Patent Application
20090253848
This application claims benefit to European Patent Application No. 08 154 209.4, filed Apr. 8, 2008, which is incorporated herein by reference in its entirety for all useful purposes.
The present invention relates to an aqueous silver-containing nonionic polyurethane dispersion. Further provided by the present invention is a process for producing the aqueous silver-containing nonionic polyurethane dispersion and also its use for producing antibacterial (antimicrobial) coatings.
Articles made of plastic and metal are used very frequently in the medical sector. Examples of such materials are implants, cannulas or catheters. A problem associated with the use of these products is the ease with which the surfaces of these materials are colonized by microbes. The consequences of using an article colonized with bacteria, such as an implant, a cannula or a catheter, are often infections through the formation of a biofilm. Such infections are particularly serious in the area of central venous catheters and also in the urological area, where catheters are used.
Before now, in the past, numerous attempts have been made to prevent the colonization of surfaces by bacteria, and hence infections. Often it has been attempted to impregnate the surface of medical implants or catheters with antibiotics. In that case, however, account must be taken of the formation and selection of resistant bacteria.
Another approach to preventing infections when using implants or catheters is to use metals or metal alloys, in the case of catheters, for example.
Of particular significance in this context is the antibacterial effect of silver. Silver and silver salts have already been known for many years to be antimicrobially active substances. The antimicrobial effect of surfaces which contain silver derives from the release of silver ions. The advantage of silver consists in its high toxicity for bacteria, even at very low concentrations. Hardes et al., Biomaterials 28 (2007) 2869-2875, report bactericidal activity for silver at a concentration of down to 35 ppb. In contrast even at a significantly higher concentration, silver is still not toxic to mammalian cells. A further advantage is the low tendency of bacteria to develop resistances to silver.
Various approaches at equipping medical devices with silver, such as catheters, for example, are described in the literature. One approach is the use of metallic silver on catheter surfaces. Thus U.S. Pat. No. 3,800,087, for example, discloses a process for metallizing surfaces, which according to DE 43 28 999 can also be used as medical devices, such as a catheter, for example. A disadvantage there is that the silver adheres poorly in the face of the challenges on the catheter, such as, for example, on storage in body fluids such as urine, by friction during introduction and removal from the body, or by repeated bending of the catheter.
Metallic coatings on medical devices, however, not only have the disadvantage of the poor adhesion to the catheter material but also the fact that application to the insides of the catheter is very involved at the least.
An improvement to the adhesion of the silver coat on a catheter plastic is described by the aforementioned DE 43 28 999 A, by the application between plastic and silver coat of metal layers with better adhesion. In the case of the products described, the silver is applied by vapour deposition in a vacuum chamber, by sputtering or else by ion implantation. These processes are very complex and costly. A further disadvantage is that the amount of elemental silver applied by vapour deposition is relatively high, while only very small amounts of active silver ions are delivered to the surrounding fluid. Furthermore, these processes can only be used to coat the outside of an implant or a catheter. It is known, however, that bacteria also attach readily to the inside of a catheter, leading to the formation of a biofilm and the infection of the patient.
Numerous applications are concerned with the use of silver salts in antimicrobial coatings which are applied to medical implants or catheters. As compared with metallic silver, silver salts have the disadvantage that in the impregnated coat, alongside the active silver, there are also anions present which under certain circumstances may be toxic, such as nitrate in silver nitrate, for example. A further problem is the rate of release of silver ions from silver salts. Certain silver salts such as silver nitrate are highly soluble in water and are therefore delivered possibly too quickly from the surface coating into the surrounding medium. Other silver salts such as silver chloride are so poorly dissolving that silver ions may be delivered too slowly to the fluid.
Thus U.S. Pat. No. 6,716,895 B1 relates to antimicrobial compositions which as one constituent comprise a hydrophilic polymer which may be selected, among others, from polyether polyurethanes, polyester polyurethanes and polyurethaneureas. The antimicrobial coating is achieved by means of oligodynamic salts, such as by using silver salts, for example. The composition is used to coat medical devices. A disadvantage of this coating, as well as the use of silver salts as already mentioned, is also that it is prepared starting from a solution of the polymeric constituents, and so it is frequently not possible to prevent residues of toxic solvents entering the human body following the implantation of medical devices which have been provided with this coating.
Further publications, exemplified by WO 2004/017738 A, WO 2001/043788 A and US 2004/0116551 A, describe a concept which involves combining different silver salts to arrive at a silver-containing coating that continuously releases silver ions. The various silver salts are mixed with different polymers, polyurethanes for example, and the combination of silver salts with different water solubilities is tailored in such a way that there is constant release of silver over the entire period in which the coated device is used. These processes, as a result of the use of a plurality of silver salts and a plurality of polymers, are complicated.
Other processes using silver ions are described by WO 2001/037670 A and US 2003/0147960 A. WO 2001/037670 A describes an antimicrobial formulation which complexes silver ions in zeolites. US 2003/0147960 A describes coatings in which silver ions are bound in a mixture of hydrophilic and hydrophobic polymers.
The processes described that use silver salts have the disadvantages mentioned before, and, moreover, are complicated to implement and therefore expensive in terms of production, and so there continues to be a need for silver-containing coatings that are improved in respect of the production process and the activity.
One interesting possibility for the antimicrobial equipping of plastics is to use nanocrystalline silver particles. The advantage to coating with metallic silver lies in the surface area of the nanocrystalline silver, which is very much greater in relation to its volume; this leads to increased release of silver ions as compared with a metallic silver coating.
Furno et al., Journal of Antimicrobial Chemotherapy 2004, 54, pp. 1019-1024, describe a process which uses supercritical carbon dioxide to impregnate nanocrystalline silver into silicone surfaces. In view of the complex impregnating operation and the obligatory use of supercritical carbon dioxide, this process is expensive and not easy to apply.
In addition there are various known processes for incorporating nanocrystalline silver into plastics. For instance, WO 01/09229 A1, WO 2004/024205 A1, EP 0 711 113 A and Münstedt et al., Advanced Engineering Materials 2000, 2(6), pages 380 to 386 describe the incorporation of nanocrystalline silver into thermoplastic polyurethanes. Pellets of a commercially available thermoplastic polyurethane are soaked in solution with colloidal silver. To increase the antimicrobial activity, WO 2004/024205 A1 and DE 103 51 611 A1 further mention the possibility of using barium sulphate as an additive. Then, from the doped polyurethane pellets, the corresponding products, such as catheters, are produced by extrusion. This procedure, described in the publications, is disadvantageous on account of the fact that the amount of silver which remains on the polyurethane pellets after immersion is not constant and/or cannot be determined beforehand. The effective silver content of the resulting products must therefore be determined afterwards, i.e. after production of the end products. In contrast, a procedure which sets with precision the effective amount of silver to be provided in the resulting end product is not known from these publications.
A similar process is described by EP 0 433 961 A. Here again, a mixture of a thermoplastic polyurethane (Pellethane), silver powder and barium sulphate is mixed and extruded.
A disadvantage of these processes is furthermore the relatively large amount of silver which is distributed throughout the plastic element. This process is therefore expensive and, as a result of the incorporation of the colloidal silver in the entire plastic matrix, the release of the silver is too slow for sufficient activity in certain cases. The improvement to the release of silver through the addition of barium sulphate represents a further, expensive work-step.
A coating solution comprising a thermoplastic polyurethane with nanocrystalline silver in an organic solvent for producing vascular prostheses is described by WO 2006/032497 A. The structure of the polyurethane is not further specified, but in view of the claiming of thermoplastics, the use of urea-free polyurethanes can be assumed. The antibacterial effect was determined by the growth of adhered Staphylococcus epidermidis cells on the surface of the test element, in comparison with a control. The antibacterial action detected for the silver-containing coatings, however, can be rated as weak, since a retardation of growth by a maximum of only 33.2 h (starting from a defined threshold growth) relative to the control surface was found. For prolonged applications, as an implant or catheter, therefore, this coating formulation is unsuitable.
