NCO- COCl group, i8 introduced into the primary copolymer. The group reactive with NCO or COCl group is preferably a hydroxyl or amino group. Suitable polyfunctional NCO- and COCl-reactive compounds are preferably polyols, such as diols or triols;
aminoalcohols, such as amino- or N-alkylam;no~lkAnols; and polyamines, such as diamines and triamines. Examples which may be mentioned are: ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-h~ne~;ol, trimethylolpropane, ethanolamine, N-methylethanolamine, ethylenediamine, propylenediamine, hexamethylenediamine and diethylenetriamine. As a result of the reaction, a modified primary copolymer is obtained, in which the NCO- and COCl-reactive groups are arranged in side ch~;n~ which are bonded via carboxylic ester (-COO-) or carboxamide (-CONH-) groups to the ~keleton of the primary copolymer, which consists of carbon atoms. The modified primary copolymer has unreacted sulfonate groups and also remaining carboxyl groups.
For NCO- and COCl-reactive modification, the primary copolymer should be reacted with less than the equivalent amount, based on the carboxyl groups of the copolymer, of the compound having two or more groups reactive with an NCO or COCl group. The reaction may be conducted in an autoclave at an elevated temperature and under increased pressure. The course of the reaction can be monitored by means of potentiometric titration or NMR spectroscopy. Alternatively, the modification can also be carried out under normal pressure O.Z. 5177 by heating the primary copolymer and the modifying substance in a high-boiling solvent, expediently in the presence of an entrA; n; ng agent for the water formed.
Since carboxyl groups are consumed during the reaction of the primary copolymer with the polyfunctional NCO-and COCl-reactive compound to give the copolymer C2, the molar proportion of the carboxy groups of the total functionality of the primary copolymer (i.e. sulfonate plu8 carboxylate groups) must be correspo~;ngly higher if a certain ratio of carboxyl to sulfonate groups i8 envisaged for copolymer C2 (and therefore for the block copolymer according to the invention).
The amount of the polyfunctional NCO- and COCl-reactive compound employed in this reaction depends on the functionality thereof (bi- or trifunctional), the molar proportion of carboxyl group~ in the primary copolymer and the desired molar ratio of carboxyl to sulfonate groups in copolymer C2 or in the block copolymer according to the invention.
1.3 Copolymer C3 A copolymer C3 is obtA;nAhle by reacting a copolymer Cl with at leant one polyfunctional NCO- and COCl-reactive compound in a polymer-analogou~ reaction such as is used for the preparation of copolymer C2, to give the copolymer C3. As a result, in addition to the NCO- and COCl-reactive groups already present in copolymer C1, further NCO- and COCl-reactive groups are introduced. The explanations in connection with copolymers Cl and C2 apply accordingly.
O.Z. 5177 2 Polyurethane or polye~ter D and polyurethane or polye~ter bloc~ B
The polyurethAnes or polyesters D bear the same relationship to the polyurethane or polyester blocks B as copolymers C to blocks A which carry sulfonate and carboxyl groups. The explanations regarding D thus also apply accordingly to B. Because of their preparation method, polyurethanes and polyesters D and blocks B do not have a pure carbon skeleton, but have a carbon skeleton with incorporated urethane or carboxylic ester bridges.
2.1 Polyurethane D with tenminal i_G~y-~ate y v~_ and polyurethane block B
Polyurethanes D are prepared by reaction of polyisocyanates with polyols, an equivalent excess of NCO
groups with respect to the OH groups being u~ed, the extent of which determines the average molecular weight. Preferably the molecular weight is not 80 high and the polyurethAnes are preferably not crosslinked or only weakly crosslinked, 80 that the products are liquid and remain soluble in protic of aprotic solvents. Namely, preferred are substantially linear polyurethane prepolymer having NCO terminal groups.
Suitable polyisocyanates are, inter alia, tolylene diisocyanate (TDl), diphenylmethane disocyanate (MDl), dicyclohexylmethane diisocyanate (H-MDl), hexamethylene diisocyanate (HDl) and/or isophorone dii~ocyanate (lPDl).
Suitable polyols are, for example, ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentylglycol and long-chain diols, Ruch as polyethylene glycol, preferably 600 O.Z. 5177 or 1000, and correspo~; ng polypropylene glycols and poly(tetramethyleneoxy) glycols. Such long-chain polyalkylene glycols are obtA;nAhle under the trademark Hypol from Hampshire Chemical GmbH, Heidelberg, and under the trademark Vestanat and Vesticoat from Huls AG. Triols and tetraols, such as trimethylolpropane and pentaerythritol, can be used only in small amounts together with diols, because of their cro881; nk; ng properties. The preparation of the polyurethanes with terminal isocyanate groups i8 well known in polyurethane chemistry and therefore does not have to be explained further.
Tho~e polymers in which the units are indeed linked to the extent of at least 50% by urethane bridges but which are additionally also built up by other linkage principles, for example contain urea or biuret bridges, are also regarded as polyurethanes D.
2.2 Polyesters with term;nal ca~hoYylic acid chloride ~lO~
D and polyester bloc~s B
Polyesters D with terminal carboxylic acid chloride groups may be prepared in two stages. A polyester is first prepared by polyco~n~ation of polycarboxylic acids and polyols, and equivalent excess of carboxyl groups with respect to the hydroxyl groups being used, the extent of which determines the average molecular weight. The preparation of polyesters from polycarboxylic acids and polyols, preferably in the presence of acid catalysts and with removal of the water of reaction, is a known reaction, which does not have to be explained further here. The excess terminal carboxyl groups are then converted into carboxylic acid chloride groups O.Z. 5177 in the customary manner, for example with phosgene, thionyl chloride, phosphorus trichloride, phophorus pentachloride or, under particularly mild conditions with oxalyl dichloride.
Preferably the molecular weight of polyester D is relatively small and desirably polyesters D are essentially linear, 80 that the products are liquid and remain soluble in protic or aprotic solvents. Namely, preferred are substantially linear polyester prepolymer having terminal carboxylic acid chloride groups. It should be noted, however, that the terminal carboxyl groups (COOH) do not have to be absolutely necessarily converted to carboxylic acid chloride (COCl) groups, if proper conditions are chosen in the subsequent step for preparing the block copolymers.
Polycarboxylic acids which are suitable for preparation of polyesters D are, inter alia, adipic acid, dodecane-1, 10-dicarboxylic acid, naphthalene-1,5-dicarboxylic acid and phthalic acid, isophthalic acid and/or terephthalic acid. Suitable polyols are, for example, those mentioned above under 2.
Those polyesters in which the units are indeed linked to the extent of at least 50% by ester bridges but which in addition are al~o built up by linkage principles, for example contain amide, imide or ether bridges, are also regarded as polyesters D.
4. Preparation of the bloc~ copolymer~
The block copolymers are obtained by reaction of copolymers C1, C2 or C3 contA; n; ng hydroxyl and/or amino groups with the polyurethanes or polyesters D described. In O.Z. 5177 the case of reaction with a polyurethane, urethane (-OCONH-) or urea (-NHCONH-) bridges which link the blocks are formed from the terminal isocyanate groups thereof in a polyaddition reaction. In the case of reaction with polyesters with terminal carboxylic acid chloride groups (or carboxyl groups), carboxylic ester (-COO-) or carboxamide (-CONH-) bridges which link the blocks are formed in a polyco~n~ation reaction.
When the terminal groups are carboxylic acid chloride groups, hydrogen chloride is liberated. When the terminal groups are carboxyl groups, water is liberated.
The polyaddition reaction proceeds virtually to completion even under mild conditions. It corresponds to the reaction, which is well known from polyurethane chemistry, of an NCO-contA;n;ng prepolymer with a chain-length~n;ng polyol and also therefore does not have to be described in detail.
The reaction is started, for example, by mixing a portion of the two components and gradually adding the rem~;n;ng proportions, it being ensured by external or internal cooling that the reaction does not become too vigorous. The reaction temperature is as a rule below 100~C. In the case of more highly viscous polyurethanes, the viscosity can be reduced and mixing of the components can be promoted by ~;ng an inert solvent, which can be removed when the reaction has ended or, if it does not interfere with the further use of the block copolymer, can remain in the reaction mixture.
