WO2012163806A1

WO2012163806A1 - Method for producing an antimicrobial plastic product

Info

Publication number: WO2012163806A1
Application number: PCT/EP2012/059763
Authority: WO
Inventors: Christoph Cichos; Irmgard Cichos
Original assignee: Spiegelberg (Gmbh & Co.) Kg
Priority date: 2011-05-27
Filing date: 2012-05-24
Publication date: 2012-12-06
Also published as: DE102011102636B3

Abstract

The invention relates to a method for producing an antimicrobial plastic product which contains partially-reduced silver orthophosphate as an antimicrobial agent. In said method, silver orthophosphate is precipitated from an aqueous solution by the reaction of a hydrogen phosphate with a silver salt in the presence of a hydroxycarboxylic acid or of a salt thereof that acts as a dispersing agent. The temperature is subsequently raised in order for a partial reduction of the silver orthophosphate particles to metallic silver to be carried out, using hydroxycarboxylic acid or the salt thereof as a reducing agent.

Description

Process for the preparation of a

antimicrobial plastic product

description

The invention relates to a process for the production of antimicrobial plastic products. The products are in particular medical products such as catheters.

Plastic surfaces are easily colonized by microorganisms and especially by bacteria. The microorganisms can settle on plastic surfaces and multiply, so that the plastic article is coated with a film of microorganisms. By contact with a plastic article whose surface is colonized with microorganisms, infections can be triggered. This is generally undesirable, but particularly disadvantageous in the use of plastic products in the medical field.

Catheters such as e.g. Central venous catheters, wound catheters, ventricular catheters, lumbar catheters, peritoneal catheters or urethral catheters are generally made from plastics. On the other hand, it is known that infections are often caused by the use of microbially contaminated catheters.

To reduce the risk of infection, plastics are antimicrobially treated. For this purpose, antimicrobially active metals and especially silver are used. In WO 95/20878 a process for the production of plastic bodies is described in which polyurethane films are coated with metallic silver. The coated with a silver layer films are then crushed. The material thus obtained is melted down and formed into plastic bodies, in particular for medical applications.

WO 01/09229 discloses a process for producing an antimicrobial plastic body from a precursor. In this process, at least one component of the precursor is treated with a metal colloid. Thereafter, the plastic body is molded. The metal colloid is preferably colloidal silver.

WO 2004/024205 describes a process for producing an antimicrobial plastic product from a precursor. In this process, the precursor is first treated with an antimicrobial metal colloid. Subsequently, a soluble or sparingly soluble salt of an antimicrobial metal is added. Then the plastic product is molded. Usable metal salts are silver sulfate and silver phosphate.

Volume 5 of the 9th edition of the Römpp Chemielexikon, Stuttgart 1992, states on page 4159 under the heading "silver phosphate":

"Ag ₃ P0 ₄ , MW 418.63. Yellow, odorless Plv., D. 6,37, mp 849 °, sol. In dilute acids, formed as a yellowish precipitate from aq. Sol. Of orthophosphates and silver nitrate; blackening gradually occurs in the light " In H. Remy, Textbook of inorganic chemistry, Academic publishing Geest & Portig K.-G., Leipzig 1959, Volume 2, page 481 is executed on silver phosphate:

Ag ₃ P0 ₄ precipitates as yellow, heavy in water, but in dilute solutions slightly soluble precipitate of solutions of orthophosphates on addition of silver nitrate. ... In the light, the connection gradually suffers black coloring. "

According to the general knowledge of the textual references in handbooks and textbooks, silver phosphate is not considered to be photostable. The decomposition under the influence of light incidentally affects not only silver phosphate but also other silver compounds such as silver chloride, silver bromide and silver iodide and was the starting point for the development of the photographic process.