A further problem is the use of solvents for the preparation of coating solutions. WO 2006/032497 A1 describes an antimicrobial implant having a flexible porous structure, comprising a biocompatible polymer as a nonwoven structure. One of the components used is a solution of a thermoplastic polyurethane in chloroform. Chloroform is known to be a highly toxic solvent. When medical products are coated that are implanted in the human body, there is a risk from residues of this toxic solvent following implantation into the human body.
A further disadvantage of colloidal silver in organic coating solutions is the often low stability of the silver nanoparticles. In organic solutions, aggregates of silver particles may be formed, and so it is impossible to establish reproducible silver activity. An organic solution to which colloidal silver has been added ought therefore to be processed to completed coatings as soon as possible after its preparation, in order to ensure consistent silver activity from batch to batch. Owing to operating practice, however, such a procedure is sometimes not possible.
Accordingly an aqueous polyurethane coating with colloidally distributed silver present is desirable as an antimicrobial coating.
US 2006/045899 describes antimicrobial formulations with the assistance of aqueous polyurethane systems. The antimicrobial formulation is a mixture of different materials, which makes manufacture of these products difficult. The nature of the aqueous polyurethane systems is not precisely described, apart from the fact that they are cationically or anionically stabilized dispersions.
CN 1760294 likewise mentions anionic polyurethane dispersions with silver powder having a particle size of 0.2 to 10 μm. According to the prior art, such particle sizes are insufficient for high antimicrobial activity.
C.-W. Chou et al., Polymer Degradation and Stability 91 (2006), 1017-1024 describe sulphonate-modified dispersions of polyether polyurethanes into which very small amounts (0.00151% to 0.0113% by weight) of colloidal silver are incorporated. The aim of these studies was to improve the thermal and mechanical properties of the polyurethane employed. An antimicrobial action was not investigated, and is improbable in view of the very small amounts of silver.
On the basis of this prior art, the object of the present invention is to provide a composition which does not have the aforementioned disadvantages. In particular the composition is to lead to coatings which are uncritical from a toxicological standpoint and which release the antimicrobial agent rapidly and persistently. The composition ought preferably to be designed in such a way that it comprises the antimicrobial agent in a predetermined amount, with the consequence, for example, that different fields of use of the composition can be covered by varying the amount of the antimicrobial agent.
An embodiment of the present invention is an aqueous dispersion comprising at least one nonionically stabilized polyurethaneurea and at least one silver-containing constituent.
Another embodiment of the present invention is the above aqueous dispersion, wherein said at least one nonionically stabilized polyurethaneurea comprises a macropolyol synthesis component which is selected from the group consisting of at least one polyester polyol, at least one polyether polyol, at least one polycarbonate polyol, and mixtures thereof.
Another embodiment of the present invention is the above aqueous dispersion, wherein said at least one nonionically stabilized polyurethaneurea comprises a macropolyol synthesis component which is selected from the group consisting of at least one polyether polyol, at least one polycarbonate polyol, and mixtures thereof.
Another embodiment of the present invention is the above aqueous dispersion, wherein said at least one nonionically stabilized polyurethaneurea is synthesized from at least the following synthesis components:
Another embodiment of the present invention is the above aqueous dispersion 1, wherein said at least one silver-containing constituent is a high-porosity silver powder, silver on support materials, or colloidal silver sols.
Another embodiment of the present invention is the above aqueous dispersion, wherein said aqueous dispersion comprises nanocrystalline silver particles with an average size in the range of from 1 to 1000 nm.
Another embodiment of the present invention is the above aqueous dispersion, wherein the amount of silver, based on the amount of solid nonionically stabilized polyurethaneurea polymer and calculated as Ag and Ag+, is in the range of from 0.1% to 10% by weight.
Yet another embodiment of the present invention is a process for preparing the above aqueous dispersion, comprising mixing at least one nonionically stabilized polyurethaneurea dispersion with at least one silver-containing constituent. Another embodiment of the present invention is the above process, comprising mixing at least one nonionically stabilized polyurethaneurea dispersion with at least one silver-containing constituent, wherein said at least one nonionically stabilized polyurethaneurea is obtained by:
Yet another embodiment of the present invention is a polyurethaneurea dispersion obtained by the above process.
Yet another embodiment of the present invention is a coating prepared from the above polyurethaneurea dispersion.
Yet another embodiment of the present invention is a surface coated with the above coating.
Yet another embodiment of the present invention is a medical device coated with the above coating.
FIG. 1 depicts a graph comparing the bacterial adherence of E. coli on different polyurethane surfaces.
This object is achieved through the provision of an aqueous dispersion which comprises at least one nonionically stabilized polyurethaneurea and at least one silver-containing constituent.
In accordance with the invention it has been found that coatings comprising polyurethaneureas which are dispersed in water and comprise a silver-containing constituent exhibit effective release of silver if the polyurethaneurea dispersion is stabilized nonionically. Corresponding experiments in accordance with the invention, and also corresponding comparative experiments, which support this finding, are described later on below.
Polyurethaneureas for the purposes of the present invention are polymeric compounds which have
(a) repeat units containing at least two urethane groups, of the following general structure
and
(b) at least one repeat unit containing urea groups
The compositions of the invention are based on polyurethaneureas which have substantially no ionic modification. By this is meant, in the context of the present invention, that the polyurethaneureas for use in accordance with the invention have essentially no ionic groups, such as, more particularly, no sulphonate, carboxylate, phosphate and phosphonate groups.
The term “substantially no ionic groups” means, in the context of the present invention, that the polyurethaneurea contains ionic groups in a fraction of in general not more than 2.50% by weight, more particularly not more than 2.00% by weight, preferably not more than 1.50% by weight, with particular preference not more than 1.00% by weight, especially not more than 0.50% by weight, and even more especially no ionic groups. Hence it is particularly preferred for the polyurethaneurea not to contain any ionic groups.
The polyurethaneureas provided in accordance with the invention in the composition are preferably substantially linear molecules, but may also be branched, though this is less preferred. By substantially linear molecules are meant systems with a slight degree of incipient crosslinking, comprising a macropolyol component as a synthesis component, generally selected from the group consisting of a polyether polyol, a polycarbonate polyol, a polyester polyol and mixtures thereof, which have an average functionality of preferably 1.7 to 2.3, more particularly 1.8 to 2.2, more preferably 1.9 to 2.1.
If mixtures of macropolyols and, if appropriate, polyols have been used in the polyurethaneurea as elucidated in more detail below, then the functionality refers to an average value arising from the totality of the macropolyols and/or polyols.
The number-average molecular weight of the polyurethaneureas preferred in accordance with the invention is preferably 1000 to 200 000, more preferably from 5000 to 100 000. The number-average molecular weight here is measured against polystyrene as standard in dimethylacetamide at 30° C.
The polyurethaneurea-based compositions of the invention are described in more detail below.
The polyurethaneureas provided in accordance with the invention are generally formed by reaction of at least one macropolyol component, at least one polyisocyanate component, at least one polyoxyalkylene ether, at least one diamine and/or amino alcohol and, if desired, a polyol component. Further synthesis components may be present in the polyurethaneurea of the invention.
The composition of the polyurethaneurea provided in accordance with the invention has units which derive from at least one macropolyol component as a synthesis component.
This macropolyol component is generally selected from the group consisting of a polyether polyol, a polycarbonate polyol, a polyester polyol and any desired mixtures of these.
In one preferred embodiment of the present invention the synthesis component is formed of a polyether polyol or a polycarbonate polyol and also of mixtures of polyether polyol and a polycarbonate polyol.
In a further embodiment of the present invention the synthesis component of a macropolyol is formed of a polyether polyol, more particularly a polyether diol. Polyether polyols and, in particular, polyether diols are particularly preferred in respect of the release of silver. Corresponding experiments according to the invention that support these findings are shown later on below.