In one variant of the polyaddition reaction, which leads to block copolymers with polyurethane blocks B, copolymer C1, C2 or C3 i~ not reacted with a polyurethane O.Z. 5177 which has already been formed, but this is prepared in situ, that is to say in the presence of the copolymer, from a polyisocyanate and a polyol and is reacted with this in the reaction mixture. At the same equivalent ratios of isocyanate groups to the total hydroxyl or amino groups in copolymer C1, C2 or C3 and in the polyols, similar block copolymers are formed.
The polycon~en~ation reaction mentioned, which gives block copolymers with polyester blocks B, is also well known in itself and requires no further explanation. It proceeds even at room temperature with evolution of heat, 80 that the desired temperature is expediently maintained by cooling. The reaction mixture is advantageously heated at higher temperatures, for example at 100~C, for some time, for example 2 hours, after the exothermic reaction has subsided. The reaction proceeds particularly smoothly and under mild conditions if a base, for example a tertiary amine, such as triethylamine, is added to neutralize the hydrogen chloride formed.
~se of the block copolymer~ according to the invention Because of their bioactive properties mentioned, the block copolymers according to the invention are suitable for coating polymer substrate~, in particular those which are compatible with the block copolymers, i.e. when identical or similar recurring units are present to a considerable extent both in the block copolymer and in the polymer substrate.
Particularly preferred polymer substrates are polyurethanes when blocks B in the block copolymer according to the O.Z. 5177 invention are polyurethane blocks, and polyesters when blocks B are polyester blocks. When the blocks and the substrates are related chemically, this evidently has the effect of a particularly good adhesion. During heating of the coated substrate to a temperature close to the melting or softening point of the lower-melting or -softening component (block copolymer or substrate), an adhesion-promoting superficial dissolving, or dissolving in one another, in the boundary region possibly take~ place.
To coat the polymer substrates, the block copolymer according to the invention may be dissolved in an inert solvent, for example in tetrahydrofuran, acetone or dimethylformamide, and the solution is applied to the substrate in a known manner, for example by dipping, spraying, knife-coating, brn~h; ng or spin coating.
In one variant of the coating process, the polymer substrate is not coated with the block copolymer but may be coated with a mixture of a copolymer C1, C2 or C3, a blocked polyisocyanate and a polyol. Suitable blocking agents are, for example, methyl ethyl ketoxime and ~-caprolactam. When the coated substrate is heated to temperatures above 100 to 140~C, the block;ng agent is split off and the polyisocyanate reacts with copolymer C1, C2 or C3 and the polyol to give the block copolymer according to the invention, as described above.
Another use of the block copolymers according to the invention is that for the preparation of compositions with other polymers, in particular with tho~e polymers which are O.Z. 5177 compatible with the particular block copolymers. This is in turn the case when identical or similar recurring units occur to a considerable extent both in the block copolymer and in the other polymer. Particularly preferred polymers are polyurethanes when the blocks B in the block copolymer according to the invention are polyurethane blocks, and polyesters when the blocks B are polyester blocks. As a result of the blocks and the polymers being related chemically, the components can easily be mixed in customary mixing devices, such as screw extruders or twin-shaft extruders, and the mixtures show no demixing phenomena at all on cooling and during a relatively long storage period.
Products (i.e., shaped articles) which are coated entirely or partly with the block copolymers according to the invention, or are made entirely or partly of the compounds mentioned, are suitable for many uses where it is important to avoid or suppress adhesion and growth of bacteria. They are thus suitable, inter alia, for hygiene, industrial, foodstuffs and bioengineering processes, such as have been described above by way of example. The objects are preferably suitable for medical uses, especially if bacteria-repellent properties and compatibility with blood are simultaneously important.
However, the advantageous properties of the objects according to the invention also manifest themselves on contact with body fluids other than blood, such as lymph, or with tissue.
Medical uses are, for example, those as catheters, for example in peritoneal dialysis, for lymph drainages, wound dressings, tubes, stents, heart valves, hoses, mPmhranes and blood bags.
O.Z. 5177 The following example i~ intended to illustrate the invention further, but not to limit its scope as described in the patent claims.
Example An NCO-reactive copolymer C2 was prepared as follows:
200 ml of a 1 M solution of maleic acid in water were mixed with 200 ml of a 1 M solution of sodium styrene sulfonate in water. The reaction mixture was provided with 1 mol%, based on the total amount of monomers, of potassium peroxidisulfate as an initiator, and nitrogen was passed through for 15 minutes. The batch was heated at 60~C and stirred under a nitrogen atmosphere for 4 hours. The reaction mixture was then stirred into ethanol, the copolymer precipitating out.
60 g of the copolymer produced above were reacted with the component shown in Table 1 and under the conditions shown there in a 200 ml autoclave. The conversion was determined by potentiometric determination of the residual acid.
O.Z. 5177 Table 1 Acid units of the 2.768 copolymer (mmol) NaOH (mmol) Ethanolamine (mmol) 2.768 Water (g) 38.0 Reaction time (hours) 10 Temperature (~C) 180 Pressure (bar) 9.9 Conversion (%) 79.4 1 g of the NCO-reactive copolymer C2 thus prepared, having a hydroxyl content of 0.0019 mol/g, and 1 g of EP-UM*
767 (a linear NCO-terminal, polyurethane prepolymer based on isophorone diisocyanate from Huls AG having 0.0017 mol/g of terminal NCO groups) were dissolved in 100 ml of dimethylformamide (DMF). After addition of 1.3 mg (3.6 ~mol) of di-n-butyltin dilaurate, the mixture was heated at 100~C
for 20 minutes. The solvent was distilled off in vacuo and the resulting block copolymer with COOH and SO3 groups remained, and was washed with water and dried.
Determination of the primarY bacterial adhesion under static conditions An overnight culture of the bacteria strain Rlebsiella pneumoniae in yeast extract-peptone-glucose nutrient medium (1% + 1% + 1%) i~ centrifuged off and taken up again in phosphate-buffed saline (=PBS; 0.05 M KH2PO4, pH 7.2 + 0.9% NaCl). The mixture is diluted to a cell concentration of 108 cells/ml with PBS buffer. The suspended bacteria are * Trade-mark O.Z. 5177 brought into contact for 3 hours with the piece of film to be investigated. For this, circular pieces of film coated on both sides and having a diameter of 1.6 cm (=4.02 cm2) are pricked onto a dissecting needle and ~hAk~n with the cell suspension. Films coated on one side are clamped in the form of a circular, flat disk of 4.5 cm diameter with a supporting m~mhrane of flexible PVC 2-3 cm thick into a membrane filter apparatus. The cell suspension is poured onto the side facing upwards, with the coating to be tested, and the system is ~hAkPn for 3 hours. The membrane filter apparatus must be tight, i.e. no cell suspension must flow out through leAk;ng cells.
At the end of the contact period, the bacteria suspension is sucked off with a water pump and, for washing, the pieces of film are ~hAk~n with 20 ml of sterile PBS
solution in a 100 ml glass beaker for 2 minutes. The piece of film is dipped into sterile PBS solution again and then extracted in 10 ml of heated TRIS/EDTA (0.1 M
trishydroxyethylaminomethane, 4 mM ethylenediaminetetraacetic acid, brought to pH 7.8 with HC1) in a boiling water bath for 2 minutes.
Small Eppendorf cups are filled with the extraction solution and are frozen immediately at -20~C until the adenosine triphosphate (ATP) extracted is determined by bioluminescence. The determination is carried out as follows:
100 ~1 of reagent mix (bioluminescence test CLS* II, BOEHRINGER M~ TM GmbH) are introduced into a transparent * Trade-mark O.Z. 5177 tube of polycarbonate, and the light pulses are integrated over a period of 10 seconds in a LUMAT LB9501 light pulse measuring instrument (Laboratorien Prof. Berthold GmbH, 75323 Bad Wildbad, Germany). A 100 ~1 sample is then added and measured again. The relative light units (RLU) are obtained by subtraction of the light pulsea in the reagent mix from the number of light pulses measured in the complete batch. This value is related to the number of bacteria adhered to the film. The conversion factor between the RLU value and the bacterial count is determined by extracting an aliquot of 0.1 ml of the bacteria suspension with 108 cells/ml of hot TRIS/EDTA and then determining the ATP content.
The block copolymer was compounded to the extent of 10% by weight into Tecoflex (a polyurethane based on 4,4-methylene(cyclohexyl isocyanate), polytetramethyleneoxy glycol and 1,4-butanediol from Thermedix, Ha~hurg). The block copolymer and polyurethane get mixed without problems and showed demixing phenomena neither on cooling nor during storage over relatively long periods of time. Measurement of the primary adhesion of bacteria under static conditions in accordance with the method above showed a reduction of 70%
compared with Tecoflex .