EP 0 251 783 A2 discloses antimicrobial compositions with which medical articles can be coated or impregnated. The antimicrobial compositions contain a silver antimicrobial compound, such as silver chloride, on a high surface area, particulate, physiologically acceptable, synthetic oxide material. In EP 0 251 783 it is explained that silver compounds in antimicrobial compositions have the disadvantage that the silver present in ionic form is unstable in the presence of light or other radiation with the result that it is reduced to metallic silver. The reduction to metallic silver goes hand in hand with a color change. If an article coated or impregnated with an antimicrobial composition containing silver compounds is exposed to light, it may become darker, which represents a significant aesthetic disadvantage. For medical items intended for introduction into the body Often, a white or substantially white appearance is often preferred. For aesthetic reasons, it is unacceptable for such articles to turn dark during use. According to the teaching of EP 0 251 783 A2, the photostability of silver chloride is to be improved by applying it to a physiologically inert, synthetic oxide carrier material in particle form with a large surface area.

According to the teaching of EP 0 251 783 A2, silver chloride on titanium oxide proved to be particularly suitable. Furthermore, EP 0 251 783 A2 expressly states that the photostability of silver phosphate can not be suppressed as much as that of silver chloride by the use of a support.

It is believed that the antimicrobial efficacy of the silver-containing plastic products is due to the release of silver cations on the surface. As far as the known antimicrobial plastic products contain metallic silver, it is necessary that this is first converted by oxidation in silver ions. This has the disadvantage that the release of silver ions depends on ambient conditions. For example, the oxidation of the silver may be hindered by reducing components in the plastic product. For this, relatively weak organic reducing agents, e.g. Polyols sufficient.

As far as the above-mentioned plastic products contain ionic silver compounds, the silver is already present in cationic form. However, the above plastic products have the disadvantage that they discolor when exposed to light. Attempting to improve the photostability by applying the silver compound to a high surface area oxide particulate carrier, according to the teachings of EP 0 251 783, is one of the ways to obtain photostability Improvement with various disadvantages. On the one hand, the carrier material itself can delay the release of the silver ions. On the other hand, the composition of a plastic product must be tailored to the respective application. In that regard, it is a great limitation when the presence of a particulate synthetic oxide carrier material is imperative to improve photostability. Finally, by using a support, the photostability of silver phosphate can not be suppressed as much as that of silver chloride, as indicated in EP 0 251 783 A2.

The above-mentioned disadvantages are overcome by the teaching of WO 2009/013016 for the preparation of partially reduced silver orthophosphate. The partially reduced silver orthophosphate according to WO 2009/013016 comprises silver phosphate particles on the surface of which metallic silver is present, with silver phosphate and metallic silver in direct contact. Such particles are not obtained according to the teaching of WO 2004/024205 mentioned above. The mentioned differences in the structure result from the different process management.

In Example 7 of WO 2004/024205, metallic silver is deposited on the filler barium sulfate. Subsequently, silver orthophosphate is precipitated. In this way, metallic silver-coated barium sulfate and free silver orthophosphate are produced.

In the production of the partially reduced silver orthophosphate according to WO 2009/013016, first the silver orthophosphate is precipitated. In this precipitation, a filler is not present. The subsequent reduction produces the direct silver phosphate-silver contact and thus microscopic electrochemical chemical half-elements. This particular structure results in significantly improved antimicrobial activity.

In addition, in plastic products containing the partially reduced silver phosphate, a high initial rate of

Silver release observed. This is particularly desirable in clinical applications for use during the

Implantation introduced germs are rapidly killed. in the

Compared to plastic roducts according to WO 2004/024205, the infection rate during implantation can be reduced.

The plastic products according to WO 2009/013016 have good photostability. Compared with the disclosure of EP 0 251 783 A2, which states that, according to the teaching of this document, the photostability of silver phosphate can be improved worse than that of silver chloride, the teaching of WO 2009/013016 represents a significant improvement.