In the text below, the individual macropolyol synthesis components are described in more detail, the present invention embracing polyurethaneureas which comprise only one synthesis component, selected from, in general, polyether polyols, polyester polyols, and polycarbonate polyols, and also embracing mixtures of these synthesis components. Furthermore, the polyurethaneureas provided in accordance with the invention may also comprise one or more different representatives of these classes of synthesis components.
The above-defined functionality of the polyurethaneureas provided in accordance with the invention is understood, where two or more different macropolyols and polyols or polyamines (which are described further on below under c) and e)) are present in the polyurethaneurea, to be the average functionality.
The hydroxyl-containing polyethers in question are those which are prepared by polymerizing cyclic ethers such as ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohydrin with themselves, in the presence of BF3 or of basic catalysts, for example, or by addition reaction of these ring compounds, where appropriate in a mixture or in succession, with starter components containing reactive hydrogen atoms, such as alcohols and amines or amino alcohols, e.g. water, ethylene glycol, propylene 1,2-glycol or propylene 1,3-glycol. Preferred hydroxyl-containing polyethers are those based on ethylene oxide, propylene oxide or tetrahydrofuran or on mixtures of these cyclic ethers. Especially preferred hydroxyl-containing polyethers are those based on polymerized tetrahydrofuran. It is also possible to add other hydroxyl-containing polyethers such as those based on ethylene oxide or propylene oxide, but in that case the polyethers based on tetrahydrofiaran are present at, preferably, 50% by weight at least.
Suitable hydroxyl-containing polycarbonates are polycarbonates of a molecular weight, as determined through the OH number, of preferably 400 to 6000 g/mol, more preferably 500 to 5000 g/mol, more particularly of 600 to 3000 g/mol, which are obtainable, for example, through reaction of carbonic acid derivatives, such as diphenyl carbonate, dimethyl carbonate or phosgene, with polyols, preferably diols. Examples of suitable such diols include ethylene glycol, 1,2- and 1,3-propanediol, 1,3- and 1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, neopentyl glycol, 1,4-bishydroxymethylcyclohexane, 2-methyl-1,3-propanediol, 2,2,4-trimethylpentane-1,3-diol, di-, tri or tetraethylene glycol, dipropylene glycol, polypropylene glycols, dibutylene glycol, polybutylene glycols, bisphenol A, tetrabromobisphenol A, and also lactone-modified diols.
The diol component preferably contains 40% to 100% by weight of hexanediol, preferably 1,6-hexanediol and/or hexanediol derivatives, preferably those which as well as terminal OH groups contain ether or ester groups, examples being products obtained by reaction of 1 mol of hexanediol with at least 1 mol, preferably 1 to 2 mol, of caprolactone or through etherification of hexanediol with itself to give the di or trihexylene glycol. Polyether-polycarbonate diols as well can be used. The hydroxyl polycarbonates ought to be substantially linear. If desired, however, they may be slightly branched as a result of the incorporation of polyfunctional components, more particularly low molecular weight polyols. Examples of those suitable for this purpose include glycerol, trimethylolpropane, hexane-1,2,6-triol, butane-1,2,4-triol, trimethylolpropane, pentaerythritol, quinitol, mannitol, sorbitol, methylglycoside or 1,3,4,6-dianhydrohexitols. Preferred polycarbonates are those based on hexane-1,6-diol, and also on co-diols with a modifying action such as butane-1,4-diol, for example, or else on s-caprolactone. Further preferred polycarbonate diols are those based on mixtures of hexane-1,6-diol and butane-1,4-diol.
The polycarbonate is preferably substantially linear in construction and has only a slight three-dimensional crosslinking, with the consequence that polyurethaneureas are formed which have the specification identified above.
The hydroxyl-containing polyesters that are suitable are, for example, reaction products of polyhydric, preferably dihydric, alcohols with polybasic, preferably dibasic, polycarboxylic acids. In place of the free carboxylic acids it is also possible to use the corresponding polycarboxylic anhydrides or corresponding polycarhoxylic esters of lower alcohols, or mixtures thereof, to prepare the polyesters.
The polycarboxylic acids may be aliphatic, cycloaliphatic, aromatic and/or heterocyclic in nature and may if appropriate be substituted, by halogen atoms, for example, and/or unsaturated. Aliphatic and cycloaliphatic dicarboxylic acids are preferred. Examples thereof include the following:
succinic acid, adipic acid, azelaic acid, sebacic acid, phthalic acid, tetrachlorophthalic acid, isophthalic acid, terephthalic acid, tetrahydrophthalic acid, hexahydrophthalic acid, cyclohexanedicarboxylic acid, itaconic acid, sebacic acid, glutaric acid, suberic acid, 2-methylsuccinic acid, 3,3-diethylglutaric acid, 2,2-dimethylsuccinic acid, maleic acid, malonic acid, fumaric acid or dimethyl terephthalate. Anhydrides of these acids can likewise be used, where they exist. Examples thereof are maleic anhydride, phthalic anhydride, tetrahydrophthalic anhydride, glutaric anhydride, hexahydrophthalic anhydride and tetrachlorophthalic anhydride.
As a polycarboxylic acid for use in small amounts, if appropriate, mention may be made here of trimellitic acid.
The polyhydric alcohols employed are preferably diols. Examples of such diols are, for example, ethylene glycol, propylene 1,2-glycol, propylene 1,3-glycol, butane-1,4-diol, butane-2,3-diol, diethylene glycol, triethylene glycol, hexane-1,6-diol, octane-1,8-diol, neopentyl glycol, 2-methyl-1,3-propanediol or neopentyl glycol hydroxypivalate. Polyester diols formed from lactones, ε-caprolactone for example, can also be employed. Examples of polyols which can be used as well if appropriate are trimethylolpropane, glycerol, erythritol, pentaerythritol, trimethylolbenzene or trishydroxyethyl isocyanurate.
The polyurethaneureas provided in accordance with the invention comprise units which originate from at least one polyisocyanate as a synthesis component.
As polyisocyanates (b) it is possible to use all of the aromatic, araliphatic, aliphatic and cycloaliphatic isocyanates that are known to the skilled person and have an average NCO functionality ≧1, preferably ≧2, individually or in any desired mixtures with one another, irrespective of whether they have been prepared by phosgene or phosgene-free processes. They may also contain iminooxadiazinedione, isocyanurate, uretdione, urethane, allophanate, biuret, urea, oxadiazinetrione, oxazolidinone, acylurea and/or carbodiimide structures. The polyisocyanates may be used individually or in any desired mixtures with one another.
Preference is given to using isocyanates from the series of the aliphatic or cycloaliphatic representatives, which have a carbon backbone (without the NCO groups present) of 3 to 30, preferably 4 to 20, carbon atoms.
Particularly preferred compounds of component (b) conform to the type specified above having aliphatically and/or cycloaliphatically attached NCO groups, such as, for example, bis(isocyanatoalkyl)ethers, bis- and tris(isocyanatoalkyl)benzenes, -toluenes, and -xylenes, propane diisocyanates, butane diisocyanates, pentane diisocyanates, hexane diisocyanates (e.g. hexamethylene diisocyanate, HDI), heptane diisocyanates, octane diisocyanates, nonane diisocyanates (e.g. trimethyl-HDI (TMDI), generally as a mixture of the 2,4,4 and 2,2,4 isomers), nonane triisocyanates (e.g. 4-isocyanatomethyl-1,8-octane diisocyanate), decane diisocyanates, decane triisocyanates, undecane diisocyanates, undecane triisocyanates, dodecane diisocyanates, dodecane triisocyanates, 1,3- and 1,4-bis(isocyanatomethyl)cyclohexanes (H6XDI), 3-isocyanatomethyl-3,5,5-trimethyl-cyclohexyl isocyanate (isophorone diisocyanate, IPDI), bis(4-isocyanatocyclo-hexyl)methane (H12MDI) or bis(isocyanatomethyl)norbornane (NBDI).