The block copolymer was swollen into a Tecoflex film by laying the film in a 20% by weight solution of the block copolymer in DMF for 30 minutes and, after removal, * Trade-mark O.Z. 5177 rin~ing it with water. Meaqurement of the primary adhesion of bacteria under static conditions in accordance with the method above showed a reduction of 75% compared with Tecoflex .
* Trade-mark O.Z. 5177
Field of the Invention The invention relates to a blood-compatible and bacteria-repellent block copolymer which comprises blocks which carry sulfonate and carboxyl groups as well as polyurethane or polyester blocks. The invention furthermore relates to a process for the preparation of the block copolymer and to its use. Finally, the invention relates to products which are coated entirely or partly with the block copolymer according to the invention.
Prior Art The colonization and multiplication of bacteria on surfaces is as a rule an undesirable phenomenon which i8 often associated with adverse consequences. Thus, in the dr;nk;ng water and drinks industry, bacterial populations may lead to a reduction in quality to an extent that it may ~n~Anger health.
Bacteria on or in packaging often cause decay of foodstuffs or even cause infections in the consumer. In bioengineering plants which are to be operated under sterile conditions, bacteria foreign to the plant represent a considerable risk to the process. Such bacteria can be introduced with raw materials or remain in some or all components of the plant if sterilization is not complete. By adhesion, parts of the bacteria population can withdraw from the normal ~Yc~nge of liquid during rinsing and cle~n;ng, and multiply in the system.
It is known that bacterial colonie~ form in water treatment plants (for example for desalination through O.Z. 5177 i CA 02241381 1998-06-22 membranes) or else in containers which are filled with dissolved or liquid undiluted organic substances. Such microbial occupation can lead to blockage and/or corrosive destruction of the plant.
Protection against adhesion and spread of bacteria in food, care, and here in particular in care of the elderly, and in medicine is of particular importance. In mass catering or selling of drinks, considerable risks exist if disposable utensils are not used, in order to avoid waste, and reusable utensils are not cleaned adequately. The harmful spread of bacteria in hoses and pipes which carry foodstuffs is known, as in bacterial multiplication in storage containers and in textiles in a damp and warm environment, for example in baths.
Such areas are the preferred habitat of bacteria, as are certain surfaces in areas of high public use, as, for example, in public means of transport, hospitals, telephone booths, schools and, in particular, in public toilets.
In care of the elderly and sick, the often reduced defenses of those affected require careful measures against infections, in particular on intensive care wards and in home care.
The use of medical objects and equipment during medical examinations, treatments and operations requires particular attention, especially if such equipment or objects come into contact with living tissue or with body fluids. In the case of long-term or permanent contact, for example with implants, catheters, stents, heart valves and heart pacemakers, bacterial contamination can become a life-O.Z. 5177 , CA 02241381 1998-06-22 threatening risk to the patient.
It has already been attempted in various ways to suppress the colonization and spread of bacteria on surfaces.
In J. Microbiol. Chemoth. 31 (1993), 261-271, S.E. Tebbs and T.S.J. Elliott describe paint-like coatings with quaternary onium salts as components having an antimicrobial action.
It i8 known that these salts are dissolved out of the coating material by water, aqueous or other polar media and by body fluids, and their action is thus only of short duration. This equally applies to the incorporation of silver salts into coatings, as described in WO 92/18098.
T. Ouchi and Y. Ohya describe in Progr.Polym.Sci. 20 (1995), 211 et seq. the immobilization of bactericidal active compounds on polymer surfaces by covalent bo~; ng or ionic interactions. In such cases, the germicidal actions are often significantly reduced compared with the pure active compound.
Heteropolar bonds often prove to be not sufficiently stable. Furthermore, the destruction of the germs as a rule leads to undesirable deposits on the surfaces, which mask further bactericidal action and form the basis for a subsequent bacteria population.
W. ~ohn~n et al. report in ZBI. Bakt. Suppl. 26, Gustav Fischer Verlag, Stuttgart-Jena-New York, 1994, pages 408 to 410 that the adhesion of StaPhylococcus ePidermidis on a polyurethane film is reduced if the film is pretreated by a glow discharge in the presence of oxygen and then grafted with acrylic acid.
In the case of objects for use for medical purposes, O.Z. 5177 i.e. for examinations, treatments and operations, as described above, not only the bacteria-repellent properties play a role, but also compatibility with blood, i.e. antithrombogenic properties which are as pronounced as possible, is also important. According to the international patent application WO 94/17904, membranes for medical purposes can be modified by treatment with a low pressure plasma such that, inter alia, their thrombogenic properties are reduced compared with untreated m~mhranes. Sulfur dioxide is also listed as one of the suitable plasma-forming gases. J.-C. Lin et al. describe in Biomaterials 16 (1995), 1017-1023, the plasma treatment of the inner surface of LDPE pipes, it being possible again to employ sulfur dioxide as the plasma-forming gas. The authors report that the surfaces modified by SO2 plasma contained sulfonate groups, were highly hydrophilic and were thrombogenic to a greater degree than the untreated surfaces.
The authors suggest that this is due to the combined action of surface chemistry, that is to say of the sulfonation, and the hydrophilicity of the surfaces.
A primary object of the present invention i8 to provide an enduringly blood-compatible and bacteria-repellent block copolymer which can be fixed to the surface of substrates, in particular substrates of plastic, permanently without 1088 of action and which is not inactivated by either bacteria which have been killed or by other deposits.
Summary of The Invention Thus, the preRent invention provides a block copolymer which comprises a block A which carries ~ulfonate O.Z. 5177 and carboxyl groups, as well as a polyurethane or polyester block B.
The molar ratio of the carboxyl group to the sulfonate group which, by interaction, results in the desired blood-compatible and bacteria-repellent properties of the block copolymer is preferably 0.1 to 10, more preferably 0.2 to 10, in particular 0.2 to 5. The sulfonate group means a salt of a sulfonic acid group (-S03H), preferably a physiologically acceptable salt such as an alkali metal salt.
The invention also provides a process for the preparation of this block copolymer, in which a copolymer C
containing a hydroxyl group and/or an amino group, as well as at least one monomer contA;n;ng a sulfonate group and at least one monomer contA;n;ng a carboxyl group, is reacted with a polyurethane D having terminal isocyanate groups or a polyester D having terminal carboxylic acid chloride groups or equivalent thereof.
In a particular embodiment of this process, the polyurethane D is produced ln situ, that is to say in the presence of the copolymer C, and then reacted with this.
The invention also provides a process for coating polymer substrates, in which the block copolymer is applied to a surface thereof.
In a particular embodiment of this process, the block copolymer is applied to a polyurethane substrate, when block B is a polyurethane block, and to a polyester substrate, when block B is a polyester block.
The invention also provides a composition of at O.Z. 5177 least one block copolymer according to the invention and at least one other polymer. The other polymer is preferably a polyurethane when block B is a polyurethane block, and a polyester when block B is a polyester block.
The block copolymer according to the invention, and coatings or compositionn thereof, are compatible with blood over a long period of time and act like heparin. At the same time, they reduce the adhesion and multiplication of bacteria to a high degree, even over a long period of time. Bacteria which are affected by this action are, inter alia, Staphylococcus aureus, StaPhYlococcus ePidermidis, StrePtococcus pyoqenes, Klebsiella pneumoniae, Pseudomonas aeruqinosa and Escherichia coli. If it is important, for medical uses in particular, that the block copolymer or a coating thereof is free from monomers or oligomers which are capable of migration, these can be extracted with nuitable solvents, such as ethanol. The physical and chemical properties of the substrate material r~m~in virtually llnc~nged after the coating. Undesirable side effects due to exogenous substrates liberated or due to bacteria which have been killed do not occur.
Description of Preferred Embodiments 1 Copolymer C and blocks A
Blocks A of the block copolymer are derived from copolymer C of the preparation process. The statements regarding copolymer C therefore apply mutatis mutandis also to blocks A, and vice versa. Because they are formed by a polymerization reaction initiated by free radicals, copolymers O.Z. 5177 C have a carbon skeleton. Of the various polymers C having a hydroxyl and/or an amino group (for l;nk;ng with polyurethane or polyeater B) and at leaat one monomer contA;n;ng a sulfonate group and at least one monomer contA;n;ng a carboxyl group, copolymer C1, C2 and C3 are described in more detail below.