However, the various processes described in WO 2009/013016 for the preparation of partially reduced silver orthophosphate are rather complicated. In these methods, a solution of a silver salt in aqueous ammonia is presented. Silver orthophosphate is precipitated by the addition of phosphoric acid. According to all process variants, the silver orthophosphate is then separated off. According to some variants, the silver orthophosphate is washed several times until the specific conductivity at 25 ° C of the last portion of washing water after separation from the solid is below 50 μ3 / αη, and after washing the silver orthophosphate is dried, optionally crushed and then suspended in deionized water , According to other variants, the silver orthophosphate is suspended directly in deionized water without washing, drying and comminution. Subsequently, the suspended silver orthophosphate is partially reduced by various variants Converted silver orthophosphate. According to all variants, the partially reduced silver orthophosphate is then separated off, washed several times until the specific conductivity at 25 ° C. of the last portion of washing water after separation from the partially reduced silver orthophosphate is below 50 pS / cm. After washing, the partially reduced silver orthophosphate is dried and incorporated into a plastic precursor. Subsequently, the plastic product is molded from it.

All process variants according to WO 2009/013016 have a two-step procedure in common. In the first stage, silver orthophosphate is precipitated by addition of phosphoric acid to an ammoniacal silver salt solution. The silver orthophosphate is isolated as an intermediate and partially reduced in a second stage.

The use of ammonia is not desirable from the point of view of occupational safety in industrial production.

The isolation and washing of the silver orthophosphate as an intermediate should ensure that no other substances are transferred from the first stage to the second stage except the silver orthophosphate. In particular, it is intended to prevent phosphoric acid from being transferred from the first stage to the second stage.

The Zweistufigkeit and the isolation of silver orthophosphate as an intermediate mean a high workload.

In all process variants according to WO 2009/013016, the particle size of the partially reduced silver orthophosphate is determined by the precipitation of the silver orthophosphate in the first stage, ie by the reaction of the ammoniacal Silver salt solution with phosphoric acid. In this reaction, the addition of stabilizer and especially dispersants should be avoided because of possible contamination of the product. This has the consequence that the particle size of the produced partially reduced silver orthophosphate can be influenced only within narrow limits and in particular a reduction of the particle size limits are set. Even if in WO 2009/013016 a normal distribution (Gaussian distribution) of the particle sizes (absolute values, no mean values) with a maximum in the range of 2 to 20 m, preferably 3 to 12 μπι and in particular 4 to 10 μιη is indicated it has proved difficult to obtain maxima at the lower limits of the ranges indicated.

For good antimicrobial efficacy of the plastic product, smaller particle sizes of the partially reduced silver orthophosphate dispersed therein are desirable.

The object of the present invention is to propose an improved process for the preparation of an antimicrobial synthetic fabric product containing partially reduced silver orthophosphate as an antimicrobial agent.

The object is achieved by a process for producing an antimicrobial plastic product, in which a) silver orthophosphate is precipitated by reacting a basic aqueous solution of a water-soluble hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with an aqueous solution of a silver salt at a first temperature to obtain an aqueous suspension of silver orthophosphate with the hydroxycarboxylic acid or its salt as a dispersant, b) the aqueous suspension thus obtained is heated to a second temperature and / or irradiated with UV light in order to convert the silver orthophosphate into partially reduced silver orthophosphate as reducing agent by means of the hydroxycarboxylic acid dissolved in the suspension or c, the partially reduced silver orthophosphate d) the solid is repeatedly washed with portions of deionized water until the specific conductivity at 25 ° C of the last portion of wash water after separation from the solid has a value below 50 S / cm, e) the solid is dried, f) the dried solid is incorporated into a plastic precursor which has not been treated with or contains a colloidal metal, and g) the plastic product is molded.