Very particularly preferred compounds of component (b) are hexamethylene diisocyanate (HDI), trimethyl-HDI (TMDI), 2-methylpentane 1,5-diisocyanate (NBDI), isophorone diisocyanate (IPDI), 1,3- and 1,4-bis(isocyanatomethyl)cyclohexane (H6XDI), bis(isocyanatomethyl)norbornane (NBDI), 3(4)-isocyanatomethyl-1-methylcyclohexyl isocyanate (IMCI) and/or 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) or mixtures of these isocyanates. Further examples are derivatives of the above diisocyanates with a uretdione, isocyanurate, urethane, allophanate, biuret, iminooxadiazinedione and/or oxadiazinetrione structure and with more than two NCO groups.
The amount of constituent (b) in the polyurethaneurea provided in accordance with the invention is preferably 1.0 to 3.5 mol, more preferably 1.0 to 3.3 mol, more particularly 1.0 to 3.0 mol, based in each case on the constituent (a) of the polyurethaneurea.
The polyurethaneurea provided in accordance with the invention comprises units which originate from at least one diamine or amino alcohol as a synthesis component and serve as what are called chain extenders (c).
Such chain extenders are, for example, diamines or polyamines and also hydrazides, e.g. hydrazine, 1,2-ethylenediamine, 1,2- and 1,3-diaminopropane, 1,4-diaminobutane, 1,6-diaminohexane, isophoronediamine, isomer mixture of 2,2,4- and 2,4,4-trimethylhexamethylenediamine, 2-methylpentamethylenediamine, diethylenetriamine, 1,3- and 1,4-xylylenediamine, α,α,α′,α′-tetramethyl-1,3- and -1,4-xylylenediamine and 4,4′-diaminodicyclohexylmethane, dimethylethylenediamine, hydrazine, adipic dihydrazide, 1,4-bis(aminomethyl)cyclohexane, 4,4′-diamino-3,3′-dimethyldicyclohexylmethane and other (C1-C4) di- and tetraalkyldicyclohexylmethanes, e.g. 4,4′-diamino-3,5-diethyl-3′,5′-diisopropyldicyclohexylmethane.
Suitable diamines or amino alcohols are generally low molecular weight diamines or amino alcohols which contain active hydrogen with differing reactivity towards NCO groups, such as compounds which as well as a primary amino group also contain secondary amino groups or which as well as an amino group (primary or secondary) also contain OH groups. Examples of such compounds are primary and secondary amines, such as 3-amino-1-methylaminopropane, 3-amino-1-ethylaminopropane, 3-amino-1-cyclohexylaminopropane, 3-amino-1-methylaminobutane, and also amino alcohols, such as N-aminoethylethanolamine, ethanolamine, 3-aminopropanol, neopentanolamine and, with particular preference, diethanolamine.
The constituent (c) of the polyurethaneurea provided in accordance with the invention can be used, in the context of the preparation of the polyurethaneurea, as a chain extender.
The amount of constituent (c) in the polyurethaneurea provided in accordance with the invention is preferably 0.1 to 1.5 mol, more preferably 0.2 to 1.3 mol, more particularly 0.3 to 1.2 mol, based in each case on the constituent (a) of the polyurethaneurea.
The polyurethaneurea provided in the present invention comprises units which originate from a polyoxyalkylene ether as a synthesis component.
The polyoxyalkylene ether is preferably a copolymer of polyethylene oxide and polypropylene oxide. These copolymer units are present in the form of end groups in the polyurethaneurea, and have the effect of making the polyurethaneurea hydrophilic.
Suitable nonionically hydrophilicizing compounds meeting the definition of component (d) are, for example, polyoxyalkylene ethers which contain at least one hydroxyl or amino group. These polymers contain in general a fraction of 30% to 100% by weight of units derived from ethylene oxide.
Nonionically hydrophilicizing compounds (d) are, for example, monofunctional polyalkylene oxide polyether alcohols containing on average 5 to 70, preferably 7 to 55, ethylene oxide units per molecule, of the kind available in conventional manner through alkoxylation of suitable starter molecules (e.g. in Ullmanns Enzyklopädie der technischen Chemie, 4th Edition, Volume 19, Verlag Chemie, Weinheim pp. 31-38).
Examples of suitable starter molecules are saturated monoalcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, the isomeric pentanols, hexanols, octanols and nonanols, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol, cyclohexanol, the isomeric methylcyclohexanols or hydroxymethylcyclohexane, 3-ethyl-3-hydroxymethyloxetane or tetrahydrofurfuryl alcohol, diethylene glycol monoalkyl ethers, such as diethylene glycol monobutyl ether, for example, unsaturated alcohols such as allyl alcohol, 1,1-dimethylallyl alcohol or oleyl alcohol, aromatic alcohols such as phenol, the isomeric cresols or methoxyphenols, araliphatic alcohols such as benzyl alcohol, anisyl alcohol or cinnamyl alcohol, secondary monoamines such as dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, bis(2-ethylhexyl)amine, N-methyl- and N-ethylcyclohexylamine or dicyclohexylamine, and also heterocyclic secondary amines such as morpholine, pyrrolidine, piperidine or 1H-pyrazole. Preferred starter molecules are saturated monoalcohols. Particular preference is given to using diethylene glycol monobutyl ether as a starter molecule.
Alkylene oxides suitable for the alkoxylation reaction are, in particular, ethylene oxide and propylene oxide, which can be used in any order or else in a mixture in the alkoxylation reaction.
The polyalkylene oxide polyether alcohols are either pure polyethylene oxide polyethers or mixed polyalkylene oxide polyethers whose alkylene oxide units are composed to an extent of at least 30 mol %, preferably at least 40 mol %, of ethylene oxide units. Preferred nonionic compounds are monofunctional mixed polyalkylene oxide polyethers which contain at least 40 mol % of ethylene oxide units and not more than 60 mol % of propylene oxide units.
When the alkylene oxides ethylene oxide and propylene oxide are used, they can be used in any order or else in a mixture in the alkoxylation reaction.
The average molar weight of the polyoxyalkylene ether is preferably 500 g/mol to 5000 g/mol, more preferably 1000 g/mol to 4000 g/mol, more particularly 1000 to 3000 g/mol.
The amount of constituent (d) in the polyurethaneurea provided in accordance with the invention is preferably 0.01 to 0.5 mol, more preferably 0.02 to 0.4 mol, more particularly 0.04 to 0.3 mol, based in each case on the constituent (a) of the polyurethaneurea.
In a further embodiment the polyurethaneurea provided in accordance with the invention further comprises units which originate from at least one polyol as a synthesis component. These polyol synthesis components, in comparison to the macropolyol, are relatively short-chain synthesis components, which through additional hard segments can give rise to stiffening.
The low molecular weight polyols (e) used to synthesize the polyurethaneureas thus have the effect, generally, of stiffening and/or branching the polymer chain. The molecular weight is preferably 62 to 500 g/mol, more preferably 62 to 400 g/mol, more particularly 62 to 200 g/mol.
Suitable polyols may contain aliphatic, alicyclic or aromatic groups. Mention may be made here, for example, of the low molecular weight polyols having up to about 20 carbon atoms per molecule, such as ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,4-butanediol, 1,3-butylene glycol, cyclohexanediol, 1,4-cyclohexanedimethanol, 1,6-hexanediol, neopentyl glycol, hydroquinone dihydroxyethyl ether, bisphenol A (2,2-bis(4-hydroxyphenyl)propane), hydrogenated bisphenol A (2,2-bis(4-hydroxycyclohexyl)propane), and also trimethylolpropane, glycerol or pentaerythritol, and mixtures of these and, if desired, other low molecular weight polyols as well. Use may also be made of ester diols such as, for example, α-hydroxybutyl-ε-hydroxycaproic acid ester, co-hydroxyhexyl-ω-hydroxybutyric acid ester, adipic acid 8-hydroxyethyl ester or terephthalic acid bis(β-hydroxyethyl) ester.