1.1 Copolymer C1 Copolymer C1 is built up from monomera (a), (b) and (c), which are olefinically unsaturated and can be polymerized to a terpolymer in a reaction initiated by free radicala.
Monomer (a) i~ an olefinically unaaturated monomer contA;n;ng a Rulfonate group. Examples which may be mentioned are vinylRulfonates and styrenesulfonateR, such as sodium vinylaulfonate and, in particular, aodium atyrenesulfonate (o-and p-isomers), aR well aa sodium methallylaulfonate. The correapQn~;ng olefinically un~aturated sulfonic acids can also be employed as monomers for the copolymerization, and a copolymer with Rulfonic acid groups is then obtained. Such copolymers and block copolymers prepared therefrom also belong to the scope of the present invention. If the ~ulfonic acid groups are subsequently neutralized, for example with aodium hydroxide, products which correapond to thoRe prepared with olefinically unsaturated ~ulfonate monomera from the beg;nn;ng are obtained.
Monomer (b) is an olefinically unsaturated monomer containing a carboxyl group. Examples of theRe are, inter alia, acrylic acid, methacrylic acid, 4-vinylsalicylic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-O.Z. 5177 vinylbenzoic acid, crotonic acid, isocrotonic acid, methylmaleic acid, dihydroxymaleic acid, fumaric acid, methyl$umaric acid, dimethylfumaric acid, allylacetic acid and, in particular, maleic acid. Instead of the carboxyl groups, the monomers employed for the polymerization can initially contain groups derived therefrom, for example ester, amide, nitrile or anhydride groups (e.g. maleic anhydride), which can be converted into carboxyl groups in the customary manner after the polymerization. The carboxyl group in the terpolymer can furthermore also be present entirely or partly in the form of carboxylate groups. This can be achieved by neutralizing the carboxyl groups, for example by sodium hydroxide, or by employing in the copolymerization the correspo~;ng compounds cont~;n;ng carboxylate groups, instead of or in addition to the monomers mentioned which contain carboxyl groups. Such copolymers cont~; n; ng carboxylate groups and the block copolymers resulting therefrom belong to the scope of the present invention.
Monomer (c) is an olefinically unsaturated monomer cont~; n; ng a hydroxyl or amino group. Monomers cont~; n; ng a hydroxyl group, include, inter alia, a hydroxy(C2-C10)alkyl (meth)acrylates, such as hydroxyethyl acrylate, hydroxyethyl methacrylate (HEMA), which is particularly preferred, 4-hydroxybutyl acrylate and 4-hydroxybutyl methacrylate. A
particularly preferred monomer containing an amino group is, for example, 4-aminostyrene.
It is of course possible to employ correspo~; ng mixtures instead of an individual monomer (a), (b) or (c), for O.Z. 5177 example a mixture of sodium p-styrenesulfonate and sodium p-vinylsulfonate in~tead of ~odium p-styrenesulfonate alone.
The monomers mentioned can furthermore contain further functional groups in addition to the olefinic double bond and the sulfonate or carboxyl group if they do not interfere with the reactions and do not impair the desired biological actions.
Copolymer C1 may consist exclusively of monomers (a), (b) and (c). In some cases, it is possible and expedient to co-use minor amount~, for example up to 30 mol percent, based on the sum of monomers (a), (b) and (c), of further ethylenically unsaturated monomers (d) with a different or no functional group during the preparation of copolymer C1 for modification of the biological and/or processing properties of the block copolymer according to the invention. Examples which may be mentioned of such monomers are vinyl ketones, such as vinyl methyl ketone or vinyl butyl ketone;
vinylaromatic monomers, such as styrene, ~-methylstyrene or vinyltoluene; vinyl esters, such as vinyl acetate or vinyl propionate; olefins, such as ethylene, propylene, 1-butene and 1-octene; diolefins, such as 1,3-butadiene and isoprene; and N-vinylpyrrolidone. Block copolymers with low proportions of such monomers are also block copolymers according to the invention.
Monomers (a), (b), (c) and, optionally, (d) can be present in copolymer C1 as blocks or in random distribution, dep~n~; ng on the reaction procedure in the polymerization.
Copolymer C1 is prepared in the customary manner by O.Z. 5177 polymerization of the monomers-(a), (b), (c) and, if appropriate, (d), initiated by free radicals, advantageously by ~olution or emulsion polymerization. A particularly suitable solvent is water, in which the monomers and also the copolymer are usually readily soluble. Strongly polar organic solvents, such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, are also particularly suitable. The other suitable solvents include tetrahydrofuran and acetone. A
suitable ~olvent for a given combination of monomers can easily be determined by orientating experiments.
Suitable polymerization initiators are, inter alia, azonitriles, alkyl peroxides, acyl peroxides, hydroperoxides, peroxyketones, peroxyesters and percarbonates, as well as all the customary photoinitiators.
The polymerization may be initiated by heat, e.g. by heating to 60 to 100~C, or by radiation of correspo~; ng wavelength. For example, it is possible to introduce initially a portion of the monomers (a), (b) and (c) and, if appropriate, (d) into the reactor, to start the polymerization and to introduce the remainder of the monomers into the reactor as a mixture, a temperature of 60 to 100~C expediently being maintained by cooling. A random copolymer C1 may be obt~;ne~ in this manner. If a certain monomer or a proportion thereof is initially introduced into the reactor and the other monomers and, if appropriate, the remaining amount of the monomer initially introduced are added in each case by themselves in portions, a block copolymer C1 is formed. These variants are of course ideally typical limit casen. In O.Z. 5177 practice, merely as a result of the different rate of reaction of the various monomers (a), (b) and (c), in addition to regions of largely random distribution, those with a predominantly block structure are obtained, and in the ~econd case, in addition to the blocks, transition zones with random distribution of the units are also obtained.
When the polymerization has ended, dep~n~; ng on the proportions of monomers (a), (b) and (c) and, if appropriate, (d) and the solvent used, a solution or emulsion of the copolymer C1 with solids contents which can be, for example, 5 to 20% by weight in the case of solution polymerization and 40 to 60% by weight in the case of emulsion polymerization i8 obtained.
1.2 Copolymer C2 Copolymer C2 i8 prepared in a two-stage reaction. A
primary copolymer is first prepared from the monomers (a) and (b) mentioned above with respect to copolymer C1, and is modified after the polymerization, as explained below. The explanations regarding monomers (a) and (b), regarding further functional groups contained therein, if appropriate, regarding the further monomers (d) of different or without functionality which may optionally be co-used, and regarding the polymerization process given in connection with copolymer C1 apply accordingly.
After the polymerization, the primary copolymer is reacted with at least one compound having two or more groups which are reactive with an NCO or COCl group. This reaction i~ conducted in a polymer-analogous manner as a second O.Z. 5177 reaction step to give copolymer C2. As a result, at least one type of a group which is reactive with an NCO- COCl group, i8 introduced into the primary copolymer. The group reactive with NCO or COCl group is preferably a hydroxyl or amino group. Suitable polyfunctional NCO- and COCl-reactive compounds are preferably polyols, such as diols or triols;
aminoalcohols, such as amino- or N-alkylam;no~lkAnols; and polyamines, such as diamines and triamines. Examples which may be mentioned are: ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-h~ne~;ol, trimethylolpropane, ethanolamine, N-methylethanolamine, ethylenediamine, propylenediamine, hexamethylenediamine and diethylenetriamine. As a result of the reaction, a modified primary copolymer is obtained, in which the NCO- and COCl-reactive groups are arranged in side ch~;n~ which are bonded via carboxylic ester (-COO-) or carboxamide (-CONH-) groups to the ~keleton of the primary copolymer, which consists of carbon atoms. The modified primary copolymer has unreacted sulfonate groups and also remaining carboxyl groups.
For NCO- and COCl-reactive modification, the primary copolymer should be reacted with less than the equivalent amount, based on the carboxyl groups of the copolymer, of the compound having two or more groups reactive with an NCO or COCl group. The reaction may be conducted in an autoclave at an elevated temperature and under increased pressure. The course of the reaction can be monitored by means of potentiometric titration or NMR spectroscopy. Alternatively, the modification can also be carried out under normal pressure O.Z. 5177 by heating the primary copolymer and the modifying substance in a high-boiling solvent, expediently in the presence of an entrA; n; ng agent for the water formed.