If in step a) silver nitrate is used as the silver salt and potassium hydrogen phosphate as the water-soluble hydrogen phosphate, then the precipitation of the silver orthophosphate is carried out according to the following reaction:

3 AgN0 ₃ + K ₂ HP0 ₄ - Ag ₃ P0 ₄ + 3 N0 ₃ ^{~ "} + 2 K ⁺ + H ⁺

The silver salt used should be precipitated essentially quantitatively in step a). Accordingly, stoichiometric amounts of silver salt and hydrogen phosphate are used. A slight excess of hydrogen phosphate can also be used. The precipitation reaction produces protons which are neutralized by the base present. To achieve quantitative precipitation, the initial pH must be alkaline. At the end of the precipitation, the pH may be basic, neutral or at best slightly acidic. It is preferred that the pH at the end of the precipitation is basic or neutral. Preferably, the aqueous solution of the water-soluble hydrogen phosphate and the hydroxycarboxylic acid or salt thereof is adjusted to a pH in the range of 10.5 to 13 before reacting with the aqueous solution of the silver salt. The adjustment of the pH can be carried out according to the invention by addition of an alkali metal hydroxide. The alkali hydroxide may be added in solid or dissolved form to the aqueous solution of the water-soluble hydrogenphosphate and the hydroxycarboxylic acid or the salt thereof.

The polybasic hydroxycarboxylic acid (or hydroxy polycarboxylic acid) serves two different purposes in the process according to the invention. On the one hand, it serves in stage a) as a dispersant in the precipitation of the silver orthophosphate. On the other hand, it is used in stage b) as a reducing agent. The peculiarity of the invention is, inter alia, that the dispersing action of the reduction process is selectively separated by the process regime. The dispersing effect is also present at room temperature. The reaction rate of the reduction is very low at room temperature. Only at higher temperatures does a reduction take place at appreciable speed. Therefore, the reduction of the silver orthophosphate after precipitation in the presence of the polybasic hydroxycarboxylic acid as a dispersant can be selectively triggered by subsequent increase in temperature. Preferably, the first temperature in step a) is in the range of 15 ° C to 35 ° C. The second temperature in step b) is preferably in the range of 70 ° C to 100 ° C. Alternatively, the reduction can be triggered selectively by irradiation with UV light.

In step b) of the process according to the invention, the silver orthophosphate is converted into partially reduced silver orthophosphate. This comprises or consists of particles of silver orthophosphate that have been partially reduced to metallic silver such that there is direct contact between silver orthophosphate and metallic silver in the particles. Preferably, the surface of the particles consists partly of silver orthophosphate and partly of metallic silver.

A characterization of pure silver orthophosphate on the one hand and partially reduced silver orthophosphate on the other hand by X-ray diffraction is shown in Figures 1 and 2 of WO 2009/013016. In the X-ray diffraction recording of the partially reduced silver orthophosphate, in addition to peaks for silver orthophosphate, bands for metallic silver can also be recognized. Accordingly, in the X-ray diffraction recording, the partially reduced silver orthophosphate obtained by the method of the present invention also has bands for metallic silver in addition to peaks for silver orthophosphate. An X-ray diffraction recording of a silver orthophosphate prepared in accordance with the present invention is shown in attached Figure 1.

The partially reduced silver orthophosphate prepared according to the invention can also be characterized by electron microscopy, in particular scanning electron microscopy. In particular, it can be ascertained by microscopic examination that the partially reduced surface of the particles has regions of different nature, ie that the surface of the particles of the partially reduced Silver orthophosphate has areas of metallic silver and districts of silver orthophosphate.

In the method of the invention, the polybasic hydroxycarboxylic acid is used in an amount sufficient to disperse the silver orthophosphate precipitated in step a) to give a stable suspension. This is the main design criterion according to which the expert can easily make the design. Moreover, the amount of polybasic hydroxycarboxylic acid must be sufficient in order to be able to partially reduce the silver orthophosphate to metallic silver in step b), but this will be the case regularly according to the abovementioned design criterion.

The process according to the invention has advantages over the process known from WO 2009/013016. The use of ammonia is not required. The isolation of the silver orthophosphate as an intermediate is avoided, whereby the production is considerably simplified. The precipitation of silver orthophosphate is carried out in the presence of a Disper ^¬ yaw means. This contributes to the fact that a partially reduced silver orthophosphate with smaller particle sizes can be produced by the process according to the invention in comparison with the prior art.