The amount of constituent (e) in the polyurethaneurea provided in accordance with the invention is preferably 0.05 to 1.0 mol, more preferably 0.05 to 0.5 mol, more particularly 0.1 to 0.5 mol, based in each case on the constituent (a) of the polyurethaneurea.
(f) Further Amine- and/or Hydroxy-Containing Units (Synthesis Component)
The reaction of the isocyanate-containing component (1) with the hydroxy- or amine-functional compounds (a), (c), (d) and, if used, (e) takes place typically with a slight NCO excess observed over the reactive hydroxy or amine compounds. In this case, at the end point of the reaction, through attainment of a target viscosity, there still always remain residues of active isocyanate. These residues must be blocked so that there is no reaction with large polymer chains. Such a reaction leads to the three-dimensional crosslinking and gelling of the batch. The processing of such a polyurethaneurea is no longer possible, or is possible only with restrictions. The batches typically contain large amounts of water. Over the course of a number of hours, on standing or on stirring of the batch at room temperature, water causes the isocyanate groups that still remain to be consumed by reaction.
If, however, the desire is to block the remaining, residual isocyanate content rapidly, the polyurethaneureas provided in accordance with the invention may also comprise monomers (f), which are located in each case at the chain ends and cap them.
These units derive on the one hand from monofunctional compounds that are reactive with NCO groups, such as monoamines, more particularly mono-secondary amines, or monoalcohols. Mention may be made here, for example, of ethanol, n-butanol, ethylene glycol monobutyl ether, 2-ethylhexanol, 1-octanol, 1-dodecanol, 1-hexadecanol, methylamine, ethylamine, propylamine, butylamine, octylamine, laurylamine, stearylamine, isononyloxypropylamine, dimethylamine, diethylamine, dipropylamine, dibutylamine, N-methylaminopropylamine, diethyl(methyl)aminopropylamine, morpholine, piperidine and suitable substituted derivatives thereof.
Since the units (f) are used essentially in the polyurethaneurea provided in accordance with the invention to destroy the NCO excess, the amount required is dependent essentially on the amount of the NCO excess, and cannot be specified generally.
Preferably, these units are not used during the synthesis. In that case, unreacted isocyanate is hydrolysed, preferably, by the dispersing water.
Although the polyurethaneurea dispersion of the invention, by virtue of the antibacterial (antimicrobial) use of the silver-containing constituent, is already sufficiently functionalized, it may be of advantage in a specific case to integrate further functionalizations into the polyurethaneurea dispersion and hence into the resultant coatings. These further possible functionalizations are now described below.
Furthermore, the polyurethaneurea dispersions of the invention may comprise further constituents typical for the intended purpose, such as additives and fillers. An example of such are active pharmacological substances, medicaments and additives which promote the release of active pharmacological substances (drug-eluting additives).
Active pharmacological substances and medicaments which may be used in the polyurethaneurea compositions of the invention are in general, for example, thromboresistant agents, antibiotic agents, antitumour agents, growth hormones, antiviral agents, antiangiogenic agents, angiogenic agents, antimitotic agents, anti-inflammatory agents, cell cycle regulators, genetic agents, hormones, and also their homologues, derivatives, fragments, pharmaceutical salts, and combinations thereof.
Specific examples of such medicaments and active pharmacological substances hence include thromboresistant (non-thrombogenic) agents and other agents for suppressing acute thrombosis, stenosis or late restenosis of the arteries, examples being heparin, streptokinase, urokinase, tissue plasminogen activator, anti-thromboxan-B2 agent; anti-B-thromboglobulin, prostaglandin-E, aspirin, dipyridimol, anti-thromboxan-A2 agent, murine monoclonal antibody 7E3, triazolopyrimidine, ciprostene, hirudin, ticlopidine, nicorandil, etc. A growth factor can likewise be utilized as a medicament in order to suppress subintimal fibromuscular hyperplasia at the arterial stenosis site, or any other cell growth inhibitor can be utilized at the stenosis site.
The medicament or active pharmacological substance may also be composed of a vasodilatator, in order to counteract vasospasm—for example, an antispasm agent such as papaverine. The medicament may be a vaso active agent per se, such as calcium antagonists, or α- and β-adrenergic agonists or antagonists. In addition the therapeutic agent may be a biological adhesive such as cyanoacrylate in medical grade, or fibrin, which is used, for example, for bonding a tissue valve to the wall of a coronary artery.
The therapeutic agent may further be an antineoplastic agent such as 5-fluorouracil, preferably with a controlling releasing vehicle for the agent (for example, for the use of an ongoing controlled releasing antineoplastic agent at a tumour site).
The therapeutic agent may be an antibiotic, preferably in combination with a controlling releasing vehicle for ongoing release from the coating of a medical device at a localized focus of infection within the body. Similarly, the therapeutic agent may comprise steroids for the purpose of suppressing inflammation in localized tissue, or for other reasons.
Specific examples of suitable medicaments include:
Further typical additives and auxiliaries such as thickeners, hand assistants, pigments, dyes, matting agents, UV stabilizers, phenolic antioxidants, light stabilizers, hydrophobicizing agents and/or flow control assistants may likewise be used in the polyurethaneurea compositions of the invention.
The polyurethaneurea dispersion of the invention comprises, besides the polyurethaneurea, at least one silver-containing constituent.
By “a silver-containing constituent” is meant, for the purposes of the present invention, any component capable of releasing silver in elemental or ionic form and hence leading to an antimicrobial (biocidal/antibacterial) effect.
The biocidal effect of silver derives from the interaction of silver ions with bacteria. In order to be able to generate the maximum number of silver ions from elemental silver, a large surface area of the silver is advantageous. Consequently, for antimicrobial applications, use is made primarily of high-porosity silver powders, silver on support materials or colloidal silver sols.
Available commercially at present, for example, are Ag-Ion (silver in a zeolite, Agion, Wakefield, Mass., USA), Ionpure® (Ag+ in glass, Ciba Spezialitätenchemie GmbH, Lampertheim, Germany), Alphasan® (AgZr phosphate, Milliken Chemical, Gent, Belgium), Irgaguard® (Ag in zeolite/glass), Hygate® (silver powder, Bio-Gate, Nuremberg, Germany), NanoSilver® PG (silver in suspension) and Nanocid® (silver on TiO2, Pars Nano Nasb Co., Tehran, Iran).
The silver powders are preferably obtained from the gas phase, a silver melt being vaporized in helium. The resultant nanoparticles agglomerate immediately and are obtained in the form of high-porosity, readily filterable powders. The disadvantage of these powders, however, is that the agglomerates can no longer be dispersed into individual particles.
Colloidal silver dispersions are obtained by reducing silver salts in organic or aqueous medium. Their preparation is more complex than that of the silver powders, but offers the advantage that unagglomerated nanoparticles are obtained. As a result of the incorporation of unagglomerated nanoparticles into polyurethaneurea compositions it is possible to produce transparent films.
For the silver-containing polyurethaneurea compositions of the invention it is possible to use any desired silver powders or colloidal silver dispersions. A multiplicity of such silver materials is available commercially.
The silver sols used preferably to formulate the silver-containing aqueous polyurethaneurea dispersion of the invention are prepared from Ag2O by reduction with a reducing agent such as aqueous formaldehyde solution following prior addition of a dispersing assistant. For this purpose the Ag2O sols are prepared, for example, batchwise, by rapid mixing of silver nitrate solution with NaOH, by means of rapid stirring, or in a continuous operation, by using a micromixer conforming to DE 10 2006 017 696. Thereafter the Ag2O nanoparticles are reduced with formaldehyde in excess, in a batch process, and, finally, are purified by centrifuging or membrane filtration, preferably by membrane filtration. This mode of production is particularly advantageous on account of the fact that it allows the amount of organic auxiliaries bound on the surface of the nanoparticles to be minimized. The product is a silver sol dispersion in water with an average particle size of approximately 10 to 150 nm, more preferably 20 to 100 nm. This silver sol dispersion can then be combined with the polyurethaneurea of the invention.