Since carboxyl groups are consumed during the reaction of the primary copolymer with the polyfunctional NCO-and COCl-reactive compound to give the copolymer C2, the molar proportion of the carboxy groups of the total functionality of the primary copolymer (i.e. sulfonate plu8 carboxylate groups) must be correspo~;ngly higher if a certain ratio of carboxyl to sulfonate groups i8 envisaged for copolymer C2 (and therefore for the block copolymer according to the invention).
The amount of the polyfunctional NCO- and COCl-reactive compound employed in this reaction depends on the functionality thereof (bi- or trifunctional), the molar proportion of carboxyl group~ in the primary copolymer and the desired molar ratio of carboxyl to sulfonate groups in copolymer C2 or in the block copolymer according to the invention.
1.3 Copolymer C3 A copolymer C3 is obtA;nAhle by reacting a copolymer Cl with at leant one polyfunctional NCO- and COCl-reactive compound in a polymer-analogou~ reaction such as is used for the preparation of copolymer C2, to give the copolymer C3. As a result, in addition to the NCO- and COCl-reactive groups already present in copolymer C1, further NCO- and COCl-reactive groups are introduced. The explanations in connection with copolymers Cl and C2 apply accordingly.
O.Z. 5177 2 Polyurethane or polye~ter D and polyurethane or polye~ter bloc~ B
The polyurethAnes or polyesters D bear the same relationship to the polyurethane or polyester blocks B as copolymers C to blocks A which carry sulfonate and carboxyl groups. The explanations regarding D thus also apply accordingly to B. Because of their preparation method, polyurethanes and polyesters D and blocks B do not have a pure carbon skeleton, but have a carbon skeleton with incorporated urethane or carboxylic ester bridges.
2.1 Polyurethane D with tenminal i_G~y-~ate y v~_ and polyurethane block B
Polyurethanes D are prepared by reaction of polyisocyanates with polyols, an equivalent excess of NCO
groups with respect to the OH groups being u~ed, the extent of which determines the average molecular weight. Preferably the molecular weight is not 80 high and the polyurethAnes are preferably not crosslinked or only weakly crosslinked, 80 that the products are liquid and remain soluble in protic of aprotic solvents. Namely, preferred are substantially linear polyurethane prepolymer having NCO terminal groups.
Suitable polyisocyanates are, inter alia, tolylene diisocyanate (TDl), diphenylmethane disocyanate (MDl), dicyclohexylmethane diisocyanate (H-MDl), hexamethylene diisocyanate (HDl) and/or isophorone dii~ocyanate (lPDl).
Suitable polyols are, for example, ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentylglycol and long-chain diols, Ruch as polyethylene glycol, preferably 600 O.Z. 5177 or 1000, and correspo~; ng polypropylene glycols and poly(tetramethyleneoxy) glycols. Such long-chain polyalkylene glycols are obtA;nAhle under the trademark Hypol from Hampshire Chemical GmbH, Heidelberg, and under the trademark Vestanat and Vesticoat from Huls AG. Triols and tetraols, such as trimethylolpropane and pentaerythritol, can be used only in small amounts together with diols, because of their cro881; nk; ng properties. The preparation of the polyurethanes with terminal isocyanate groups i8 well known in polyurethane chemistry and therefore does not have to be explained further.
Tho~e polymers in which the units are indeed linked to the extent of at least 50% by urethane bridges but which are additionally also built up by other linkage principles, for example contain urea or biuret bridges, are also regarded as polyurethanes D.
2.2 Polyesters with term;nal ca~hoYylic acid chloride ~lO~
D and polyester bloc~s B
Polyesters D with terminal carboxylic acid chloride groups may be prepared in two stages. A polyester is first prepared by polyco~n~ation of polycarboxylic acids and polyols, and equivalent excess of carboxyl groups with respect to the hydroxyl groups being used, the extent of which determines the average molecular weight. The preparation of polyesters from polycarboxylic acids and polyols, preferably in the presence of acid catalysts and with removal of the water of reaction, is a known reaction, which does not have to be explained further here. The excess terminal carboxyl groups are then converted into carboxylic acid chloride groups O.Z. 5177 in the customary manner, for example with phosgene, thionyl chloride, phosphorus trichloride, phophorus pentachloride or, under particularly mild conditions with oxalyl dichloride.
Preferably the molecular weight of polyester D is relatively small and desirably polyesters D are essentially linear, 80 that the products are liquid and remain soluble in protic or aprotic solvents. Namely, preferred are substantially linear polyester prepolymer having terminal carboxylic acid chloride groups. It should be noted, however, that the terminal carboxyl groups (COOH) do not have to be absolutely necessarily converted to carboxylic acid chloride (COCl) groups, if proper conditions are chosen in the subsequent step for preparing the block copolymers.
Polycarboxylic acids which are suitable for preparation of polyesters D are, inter alia, adipic acid, dodecane-1, 10-dicarboxylic acid, naphthalene-1,5-dicarboxylic acid and phthalic acid, isophthalic acid and/or terephthalic acid. Suitable polyols are, for example, those mentioned above under 2.
Those polyesters in which the units are indeed linked to the extent of at least 50% by ester bridges but which in addition are al~o built up by linkage principles, for example contain amide, imide or ether bridges, are also regarded as polyesters D.
4. Preparation of the bloc~ copolymer~
The block copolymers are obtained by reaction of copolymers C1, C2 or C3 contA; n; ng hydroxyl and/or amino groups with the polyurethanes or polyesters D described. In O.Z. 5177 the case of reaction with a polyurethane, urethane (-OCONH-) or urea (-NHCONH-) bridges which link the blocks are formed from the terminal isocyanate groups thereof in a polyaddition reaction. In the case of reaction with polyesters with terminal carboxylic acid chloride groups (or carboxyl groups), carboxylic ester (-COO-) or carboxamide (-CONH-) bridges which link the blocks are formed in a polyco~n~ation reaction.
When the terminal groups are carboxylic acid chloride groups, hydrogen chloride is liberated. When the terminal groups are carboxyl groups, water is liberated.
The polyaddition reaction proceeds virtually to completion even under mild conditions. It corresponds to the reaction, which is well known from polyurethane chemistry, of an NCO-contA;n;ng prepolymer with a chain-length~n;ng polyol and also therefore does not have to be described in detail.
The reaction is started, for example, by mixing a portion of the two components and gradually adding the rem~;n;ng proportions, it being ensured by external or internal cooling that the reaction does not become too vigorous. The reaction temperature is as a rule below 100~C. In the case of more highly viscous polyurethanes, the viscosity can be reduced and mixing of the components can be promoted by ~;ng an inert solvent, which can be removed when the reaction has ended or, if it does not interfere with the further use of the block copolymer, can remain in the reaction mixture.
In one variant of the polyaddition reaction, which leads to block copolymers with polyurethane blocks B, copolymer C1, C2 or C3 i~ not reacted with a polyurethane O.Z. 5177 which has already been formed, but this is prepared in situ, that is to say in the presence of the copolymer, from a polyisocyanate and a polyol and is reacted with this in the reaction mixture. At the same equivalent ratios of isocyanate groups to the total hydroxyl or amino groups in copolymer C1, C2 or C3 and in the polyols, similar block copolymers are formed.
The polycon~en~ation reaction mentioned, which gives block copolymers with polyester blocks B, is also well known in itself and requires no further explanation. It proceeds even at room temperature with evolution of heat, 80 that the desired temperature is expediently maintained by cooling. The reaction mixture is advantageously heated at higher temperatures, for example at 100~C, for some time, for example 2 hours, after the exothermic reaction has subsided. The reaction proceeds particularly smoothly and under mild conditions if a base, for example a tertiary amine, such as triethylamine, is added to neutralize the hydrogen chloride formed.
~se of the block copolymer~ according to the invention Because of their bioactive properties mentioned, the block copolymers according to the invention are suitable for coating polymer substrate~, in particular those which are compatible with the block copolymers, i.e. when identical or similar recurring units are present to a considerable extent both in the block copolymer and in the polymer substrate.
Particularly preferred polymer substrates are polyurethanes when blocks B in the block copolymer according to the O.Z. 5177 invention are polyurethane blocks, and polyesters when blocks B are polyester blocks. When the blocks and the substrates are related chemically, this evidently has the effect of a particularly good adhesion. During heating of the coated substrate to a temperature close to the melting or softening point of the lower-melting or -softening component (block copolymer or substrate), an adhesion-promoting superficial dissolving, or dissolving in one another, in the boundary region possibly take~ place.