The plastic product obtainable by the process according to the invention releases silver ions in the concentration required for the effect according to the invention over a sufficiently long period of time. The silver ion concentration is high enough to reliably achieve antimicrobial efficacy. However, it does not become so large that cytotoxic effects can occur. For the purposes of the present invention, the term "solid" is used to refer to partially reduced silver orthophosphate Other terms which may be further constituents of the plastic product according to the invention include other terms, for example the term "filler". Thus, the term "solid" does not refer to such further ingredients or additives unless expressly stated otherwise.

In the context of the present invention, the term "plastic product" is used to refer to semi-finished products and ready-to-use products whose surface consists at least in part of the plastic according to the invention The plastic product may consist entirely of the plastic according to the invention limited to such plastic products.

It is preferable that, based on the total amount of water used in the process, the respective amounts of water are such that the aqueous solution used in the reaction of the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a), containing 60 to 90 vol.% Of the amount of water, and the aqueous solution, in the reaction of the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a) is added, 10 to 40 vol.% Of the amount of water.

Preferably, a hydrogen phosphate is used, which corresponds to the formula Me ₂ HP0 ₄ , in which Me means a metal ion in the oxidation state +1. Examples of Me are lithium, Sodium or potassium ions. The preferred hydrogen phosphate is di-potassium hydrogen phosphate.

The polybasic hydroxycarboxylic acid (or

Hydroxypolycarboxylic acid) is generally an ethane or propane substituted with at least two carboxyl groups and at least one hydroxy group, and in particular citric acid, tartaric acid or malic acid. The salt of the polybasic hydroxycarboxylic acid is preferably trisodium citrate.

The silver salt is preferably silver nitrate.

The first temperature and the time for reacting the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a) should preferably be such that less than 0.1 during the precipitation of the silver orthophosphate % of the silver ions are reduced to metallic silver.

Preferably, in step b) the second temperature for the thermal treatment and / or the intensity of the irradiation as well as the duration of the thermal treatment and / or the irradiation will be chosen such that 5 to 45% of the silver ions are reduced to metallic silver.

According to one embodiment of the invention, the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof are initially charged and the aqueous solution of a silver salt is added. Preferably, the aqueous solution of the silver salt is added in portions or continuously over a period of 15 to 45 minutes. According to a further embodiment of the invention, the aqueous solution of the silver salt is initially charged and the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof are added. Preferably, the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof is added in portions or continuously over a period of 15 to 45 minutes.

Preferably, in step b), the second temperature for the thermal treatment is set at 70 ° C to 100 ° C and the thermal treatment is carried out for 60 to 180 minutes.

For good antimicrobial efficacy of a plastic product, the particle number, i. the number of particles homogeneously dispersed in the plastic is of essential importance. For a given mass of partially reduced silver orthophosphate, the number of particles increases with decreasing particle size. The process according to the invention makes it possible to adjust both the particle size of the intermediate silver orthophosphate and, depending on this, the particle size of the partially reduced silver orthophosphate produced therefrom by reduction.

As already mentioned above, the presence of a dispersant in step a) first influences the particle size in the precipitation of the silver orthophosphate, which indirectly also determines the particle size of the partially reduced silver orthophosphate produced therefrom.

According to the invention, the particle size can be further influenced by preparing the aqueous suspension of silver orthophosphate using a dispersing device. Preferred dispersing devices are Stirrer and ultrasonic probes. Preferred stirrers are designs for special shear stress, in particular Ultraturrax.

Finally, according to the invention, the particle size of the resulting silver orthophosphate and, dependent thereon, also the particle size of the partially reduced silver orthophosphate prepared therefrom can be influenced via the adjustment of the ratio of solid fraction to liquid fraction in the suspension obtained in stage a). If, for example, the solid / liquid ratio at room temperature is reduced from 1:10 to 1:20, the silver orthophosphate becomes more finely divided, that is to say, in particular the proportion with particle sizes smaller than 1 μπι becomes larger.