In the nonionic polyurethaneurea dispersions of the invention it is possible to use nanocrystalline silver particles having an average size of 1 to 1000 nm, preferably 5 to 500 nm, very preferably of 10 to 250 nm. The silver nanoparticles may be in dispersion in organic solvents or water, preferably in water-miscible organic solvents or water, very preferably in water. The nonionic polyurethaneurea composition of the invention is generally prepared by adding the silver dispersion to the polyurethaneurea and then carrying out homogenization by stirring or shaking.
The amount of nanocrystalline silver, based on the amount of solid polymer in the aqueous polyurethaneurea dispersion and also in the resultant coatings, on the assumption of a homogeneous composition, and calculated as Ag and Ag+, can be varied. Typical concentrations range from 0.1% to 10%, preferably from 0.3% to 5%, more preferably from 0.5% to 3%, by weight.
The advantage of the use of the silver-containing nonionic polyurethaneurea composition of the invention in the form of an aqueous dispersion for producing antimicrobial coatings lies, in comparison to alternative processes, in the great ease of combination of the aqueous polyurethane dispersions and the aqueous colloidal silver dispersions. Different silver concentrations can be set easily and precisely as required for different applications. Many processes of the prior art are substantially more involved and are also not as precise, in terms of the quantity of silver, as the process for preparing the compositions of the invention. This is true in particular of those processes in which polyurethane pellets are provided before being processed, by impregnation, with an antimicrobial agent.
In one particularly preferred embodiment the antimicrobial silver is in the form of high-porosity silver powders, silver on support materials, or in the form of colloidal silver sols, with 0.1% to 10% by weight of silver being present based on the solid polyurethaneurea polymer in the aqueous dispersion and in the coating that results therefrom, on the assumption of a homogeneous composition.
In a further particularly preferred embodiment the antimicrobial silver is in the form of colloidal silver sots in aqueous medium or in water-miscible organic solvents, with a particle size of 1 to 1000 nm, the amount added being 0.3% to 5% by weight, based on the solid polyurethaneurea polymer.
In a further particularly preferred embodiment, the antimicrobial silver is in the form of colloidal silver sols in aqueous medium, with an average particle size of 1 to 500 nm, the amount added being 0.5% to 3% by weight, based on the solid polyurethaneurea polymer in the aqueous dispersion and in the coating that results therefrom, on the assumption of a homogeneous composition.
In one preferred embodiment the nonionically stabilized polyurethaneurea dispersion of the invention comprises a polyurethaneurea which is synthesized at least from
In a further embodiment of the present invention the nonionically stabilized polyurethaneurea dispersion of the invention comprises a polyurethaneurea which is synthesized at least from
In a further embodiment of the present invention the nonionically stabilized polyurethaneurea dispersion of the invention comprises a polyurethaneurea which is synthesized at least from
Particularly preferred in accordance with the invention are polyurethaneurea dispersions comprising a polyurethaneurea which is synthesized from
Further preferred in accordance with the invention are polyurethaneurea dispersions comprising a polyurethaneurea which is synthesized from
Even further preferred in accordance with the invention are polyurethaneurea dispersions comprising a polyurethaneurea which is synthesized from
The nonionically stabilized polyurethaneurea dispersions of the invention can be used for example in the form of an aqueous dispersion for a multiplicity of different applications. In the foreground here, in particular, are applications relating to the production of coatings, where the issue is the antimicrobial equipping of articles of a general nature. With very particular preference the nonionically stabilized polyurethane dispersion compositions of the invention are used, for example, in the form of an aqueous dispersion in the production of coatings on medical devices.
The term “medical device” is to be understood broadly in the context of the present invention. Suitable, non-limiting examples of medical devices (including instruments) are contact lenses; cannulas; catheters, for example urological catheters such as urinary catheters or ureteral catheters; central venous catheters; venous catheters or inlet or outlet catheters; dilation balloons; catheters for angioplasty and biopsy; catheters used for introducing a stent, an embolism filter or a vena cava filter; balloon catheters or other expandable medical devices; endoscopes; laryngoscopes; tracheal devices such as endotracheal tubes, respirators and other tracheal aspiration devices; bronchoalveolar lavage catheters; catheters used in coronary angioplasty; guide rods, insertion guides and the like; vascular plugs; pacemaker components; cochlear implants; dental implant tubes for feeding, drainage tubes; and guide wires.
The coating solutions of the invention may be used, furthermore, for producing protective coatings, for example for gloves, stents and other implants; external (extracorporeal) blood lines (blood-carrying pipes); membranes; for example for dialysis; blood filters; devices for circulatory support; dressing material for wound management; urine bags and stoma bags. Also included are implants which comprise a medically active agent such as medically active agents for stents or for balloon surfaces or for contraceptives.
Typically the medical device is formed from catheters, endoscopes, laryngoscopes, endotracheal tubes, feeding tubes, guide rods, stents, and other implants.
There are many materials suitable as a substrate of the surface to be coated, such as metals, textiles, ceramics or plastics, the use of metals and plastics being preferred for the production of medical devices.
Examples of metals include medical stainless steel or nickel-titanium alloys.
In the case of catheters, these are preferably manufactured from plastics such as polyamide, block copolymers of styrene and unsaturated compounds such as ethylene, butylene and isoprene, polyethylene or copolymers of polyethylene and polypropylene, silicone, polyvinyl chloride (PVC) and/or polyurethanes. For improved adhesion of the polyurethaneurea compositions of the invention, the surface of the medical article may have been subjected beforehand to a surface treatment, such as to coating with an adhesion promoter.
The present invention further provides, therefore, coatings which are obtained starting from the above-described polyurethaneurea dispersions.
The stated synthesis components (a), (b), (d) and, if desired, (e) are reacted such that first of all an isocyanate-functional prepolymer free of urea groups is prepared, the amount-of-substance ratio of isocyanate groups to isocyanate-reactive groups being 0.8 to 3.5, preferably 0.9 to 3.0, more preferably 1.0 to 2.5, and thereafter the remaining isocyanate groups are given an amino-functional chain extension or chain termination, before, during or in water after the dispersing, the ratio of equivalents of isocyanate-reactive groups of the compounds used for chain extension to free isocyanate groups of the prepolymer being between 40% to 150%, preferably between 50% to 120%, more preferably between 60% to 120%.
The polyurethaneureas of the invention are prepared preferably by the process known as the acetone process, in the form of a dispersion.
For the preparation of the polyurethaneureas by this acetone process, some or all of the synthesis components (a), (d) and, if used, (e), which must not contain any primary or secondary amino groups, and the polyisocyanate component (b), for the preparation of an isocyanate-functional polyurethane prepolymer, are typically introduced and, where appropriate, are diluted with a water-miscible solvent which is nevertheless inert towards isocyanate groups, and the batch is heated to temperatures in the range from 50 to 120° C. To accelerate the isocyanate addition reaction it is possible to use the catalysts known in polyurethane chemistry, an example being dibutyltin dilaurate. Preference is given to synthesis without catalyst.
Suitable solvents are the typical aliphatic, keto-functional solvents such as, for example, acetone, butanone, which can be added not only at the beginning of the preparation but also, if desired, in portions later on as well. Acetone and butanone are preferred. Other solvents, such as xylene, toluene, cyclohexane, butyl acetate, methoxypropyl acetate or solvents with ether units or ester units, for example, may likewise be used and may be removed in whole or in part by distillation or may remain entirely in the dispersion.
Subsequently any constituents of (a), (b), (d) and, if used, (e) not added at the beginning of the reaction are metered in.
In the preparation of the polyurethane prepolymer, the amount-of-substance ratio of isocyanate groups to isocyanate-reactive groups is 0.8 to 3.5, preferably 0.9 to 3.0, more preferably 1.0 to 2.5.