To coat the polymer substrates, the block copolymer according to the invention may be dissolved in an inert solvent, for example in tetrahydrofuran, acetone or dimethylformamide, and the solution is applied to the substrate in a known manner, for example by dipping, spraying, knife-coating, brn~h; ng or spin coating.
In one variant of the coating process, the polymer substrate is not coated with the block copolymer but may be coated with a mixture of a copolymer C1, C2 or C3, a blocked polyisocyanate and a polyol. Suitable blocking agents are, for example, methyl ethyl ketoxime and ~-caprolactam. When the coated substrate is heated to temperatures above 100 to 140~C, the block;ng agent is split off and the polyisocyanate reacts with copolymer C1, C2 or C3 and the polyol to give the block copolymer according to the invention, as described above.
Another use of the block copolymers according to the invention is that for the preparation of compositions with other polymers, in particular with tho~e polymers which are O.Z. 5177 compatible with the particular block copolymers. This is in turn the case when identical or similar recurring units occur to a considerable extent both in the block copolymer and in the other polymer. Particularly preferred polymers are polyurethanes when the blocks B in the block copolymer according to the invention are polyurethane blocks, and polyesters when the blocks B are polyester blocks. As a result of the blocks and the polymers being related chemically, the components can easily be mixed in customary mixing devices, such as screw extruders or twin-shaft extruders, and the mixtures show no demixing phenomena at all on cooling and during a relatively long storage period.
Products (i.e., shaped articles) which are coated entirely or partly with the block copolymers according to the invention, or are made entirely or partly of the compounds mentioned, are suitable for many uses where it is important to avoid or suppress adhesion and growth of bacteria. They are thus suitable, inter alia, for hygiene, industrial, foodstuffs and bioengineering processes, such as have been described above by way of example. The objects are preferably suitable for medical uses, especially if bacteria-repellent properties and compatibility with blood are simultaneously important.
However, the advantageous properties of the objects according to the invention also manifest themselves on contact with body fluids other than blood, such as lymph, or with tissue.
Medical uses are, for example, those as catheters, for example in peritoneal dialysis, for lymph drainages, wound dressings, tubes, stents, heart valves, hoses, mPmhranes and blood bags.
O.Z. 5177 The following example i~ intended to illustrate the invention further, but not to limit its scope as described in the patent claims.
Example An NCO-reactive copolymer C2 was prepared as follows:
200 ml of a 1 M solution of maleic acid in water were mixed with 200 ml of a 1 M solution of sodium styrene sulfonate in water. The reaction mixture was provided with 1 mol%, based on the total amount of monomers, of potassium peroxidisulfate as an initiator, and nitrogen was passed through for 15 minutes. The batch was heated at 60~C and stirred under a nitrogen atmosphere for 4 hours. The reaction mixture was then stirred into ethanol, the copolymer precipitating out.
60 g of the copolymer produced above were reacted with the component shown in Table 1 and under the conditions shown there in a 200 ml autoclave. The conversion was determined by potentiometric determination of the residual acid.
O.Z. 5177 Table 1 Acid units of the 2.768 copolymer (mmol) NaOH (mmol) Ethanolamine (mmol) 2.768 Water (g) 38.0 Reaction time (hours) 10 Temperature (~C) 180 Pressure (bar) 9.9 Conversion (%) 79.4 1 g of the NCO-reactive copolymer C2 thus prepared, having a hydroxyl content of 0.0019 mol/g, and 1 g of EP-UM*
767 (a linear NCO-terminal, polyurethane prepolymer based on isophorone diisocyanate from Huls AG having 0.0017 mol/g of terminal NCO groups) were dissolved in 100 ml of dimethylformamide (DMF). After addition of 1.3 mg (3.6 ~mol) of di-n-butyltin dilaurate, the mixture was heated at 100~C
for 20 minutes. The solvent was distilled off in vacuo and the resulting block copolymer with COOH and SO3 groups remained, and was washed with water and dried.
Determination of the primarY bacterial adhesion under static conditions An overnight culture of the bacteria strain Rlebsiella pneumoniae in yeast extract-peptone-glucose nutrient medium (1% + 1% + 1%) i~ centrifuged off and taken up again in phosphate-buffed saline (=PBS; 0.05 M KH2PO4, pH 7.2 + 0.9% NaCl). The mixture is diluted to a cell concentration of 108 cells/ml with PBS buffer. The suspended bacteria are * Trade-mark O.Z. 5177 brought into contact for 3 hours with the piece of film to be investigated. For this, circular pieces of film coated on both sides and having a diameter of 1.6 cm (=4.02 cm2) are pricked onto a dissecting needle and ~hAk~n with the cell suspension. Films coated on one side are clamped in the form of a circular, flat disk of 4.5 cm diameter with a supporting m~mhrane of flexible PVC 2-3 cm thick into a membrane filter apparatus. The cell suspension is poured onto the side facing upwards, with the coating to be tested, and the system is ~hAkPn for 3 hours. The membrane filter apparatus must be tight, i.e. no cell suspension must flow out through leAk;ng cells.
At the end of the contact period, the bacteria suspension is sucked off with a water pump and, for washing, the pieces of film are ~hAk~n with 20 ml of sterile PBS
solution in a 100 ml glass beaker for 2 minutes. The piece of film is dipped into sterile PBS solution again and then extracted in 10 ml of heated TRIS/EDTA (0.1 M
trishydroxyethylaminomethane, 4 mM ethylenediaminetetraacetic acid, brought to pH 7.8 with HC1) in a boiling water bath for 2 minutes.
Small Eppendorf cups are filled with the extraction solution and are frozen immediately at -20~C until the adenosine triphosphate (ATP) extracted is determined by bioluminescence. The determination is carried out as follows:
100 ~1 of reagent mix (bioluminescence test CLS* II, BOEHRINGER M~ TM GmbH) are introduced into a transparent * Trade-mark O.Z. 5177 tube of polycarbonate, and the light pulses are integrated over a period of 10 seconds in a LUMAT LB9501 light pulse measuring instrument (Laboratorien Prof. Berthold GmbH, 75323 Bad Wildbad, Germany). A 100 ~1 sample is then added and measured again. The relative light units (RLU) are obtained by subtraction of the light pulsea in the reagent mix from the number of light pulses measured in the complete batch. This value is related to the number of bacteria adhered to the film. The conversion factor between the RLU value and the bacterial count is determined by extracting an aliquot of 0.1 ml of the bacteria suspension with 108 cells/ml of hot TRIS/EDTA and then determining the ATP content.
The block copolymer was compounded to the extent of 10% by weight into Tecoflex (a polyurethane based on 4,4-methylene(cyclohexyl isocyanate), polytetramethyleneoxy glycol and 1,4-butanediol from Thermedix, Ha~hurg). The block copolymer and polyurethane get mixed without problems and showed demixing phenomena neither on cooling nor during storage over relatively long periods of time. Measurement of the primary adhesion of bacteria under static conditions in accordance with the method above showed a reduction of 70%
compared with Tecoflex .
The block copolymer was swollen into a Tecoflex film by laying the film in a 20% by weight solution of the block copolymer in DMF for 30 minutes and, after removal, * Trade-mark O.Z. 5177 rin~ing it with water. Meaqurement of the primary adhesion of bacteria under static conditions in accordance with the method above showed a reduction of 75% compared with Tecoflex .
* Trade-mark O.Z. 5177
Claims (31)
1. A block copolymer comprising a block A which carries sulfonate and carboxyl groups and a polyurethane or polyester block B.
2. The block copolymer according to claim 1, wherein block A is derived from a copolymer C which comprises residues of:
(a) at least one monomer containing a sulfonate group, (b) at least one monomer containing a carboxyl group, and (c) at least one monomer containing a hydroxyl or an amino group.
(a) at least one monomer containing a sulfonate group, (b) at least one monomer containing a carboxyl group, and (c) at least one monomer containing a hydroxyl or an amino group.
3. The block copolymer according to claim 2, wherein copolymer C comprises residues of:
(a) a vinylsulfonate or styrenesulfonate, and (b) a monomer selected from the group consisting of acrylic acid, methacrylic acid, 4-vinylsalicylic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic, crotonic acid, isocrotonic acid, methylmaleic acid, hydroxymaleic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid and maleic acid.
(a) a vinylsulfonate or styrenesulfonate, and (b) a monomer selected from the group consisting of acrylic acid, methacrylic acid, 4-vinylsalicylic acid, vinylacetic acid, cinnamic acid, 4-vinylbenzoic acid, 2-vinylbenzoic, crotonic acid, isocrotonic acid, methylmaleic acid, hydroxymaleic acid, fumaric acid, methylfumaric acid, dimethylfumaric acid, allylacetic acid and maleic acid.