The setting of the solid / liquid ratio takes place with regard to the silver orthophosphate composition resulting from the precipitation. Thereafter, the amount of liquid to be used depends.

Preferably, a partially reduced silver orthophosphate is prepared with such a particle size distribution as measured by laser diffraction that at least 15 wt.% Have a particle size of less than 1.0 m and at least 90 wt.% Have a particle size of less than 5 μπι. In the case of a normal distribution (Gaussian distribution) of the particle sizes, it is preferred that their maximum lies below 4 μm, in particular below 3 μm, and most preferably below 2 μm.

For example, in step a), a suspension having a ratio at room temperature of solid portion to liquid portion of 1: 5 to 1:15 is prepared wherein at least 15% by weight of the silver orthophosphate particles have a particle size of less than 1.0 have μιη. Alternatively, in step a), a suspension having a ratio at room temperature of solid fraction to liquid fraction of less than 1:15 to 1:25 is prepared wherein at least 30% by weight of the silver orthophosphate particles have a particle size of less than 1 , 0 μιη have.

As explained above, the reaction rate of reduction by the polybasic hydroxycarboxylic acid at room temperature is very low. In step b), the reaction rate of the reduction is increased by raising the temperature. In this case, the skilled person can set the reaction rate by selecting the temperature so that he can control the extent of reduction for the preparation of the partially reduced silver orthophosphate over the reaction time. Preferably, the temperature and reaction time in step b) are selected to produce a partially reduced silver orthophosphate having a weight ratio of silver ions of the silver orthophosphate to silver atoms of the metallic silver in the range of 95: 5 to 55:45.

The partially reduced silver orthophosphate is obtained in aqueous suspension and must be recovered from this suspension as a finely divided solid. Suitable separation processes are known to the person skilled in the art. For example, the finely divided solid can be separated from the aqueous solution by centrifugation. Conveniently, the aqueous suspension of partially reduced silver orthophosphate obtained in step b) is cooled to a temperature in the range of 15 ° C to 25 ° C before the solid is separated in step c).

According to the invention, the partially reduced silver orthophosphate after separation from the aqueous solution is repeatedly washed with portions of deionized water. To this end the silver orthophosphate is preferably first dispersed for each wash ^¬ process in ultrapure water and subsequently separated off again by centrifugation. The washing operations are repeated until the specific conductivity of the last portion of washing water after separation from the solid has a value below 50 S / cm and preferably below 20 pS. Repeated washing is important to the photostability of the antimicrobial plastic product and the partially reduced silver orthophosphate contained therein.

The specific electrical conductivity is the reciprocal of the specific resistance. The unit is (Ω cm) ^-1 or S / cm. Here S = l / Ω is the short form for Siemens, the unit of the electrical conductance, which is defined as the reciprocal of the electrical resistance. The electrical conductivity depends on the temperature and ion conductors on the concentration, the degree of dissociation and the solvent. For the purposes of the present invention, the electrical conductivity refers to the reference temperature 25 ° C.

Conductivity meters are also called conductometers. Conductometers suitable according to the invention are commercially available under the names Sartorius PP-20 and Sartorius PP-50. The manufacturer is Sartorius AG, Weender Landstraße 94-108, Göttingen, Germany. The measuring cells PY-COl - PY-C03 offered by Sartorius AG for these conductometers are four-electrode measuring cells with platinum electrodes. The

Conductivity measurement is performed with these conductometers using an alternating voltage or an alternating current. The most common frequency is 50 Hz.

The partially purified by repeated washing partially reduced silver orthophosphate is then dried. Drying can be done in any way for example in a drying cabinet. The solid is preferably dried in step e) at a temperature in the range of 80 ° C to 105 ° C. The resulting dried partially reduced silver orthophosphate is then suitable for incorporation into a plastic precursor.