The reaction of components (a), (b), (d) and, if used, (e) to form the prepolymer takes place partially or completely, but preferably completely. In this way, polyurethane prepolymers which contain free isocyanate groups are obtained, in bulk or in solution.
Subsequently, in a further process step, if it has not yet taken place or has taken place only partly, the resulting prepolymer is dissolved by means of aliphatic ketones such as acetone or butanone.
Subsequently, possible NH2—, NH-functional and/or OH-functional components are reacted with the remaining isocyanate groups. This chain extension/termination may be carried out alternatively in solvent prior to dispersing, during dispersing or in water after dispersing has taken place. Preference is given to carrying out the chain extension prior to dispersing in water.
Where compounds conforming to the definition of (c) with NH2, NH and/or OH groups are used for the chain extension, the chain extension of the prepolymers takes place preferably prior to the dispersing.
The degree of chain extension, in other words the ratio of equivalents of NCO-reactive groups of the compounds used for chain extension to free NCO groups of the prepolymer is between 40% to 150%, preferably between 50% to 120%, more preferably between 60% to 120%.
The aminic/hydroxy-containing components (c) may be used if desired in water-diluted or solvent-diluted form in the process of the invention, individually or in mixtures, in which case any sequence of addition is possible in principle. If water or organic solvents are used as diluents, the diluent content is preferably 70% to 95% by weight.
The preparation of the polyurethane dispersion from the prepolymers takes place subsequent to chain extension. For this purpose, either the dissolved and chain-extended polyurethane polymer is introduced into the dispersing water, where appropriate with strong shearing, such as vigorous stirring, for example, or, conversely, the dispersing water is stirred into the prepolymer solutions. Preferably the water is added to the dissolved prepolymer.
The solvent still present in the dispersions after the dispersing step is typically then removed by distillation. Its removal during the actual dispersing step is likewise a possibility.
The solids content of the polyurethane dispersion is between 20% to 70% by weight, preferably 20% to 65% by weight. For coating experiments, these dispersions can be diluted as desired with water in order to allow the thickness of the coating to be varied.
The present invention further provides a process for preparing the polyurethaneurea dispersion of the invention by mixing a nonionically stabilized polyurethaneurea as defined above and/or a polyurethaneurea as obtained above with a silver-containing constituent as defined above.
As already mentioned, the polyurethaneurea dispersions of the invention can be used to coat a variety of substrates such as, for example, metal, plastic, ceramic, paper, leather or textile fabrics. The coatings may be applied by various techniques such as spraying, dipping, knifecoating, printing or transfer coating to any conceivable substrates. Preferred applications of these polyurethaneurea compositions are, for example, for surfaces of medical devices and implants, as already mentioned above.
The advantages of the polyurethaneurea dispersions of the invention are set out by means of exemplary embodiments and corresponding comparative experiments in the following examples.
All the references described above are incorporated by reference in their entireties for all useful purposes.
While there is shown and described certain specific structures embodying the invention, it will be manifest to those skilled in the art that various modifications and rearrangements of the parts may be made without departing from the spirit and scope of the underlying inventive concept and that the same is not limited to the particular forms herein shown and described.
The NCO content of the resins described in the inventive and comparative examples was determined by titration in accordance with DIN EN ISO 11909.
The solids contents were determined in accordance with DIN-EN ISO 3251.1 g of polyurethane dispersion was dried at 11 15° C. to constant weight (15-20 min) using an infrared drier.
The average particle sizes of the polyurethane dispersions are measured using the High Performance Particle Sizer (HPPS 3.3) from Malvern Instruments.
Unless noted otherwise, amounts indicated in % are % by weight and relate to the overall solution obtained.
This example describes the preparation of an inventive polyurethaneurea dispersion.
277.2 g of Desmophen® C 2200, 33.1 g of polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and this initial charge was homogenized by stirring for 5 minutes. Added to this mixture at 65° C. over the course of 1 minute were, first of all, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture is heated to 110° C. After 3 h 40 minutes the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 15 minutes. Subsequently, over the course of 15 minutes, dispersion was carried out by addition of 590 g of water. This was followed by removal of the solvent by vacuum distillation. A storage-stable polyurethane dispersion was obtained which had a solids content of 41.5% and an average particle size of 164 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion.
277.2 g of Desmophen® C 1200, 33.1 g of polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and this initial charge was homogenized by stirring for 5 minutes. Added to this mixture at 65° C. over the course of 1 minute were, first of all, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture is heated to 111° C. After 2.5 hours the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 5 minutes. Subsequently, over the course of 15 minutes, dispersion was carried out by addition of 590 g of water. This was followed by removal of the solvent by vacuum distillation. A storage-stable polyurethane dispersion was obtained which had a solids content of 40.4% and an average particle size of 146 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion.
277.2 g of PolyTHF® 2000, 33.1 g of polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and this initial charge was homogenized by stirring for minutes. Added to this mixture at 65° over the course of 1 minute were, first of all, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture is heated to 110° C. After 18 hours the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 5 minutes. Subsequently, over the course of 15 minutes, dispersion was carried out by addition of 590 g of water. This was followed by removal of the solvent by vacuum distillation. A storage-stable polyurethane dispersion was obtained which had a solids content of 40.7% and an average particle size of 166 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion.
269.8 g of PolyTHF® 2000, 49.7 g of polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and this initial charge was homogenized by stirring for 5 minutes. Added to this mixture at 65° C. over the course of 1 minute were, first of all, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture is heated to 100° C. After 17.5 hours the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 5 minutes. Subsequently, over the course of 15 minutes, dispersion was carried out by addition of 590 g of water. This was followed by removal of the solvent by vacuum distillation. A storage-stable polyurethane dispersion was obtained which had a solids content of 41.6% and an average particle size of 107 nm.
This example describes the preparation of an inventive polyurethaneurea dispersion.
282.1 g of PolyTHF® 2000, 22.0 g of polyether LB 25 and 6.7 g of neopentyl glycol were introduced at 65° C. and this initial charge was homogenized by stirring for 5 minutes. Added to this mixture at 65° C. over the course of 1 minute were, first of all, 71.3 g of 4,4′-bis(isocyanatocyclohexyl)methane (H12MDI) and thereafter 11.9 g of isophorone diisocyanate. The mixture is heated to 110° C. After 21.5 hours the theoretical NCO value was reached. The completed prepolymer was dissolved at 50° C. in 711 g of acetone and then at 40° C. a solution of 4.8 g of ethylenediamine in 16 g of water was metered in over the course of 10 minutes. The subsequent stirring time was 5 minutes. Subsequently, over the course of 15 minutes, dispersion was carried out by addition of 590 g of water. This was followed by removal of the solvent by vacuum distillation. A storage-stable polyurethane dispersion was obtained which had a solids content of 37.5% and an average particle size of 195 nm.
A 0.054 molar silver nitrate solution was admixed with a mixture of 0.054 molar sodium hydroxide solution and the dispersing assistant Disperbyk 190 (manufacturer: BYK Chemie) (1 μl) in a volume ratio of 1:1 and the mixture was stirred for 10 minutes. A brown Ag2O nanosol was formed. Added to this reaction mixture with stirring was an aqueous 4.6 molar formaldehyde solution, and so the molar ratio of Ag+ to reducing agent was 1:10. This mixture was heated to 60° C., held at that temperature for 30 minutes and then cooled. The particles were purified by centrifugation (60 minutes at 30 000 rpm) and redispersed in fully demineralized water by introduction of ultrasound (1 minute). This operation was repeated twice. A colloidally stable sol with a solids content of 5% by weight (silver particles and dispersing assistant) was obtained in this way. The yield is just under 100%. After centrifugation, according to elemental analysis, the silver dispersion contains 3% by weight of Disperbyk 190, based on the silver content. An analysis by means of laser correlation spectroscopy showed an effective diameter for the particles of 73 nm.