4. The block copolymer according to claim 3, wherein the hydroxyl and/or amino group is provided by a monomer which comprises a hydroxyl or amino group, which monomer is selected from the group consisting of hydroxyethyl acrylate, hydroxyethyl methacrylate, 4-hydroxybutyl acrylate, 4-hydroxybutyl methacrylate and 4-aminostyrene.
5. The block copolymer according to claim 1, wherein block A is derived from a copolymer C which is formed by:
a free radical polymerization of:
(a) at least one monomer containing a sulfonate group, and (b) at least one monomer containing a carboxyl group to from a primary copolymer, and a reaction of the primary copolymer with a compound having at least two groups selected from hydroxyl and amino groups.
a free radical polymerization of:
(a) at least one monomer containing a sulfonate group, and (b) at least one monomer containing a carboxyl group to from a primary copolymer, and a reaction of the primary copolymer with a compound having at least two groups selected from hydroxyl and amino groups.
6. The block copolymer according to claim 5, wherein the compound having at least two groups selected from hydroxyl and amino groups is a diol, a triol, an aminoalcohol, a diamine or a triamine.
7. The block copolymer according to any one of claims 1 to 6, wherein block B is derived from a polyurethane with terminal isocyanate groups or a polyester with terminal carboxylic acid chloride groups.
8. The block copolymer according to claim 7, wherein the polyurethane comprises residues of a polyisocyanate selected from the group consisting of tolylene diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, hexamethylene diisocyanate and isophone diisocyanate, and a polyol selected from the group consisting of ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentylglycol, polyethylene glycol, polypropylene glycol and poly(tetramethyleneoxy)glycol.
9. The block copolymer according to claim 7, wherein the polyester comprises residues of a polycarboxylic acid selected from the group consisting of adipic acid dodecane-1,
10-dicarboxylic acid, naphthalene-1,5-dicarboxylic acid, phthalic acid, isophthalic acid and terephthalic acid, and a polyol selected from the group consisting of ethylene glycol, propylene glycol, 1,4-butanediol, 1,6-hexanediol, neopentylglycol, polyethylene glycol, polypropylene glycol and poly(tetramethyleneoxy)glycol.
10. The block copolymer according to claim 9, wherein the terminal carboxylic acid chloride groups are provided by reaction with phosgene, thionyl chloride, phosphorous trichloride, phosphorous pentachloride or oxalyl dichloride.
10. The block copolymer according to claim 9, wherein the terminal carboxylic acid chloride groups are provided by reaction with phosgene, thionyl chloride, phosphorous trichloride, phosphorous pentachloride or oxalyl dichloride.
11. The block copolymer as claimed in any one of claims 1 to 10, wherein the molar ratio of carboxyl groups to sulfonate groups is 0.1 to 10.
12. The block copolymer as claimed in claim 11, wherein the molar ratio of carboxyl groups to sulfonate groups is 0.2 to 5.
13. A composition comprising at least one block copolymer as claimed in any one of claims 1 to 10 and at least one further polymer.
14. The composition as claimed in claim 13, wherein the block copolymer and the further polymer comprise identical or similar recurring units.
15. The composition according to claim 13 or 14, wherein if block B is derived from a polyurethane, the further polymer is a polyurethane.
16. The composition according to claim 13 or 14, wherein if block B is derived from a polyester, the further polymer is a polyester.
17. The composition according to claim 15, wherein the further polymer comprises residues of 4,4-methylene(cyclohexyl isocyanate), poly(tetramethyleneoxy) glycol and 1,4-butanediol.
18. A process for the preparation of a block copolymer as claimed in any one of claims 1 to 12, which comprises reacting a copolymer C, which comprises hydroxyl groups and/or amino groups and at least one monomer (a) which comprises a sulfonate group and at least one monomer (b) which comprises a carboxyl group, with a polyurethane D with terminal isocyanate groups or a polyester D with terminal carboxylic acid chloride groups.
19. The process as claimed in claim 18, wherein polyurethane D is prepared in the presence of copolymer C and is reacted with this in the reaction mixture.
20. The process as claimed in claim 18, wherein a polyester D which is prepared in two stages:
(a) preparing a polyester with terminal carboxyl groups by polycondensation of polycarboxylic acids with polyols, an equivalent excess of carboxyl groups with respect to the hydroxyl groups being used, and then (b) converting the excess terminal carboxyl groups into carboxylic acid chloride groups with a chlorinating agent in the customary manner is used.
(a) preparing a polyester with terminal carboxyl groups by polycondensation of polycarboxylic acids with polyols, an equivalent excess of carboxyl groups with respect to the hydroxyl groups being used, and then (b) converting the excess terminal carboxyl groups into carboxylic acid chloride groups with a chlorinating agent in the customary manner is used.
21. The process as claimed in any one of claims 18 to 20, wherein copolymer C comprises a monomer (a) which comprises sulfonate groups, a monomer (b) which comprises carboxyl groups and a monomer (c) which comprises hydroxyl and/or amino groups.
22. The process as claimed in any one of claims 18 to 20, wherein copolymer C is formed from a primary copolymer comprising a monomer (a) which comprises sulfonate groups and a monomer (b) which comprises carboxyl groups by a polymer-analogous reaction with a polyfunctional NCO-reactive compound.
23. A process for coating a plastic substrate, wherein the coating composition comprises a block copolymer as claimed in any one of claims 1 to 12, which process comprises applying the coating composition to a surface of the substrate.
24. The process as claimed in claim 23, wherein the plastic substrate is a polyurethane if blocks B of the block copolymer are polyurethane blocks, and a polyester if blocks B
of the block copolymer are polyester blocks.
of the block copolymer are polyester blocks.
25. The process as claimed in claim 23 or 24, wherein the coating composition is applied by dipping, spraying, knife-coating, brushing or spin coating.
26. A product which has been coated entirely or partly with a block copolymer as claimed in any one of claims 1 to 12 or is made entirely or partly of a composition as claimed in any one of claims 13 to 17 for hygiene, industrial, foodstuffs or bioengineering purposes.
27. A product which has been coated entirely or partly with a block copolymer as claimed in any one of claims 1 to 12 or is made entirely or partly of a composition as claimed in any one of claims 13 to 17 for medical purposes.
28. The product as claimed in claim 27, which product is a catheter, lymph drainage, wound dressing, tube, stent, heart valve, hose, membrane or blood bag.
29. A block copolymer comprising:
(A) a block which carries a physiologically acceptable sulfonic acid salt (sulfonate) group and a carboxyl group at a carboxyl/sulfonate molar ratio of 0.1 to 10, and (B) a polyurethane or polyester block, wherein the block copolymer is prepared by reacting:
(C) a copolymer which is formed by a process involving a free radical polymerization, has a carbon skeleton and at least one of hydroxyl and amino groups and is selected from the group consisting of:
(C1) a copolymer which is a free radical polymerization product of (a) an ethylenically unsaturated monomer having a sulfonate group, (b) an ethylenically unsaturated monomer having a carboxyl, carboxylate or acid anhydride group, (c) an ethylenically unsaturated monomer having a hydroxyl or amino group and optionally (d) an ethylenically unsaturated monomer having no functional group or a different functional group selected from the group consisting of a vinyl ketone, a vinyl aromatic monomer, a vinyl ester, an olefin, a diolefin and N-vinylpyrrolidone, (C2) a copolymer which is prepared by a first stage free radical polymerization of the ethylenically unsaturated monomers (a), (b) and optionally (d) mentioned above to produce a primary copolymer having a sulfonate group and a carboxyl, carboxylate or acid anhydride group and a second stage reaction of the carboxyl, carboxylate or acid anhydride group of the primary copolymer with a less than equivalent amount of a compound having two or more hydroxyl or amino groups to obtain a modified primary copolymer having a carbon skelton and hydroxyl or amino groups arranged in side chains and bonded via carboxylic ester or carboxamide groups, and (C3) a copolymer which is prepared by reacting the carboxyl, carboxylate or acid anhydride group of the copolymer (C1) with a less than equivalent amount of a compound having two or more hydroxyl or amino groups, with (D) a substantially linear polyurethane prepolymer having terminal isocyanate groups or a polyester having terminal carboxylic acid and chloride groups.
whereby the block (A) and the block (B) are linked by urethane (-OCONH-), urea (-NHCONH-), carboxylic ester (-COO-) or carboxamide (-CONH-) bridges.