Another variant for obtaining the dry partially reduced silver orthophosphate is the use of so-called spray drying. For this purpose, the water-containing suspension is atomized into a heated chamber, while the water is evaporated and the solid is deposited. An advantage of spray-drying is that in one process step the solid / liquid separation and the drying can be realized. However, their use is only possible for the suspension of the last washing stage, because during evaporation, the ingredients dissolved in the water remain in the solid phase. Spray drying units are available in sizes from laboratory scale to large-scale systems.

The term "plastic pre-product" in the context of the present invention refers to materials from which plastic moldings or the "plastic product" can be produced by molding. The plastic pre-product can be present for example in the form of granules or pellets or as a powder. The plastic precursor can be a one-component system in which one component can be converted into a plastic molding by molding. However, the plastic precursor can also be a multicomponent system in which the components are first mixed together immediately before molding and curing of the plastic takes place during molding or after molding. Fillers or additives are not precursors for the purposes of the present invention. An essential component of the plastic orproduktes are polymeric compounds, in particular those which are commonly used in the medical field.

Preferred polymers are polyurethanes, polycarbonates, silicones, polyvinyl chloride, polyacrylates, polyesters, polyolefins, polystyrene and polyamides. Polyethylene, polypropylene, crosslinked polysiloxanes, (meth) acrylate-based polymers, cellulose and cellulose derivatives, ABS, tetrafluoroethylene polymers,

Polyethylene terephthalates and the corresponding copolymers can be used as polymeric compounds. Examples of suitable copolymers according to the invention are styrene-acrylonitrile copolymers and also copolymers of ethylene and a higher α-olefin.

In addition to one or more polymeric materials, the precursor may comprise additives. Additives may be, for example, inorganic or organic substances. The precursor may in particular comprise all inorganic and organic substances that are inert and medically safe. These include, in particular, sparingly water-soluble materials such as zirconium dioxide, zirconium silicate, titanium dioxide, zinc oxide, calcium fluoride, calcium carbonate, aluminosilicates, hydroxyapatite, fluorapatite, barium sulfate, calcium sulfate and carbon in its various forms. Such substances can already be used as fillers in a commercially available

On the other hand, in the context of the present invention, they can also be added as a further component to a commercially available plastic precursor and incorporated into the plastic precursor.

The plastic precursor may also contain other additives such as pigments, antioxidants, plasticizers, photostabilizers for the polymer, etc. In the process according to the invention, metallic silver is produced on silver phosphate. More generally, in the process, particles are formed which partially precipitate out

Silver orthophosphate and partially made of metallic silver. This results in many microscopic electrochemical half-elements Ag / Ag ₃ P0 ₄ whose potentials depend only on the concentration of phosphation in the surrounding aqueous phase. Thermodynamically it can be shown that this shifts the free enthalpy for the reaction Ag ° Ag ⁺ + e into the negative range, thus making the reduction of silver ions to silver more difficult.

The reduction in step b) can be carried out so that 1% by weight to 65% by weight of the suspended silver orthophosphate are reduced to metallic silver. When the extent of reduction is in the range of up to 40% by weight, a partially reduced silver orthophosphate is formed which generally has an excess of silver ions of the silver orthophosphate over silver atoms of the metallic silver and at least not more than one silver atom per silver ion.

In the method according to the invention, only ultrapure water is preferably used. Ultrapure water can be obtained, for example, by distillation over a multidose column. Ultrapure water can also be obtained by deionization. The conductivity of the ultrapure water is very low and is in any case below

The invention provides partially reduced silver phosphate as an agent for the antimicrobial finishing of plastics, the plastics thus treated not having the problem of photoinstability, as described for silver phosphate in the literature. It is not requires that the partially reduced silver orthophosphate be applied to a support prior to incorporation into the plastic precursor. According to a preferred mode of operation according to the invention, the partially reduced silver orthophosphate is added directly to the plastic precursor or the plastics material without first being applied to or mixed with an inorganic carrier material or an inorganic filler.