50 ml of the polyurethane dispersions from Examples 1 to 5 were admixed with a 15.1% aqueous colloidal silver dispersion, whose preparation is described above, and the mixtures were homogenized by shaking. The amount of silver dispersion added to the polyurethane dispersions of Examples 1 to 5 is such that the dispersions contain 1% by weight of silver, based on the solid polymer content.
The silver-containing coatings for the measurement of silver release were produced on glass slides measuring 25×75 mm with the aid of a spincoater (RC5 Gyrset® 5, Karl Stiss, Garching, Germany). For this purpose a slide treated with 3-aminopropyltriethoxysilane for improved adhesion was clamped in on the sample plate of the spin coater and was covered homogeneously with about 2.5-3 g of aqueous undiluted polyurethane dispersion. Rotation of the sample plate at 1300 revolutions per minute for 20 seconds gave a homogeneous coating, which was dried at 100° C. for 15 minutes and then at 50° C. for 24 hours. From the slides thus obtained, sections of around 4.5 cm2 were produced and were used for measuring the amounts of silver released.
The slide pieces with various silver-containing polyurethane coatings of Examples 6a to 6e were covered with 2.5 ml of distilled water in a tablet tube and stored in an incubator at 37° C. for one week. The water was removed and the amount of silver delivered from the film to the liquid was determined by atomic absorption spectroscopy. The dry films on the glass sections were again covered with 2.5 ml of water and stored further at 37° C. The entire process was repeated 5 times, allowing silver release to be determined for a number of weeks.
The results show that the coatings deliver silver over a relatively long period of time.
2.5 g of the silver-containing polyurethane dispersions of Examples 6b and 6d were weighed out into aluminium containers (6.4 cm in diameter, 1.3 cm high). The aqueous dispersion was left to dry first at room temperature for 2 h and then the polymers, which were still moist, were dried in a drying cabinet at 50° C. for 25 hours. The resulting polyurethane mouldings were parted from the aluminium trays, and small plaques with a diameter of 5 mm were cut. These silver-containing polyurethane plaques with a thickness of 150 μm, were tested for their antimicrobial activity against Escherichia coli.
Polyurethane plaques comprising the silver-containing polyurethane dispersions of Examples 6b and 6d, with a diameter of 5 mm, were investigated for their bactericidal action in a bacterial suspension of Escherichia coli ATCC 25922. A bacterial culture of Escherichia coli ATCC 25922 was produced by taking colonies from an agar plate, colonized and grown overnight at 37° C., with Columbia agar (Columbia blood agar plates, Becton Dickinson, # 254071) and suspending the colonies in 0.9% strength sodium chloride solution. An aliquot of this solution was transferred to PBS (PBS pH 7.2, Gibco, #20012) with 5% Müller Hinton medium (Becton Dickinson, N257092), to give an OD600 of 0.0001. This solution corresponds to a microbe count of 1×105 microbes per ml. The microbe count was determined by serial dilution and plating out of the dilution stages onto agar plates. The cell count was reported in the form of colony-forming units (CFU/ml).
The polyurethane plaques comprising the silver-containing polyurethane dispersions of Examples 6b and 6d, with a diameter of 5 mm, were each placed in one well of a 24-well microtitre plate. Pipetted into the wells, onto the plaques, was 1 ml of the E. coli ATCC 25922 suspension with a microbe count of 1×105 microbes per ml, and the plate was incubated at 37° C. for 24 hours. Immediately after batch preparation, and after 2, 4, 6 and 24 hours, 20 μl were withdrawn from each well and a microbe count determination was carried out. After 24 hours, the sample plaques were removed and transferred to a new 24-well microtitre plate. Again, 1 ml of a bacterial suspension of E. coli ATCC 25922, prepared as above, was applied to the plaques, followed by incubation at 37° C., and, directly after batch preparation and after 24 hours, 20 μl samples were taken, and the microbe count was determined. This was repeated up to 10 days.
The results show an antibacterial coating of more than one week. Freshly added bacterial suspension is killed continually down to very low microbe counts.
The silver-containing coatings for the measurement of antimicrobial activity were produced on glass slides measuring 25×75 mm with the aid of a spincoater (RC5 Gyrset 5, Karl Stiss, Garching, Germany). For this purpose a slide treated with 3-aminopropyltriethoxysilane for improved adhesion was clamped in on the sample plate of the spin coater and was covered homogeneously with about 2.5-3 g of aqueous undiluted polyurethane dispersion. Rotation of the sample plate at 1300 revolutions per minute for 20 seconds gave a homogeneous coating, which was dried at 100° C. for 15 minutes and then at 50° C. for 24 hours. The coated slides obtained were employed directly for measuring the antimicrobial activity.
The antimicrobial activity was tested in accordance with the following specification:
The test microbe, E. coli ATCC 25922, was cultured in an overnight culture on Columbia agar (Columbia blood agar plates, Becton Dickinson, # 254071) at 37° C. Thereafter, colonies were suspended in PBS (PBS pH 7.2, Gibco, #20012) with 5% Müller Hinton medium (Becton Dickinson, #257092) and a cell count of approximately 1×105 microbes/ml was set (“microbial suspension”). The test material was transferred to a Falcon tube filled with 30 ml of microbial suspension, and incubated at 37° C. overnight. After 24 hours, 20 μl of the cell suspension were taken for the purpose of monitoring growth. The cell count was determined by carrying out serial dilution and plating out the dilution stages on agar plates. The cell count is reported in the form of colony-forming units (CFU/ml).
The coating of Example 6d was tested for antimicrobial action over 15 days. For this purpose the specification above was continued such that, after the microbe count had been determined, fresh bacterial suspension of known concentration is applied to the coating again and, after 24 hours, a microbe count is determined again. The film was irrigated in PBS buffer on days 4-6 and 9-14.
Silver release from sulphonate-containing dispersions
Dispercoll® U 53 and Impranil® DLN are used. Both are polyester-containing polyurethaneureas based on aliphatic diisocyanates and stabilized by sulphonic acid groups\
Comparison to nonionic dispersions of the invention:
Furthermore, in investigations into the bacterial adherence of E. coli on different polyurethane surfaces, it is possible to ascertain that two coatings, obtained starting from nonionic dispersions (Examples 2 and 4), have a relatively low affinity for E. coli even without the use of Ag. The experiment was carried out in a method based on Japanese standard JIS Z 2801.
For this purpose the test microbe, E. coli ATCC 25922, was cultured in an overnight culture on Columbia agar at 37° C. Thereafter a number of colonies were suspended in phosphate-buffered saline (PBS) with 5% Müller Hinton medium, and a cell count of approximately 1×105 microbes/ml was set. 100 μl of each of these suspensions was distributed over the test material (in this case, the coatings without nanocrystalline silver) using a piece of Parafilm measuring 20×20 mm, so that the surface is uniformly wetted with cell suspension. Thereafter the test material with the bacterial suspension was incubated in a humidity chamber at 37° C. for 6 hours. After 6 hours, 20 μl of the cell suspension were taken for the purpose of monitoring growth. The cell count was determined by carrying out serial dilution and plating out the dilution stages on agar plates. Only living cells were counted in this determination. For all of the materials under investigation, a microbial growth to about 107 to 108 microbes/ml was found. Without the addition of nanocrystalline silver, therefore, the test materials do not hinder microbial growth.
Subsequently the Parafilm was removed from the test material, and the test material was washed with three times 4 ml of PBS in order to remove free-floating cells. Thereafter the test material was transferred to 15 ml of PBS and sonicated in an ultrasound bath for 30 seconds in order to detach the bacteria adhering to the surface of the test material. The results are shown in
From this result it is possible to infer that nonionic dispersions exhibit relatively low affinity for E. coli in comparison to a sulphonate-containing dispersion (Impranil DLN) without further auxiliary means. This alone, however, does not provide protection from infection, but the relatively low concentration of bacteria on the surface can then be broken down completely, easily, with a relatively low concentration of silver.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08154209.4 | Apr 2008 | EP | regional |