(A) a block which carries a physiologically acceptable sulfonic acid salt (sulfonate) group and a carboxyl group at a carboxyl/sulfonate molar ratio of 0.1 to 10, and (B) a polyurethane or polyester block, wherein the block copolymer is prepared by reacting:
(C) a copolymer which is formed by a process involving a free radical polymerization, has a carbon skeleton and at least one of hydroxyl and amino groups and is selected from the group consisting of:
(C1) a copolymer which is a free radical polymerization product of (a) an ethylenically unsaturated monomer having a sulfonate group, (b) an ethylenically unsaturated monomer having a carboxyl, carboxylate or acid anhydride group, (c) an ethylenically unsaturated monomer having a hydroxyl or amino group and optionally (d) an ethylenically unsaturated monomer having no functional group or a different functional group selected from the group consisting of a vinyl ketone, a vinyl aromatic monomer, a vinyl ester, an olefin, a diolefin and N-vinylpyrrolidone, (C2) a copolymer which is prepared by a first stage free radical polymerization of the ethylenically unsaturated monomers (a), (b) and optionally (d) mentioned above to produce a primary copolymer having a sulfonate group and a carboxyl, carboxylate or acid anhydride group and a second stage reaction of the carboxyl, carboxylate or acid anhydride group of the primary copolymer with a less than equivalent amount of a compound having two or more hydroxyl or amino groups to obtain a modified primary copolymer having a carbon skelton and hydroxyl or amino groups arranged in side chains and bonded via carboxylic ester or carboxamide groups, and (C3) a copolymer which is prepared by reacting the carboxyl, carboxylate or acid anhydride group of the copolymer (C1) with a less than equivalent amount of a compound having two or more hydroxyl or amino groups, with (D) a substantially linear polyurethane prepolymer having terminal isocyanate groups or a polyester having terminal carboxylic acid and chloride groups.
whereby the block (A) and the block (B) are linked by urethane (-OCONH-), urea (-NHCONH-), carboxylic ester (-COO-) or carboxamide (-CONH-) bridges.
30. The block copolymer according to claim 29, wherein:
the copolymer (C) is the copolymer (C2);
the ethylenically unsaturated monomer (b) is maleic anhydride; and the compound having two or more hydroxyl or amino groups used in the preparation of the copolymer (C2) is an amino alcohol.
the copolymer (C) is the copolymer (C2);
the ethylenically unsaturated monomer (b) is maleic anhydride; and the compound having two or more hydroxyl or amino groups used in the preparation of the copolymer (C2) is an amino alcohol.
31. A coating composition comprising:
a blocked polyisocyanate;
a polyol; and (C) a copolymer which is formed by a process involving a free radical polymerization, has a carbon skeleton and at least one of hydroxyl and amino groups and is selected from the group consisting of:
(C1) a copolymer which is a free radical polymerization product of (a) an ethylenically unsaturated monomer having a sulfonate group, (b) an ethylenically unsaturated monomer having a carboxyl, carboxylate or acid anhydride group, (c) an ethylenically unsaturated monomer having a hydroxyl or amino group and optionally (d) an ethylenically unsaturated monomer having no functional group or a different functional group selected from the group consisting of a vinyl ketone, a vinyl aromatic monomer, a vinyl ester, an olefin, a diolefin and N-vinylpyrrolidone, (C2) a copolymer which is prepared by a first stage free radical polymerization of the ethylenically unsaturated monomers (a), (b) and optionally (d) mentioned above to produce a primary copolymer having a sulfonate group and a carboxyl, carboxylate or acid anhydride group and a second stage reaction of the carboxyl, carboxylate or acid anhydride group of the primary copolymer with a less than equivalent amount of a compound having two or more hydroxyl or amino groups to obtain a modified primary copolymer having a carbon skelton and hydroxyl or amino groups arranged in side chains and bonded via carboxylic ester or carboxamide groups, and (C3) a copolymer which is prepared by reacting the carboxyl, carboxylate or acid anhydride group of the copolymer (C1) with a less than equivalent amount of a compound having two or more hydroxyl or amino groups.
a blocked polyisocyanate;
a polyol; and (C) a copolymer which is formed by a process involving a free radical polymerization, has a carbon skeleton and at least one of hydroxyl and amino groups and is selected from the group consisting of:
(C1) a copolymer which is a free radical polymerization product of (a) an ethylenically unsaturated monomer having a sulfonate group, (b) an ethylenically unsaturated monomer having a carboxyl, carboxylate or acid anhydride group, (c) an ethylenically unsaturated monomer having a hydroxyl or amino group and optionally (d) an ethylenically unsaturated monomer having no functional group or a different functional group selected from the group consisting of a vinyl ketone, a vinyl aromatic monomer, a vinyl ester, an olefin, a diolefin and N-vinylpyrrolidone, (C2) a copolymer which is prepared by a first stage free radical polymerization of the ethylenically unsaturated monomers (a), (b) and optionally (d) mentioned above to produce a primary copolymer having a sulfonate group and a carboxyl, carboxylate or acid anhydride group and a second stage reaction of the carboxyl, carboxylate or acid anhydride group of the primary copolymer with a less than equivalent amount of a compound having two or more hydroxyl or amino groups to obtain a modified primary copolymer having a carbon skelton and hydroxyl or amino groups arranged in side chains and bonded via carboxylic ester or carboxamide groups, and (C3) a copolymer which is prepared by reacting the carboxyl, carboxylate or acid anhydride group of the copolymer (C1) with a less than equivalent amount of a compound having two or more hydroxyl or amino groups.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19726735.1 | 1997-06-24 | ||
| DE1997126735 DE19726735A1 (en) | 1997-06-24 | 1997-06-24 | Blood-compatible and bacteria-repellent block copolymer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2241381A1 true CA2241381A1 (en) | 1998-12-24 |
Family
ID=7833462
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2241381 Abandoned CA2241381A1 (en) | 1997-06-24 | 1998-06-22 | Blood-compatible and bacteria-repellent block copolymer |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0887368A1 (en) |
| JP (1) | JPH11100429A (en) |
| CA (1) | CA2241381A1 (en) |
| DE (1) | DE19726735A1 (en) |
| NO (1) | NO982942L (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021212153A3 (en) * | 2020-04-17 | 2021-11-25 | Kraton Polymers Llc | Antimicrobial spray composition |
| WO2021212147A3 (en) * | 2020-04-17 | 2021-12-02 | Kraton Polymers Llc | Bio-secure protective equipment and methods for making |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7105198B2 (en) * | 2002-01-14 | 2006-09-12 | Medtronic Vascular, Inc. | Method for coating stent |
| US20030225451A1 (en) * | 2002-01-14 | 2003-12-04 | Rangarajan Sundar | Stent delivery system, device, and method for coating |
| US8680362B2 (en) * | 2010-06-28 | 2014-03-25 | The Procter & Gamble Company | Substrate coated with a hydrophilic elastomer |
| US8409664B2 (en) | 2010-06-28 | 2013-04-02 | The Procter & Gamble Company | Superabsorbent polymer particles coated with a hydrophilic elastomer and absorbent article comprising such particles |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0639495B2 (en) * | 1989-07-31 | 1994-05-25 | 東洋製罐株式会社 | Process for producing antibacterial polymer and use thereof |
-
1997
- 1997-06-24 DE DE1997126735 patent/DE19726735A1/en not_active Withdrawn
-
1998
- 1998-05-05 EP EP98108163A patent/EP0887368A1/en not_active Withdrawn
- 1998-06-22 CA CA 2241381 patent/CA2241381A1/en not_active Abandoned
- 1998-06-24 NO NO982942A patent/NO982942L/en not_active Application Discontinuation
- 1998-06-24 JP JP10177394A patent/JPH11100429A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021212153A3 (en) * | 2020-04-17 | 2021-11-25 | Kraton Polymers Llc | Antimicrobial spray composition |
| WO2021212147A3 (en) * | 2020-04-17 | 2021-12-02 | Kraton Polymers Llc | Bio-secure protective equipment and methods for making |
Also Published As
| Publication number | Publication date |
|---|---|
| DE19726735A1 (en) | 1999-01-07 |
| NO982942D0 (en) | 1998-06-24 |
| NO982942L (en) | 1998-12-28 |
| JPH11100429A (en) | 1999-04-13 |
| EP0887368A1 (en) | 1998-12-30 |
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