On the other hand, the invention is also. not restricted to filler-free plastic products. Some commercially available plastic precursors already contain a filler and other additives such as e.g. Antioxidants, pigments, plasticizers, etc. The invention extends to methods in which such plastic orprodukte are used, which already contain inorganic fillers.

It is also possible according to the invention that the dried partially reduced silver orthophosphate is first mixed with an inorganic filler before the mixture is incorporated into the plastic precursor. This may be useful, for example, to prevent the formation of agglomerates if the partially reduced Silberorthophospat is to be stored for a long time before further processing.

The invention also extends to methods in which additionally at least one further material which is sparingly soluble in water is incorporated into the plastic precursor. The further material may be, for example, zirconia, zirconium silicate, titanium dioxide, zinc oxide, calcium fluoride, calcium carbonate, an aluminosilicate, hydroxyapatite, fluoroapatite, barium sulfate, calcium sulfate or carbon in one of its forms, for example graphite. This can be done by first incorporating the partially reduced silver orthophosphate into the plastic precursor and then the further material is incorporated into the plastic pre-product. However, it is also possible to proceed by first mixing the partially reduced silver orthophosphate with the further sparingly soluble material and then incorporating this mixture into the plastic precursor.

If the plastic precursor is a two-component system, then the partially reduced silver orthophosphate may first be mixed into one component before the second component is added.

For the incorporation of the partially reduced silver orthophosphate and, if appropriate, further sparingly water-soluble material, various processes are available to the person skilled in the art. The incorporation is preferably carried out with the aid of a mixer, stirrer, kneader, rolling mill or extruder.

The partially reduced silver orthophosphate is preferably used in an amount of 0.1% by weight to 10% by weight, especially 0.5% by weight to 5% by weight, and most preferably 1% by weight to 3% by weight, based on the Total weight of the plastic product, incorporated into the plastic pre-product.

When all desired components have been incorporated into the plastic precursor, the plastic product is molded therefrom. The molding is preferably carried out by extrusion, injection molding, pressing or hot pressing.

The extrusion is a special case so far as it can be used on the one hand for the incorporation of solids into the plastic ^¬ precursor and on the other hand, for the molding of the plastic ^¬ product. By choosing a suitable extruder, the incorporation of solids into the plastic precursor and the molding of the plastic product can thus be carried out with the aid of the same apparatus. It can be shaped a variety of products. Examples of medical devices are venous catheters, peripheral venous cannulas, Sheldon catheters, Hickman-type catheters, port catheters, at least the port chamber consisting of material produced according to the invention, expediently also all other constituents thereof, ventricular catheters, lumbar catheters, peritoneal catheters, bladder catheters, nephrostomy catheters, Urether stents, torax drains and attached suction system, endotracheal tubes, toothbrushes (bristles and handles), surgical sutures, suture material for antimicrobial textiles, antimicrobial coating materials such as respiratory tubes, antimicrobial wound dressings and burn dressings.

The invention is not limited to medical applications. Antimicrobial equipment is also desired in plastic products that are touched by different people. Examples of such products are telephone handsets, door handles or computer keyboards.

The plastic product produced according to the invention contains partially reduced silver orthophosphate and is free of colloidal metal and in particular free of nanosilver, i. of metallic silver with particle sizes in the range of 1 to 100 nm.

The plastic product produced according to the invention contains plastic and partially reduced silver orthophosphate dispersed therein, which consists of silver orthophosphate particles which have been partially reduced to metallic silver. The particles have direct contact between silver orthophosphate and metallic silver. The surface of the Particles consist partly of silver orthophosphate and partly of metallic silver.

The partially reduced silver orthophosphate preferably has a ratio of silver ions of the silver orthophosphate to silver atoms of the metallic silver in the range of 95: 5 to 55:45, i. the silver ions are in excess compared to the silver atoms.

The size of the particles of partially reduced silver phosphate can be measured for example by laser diffraction. The measurement can be carried out according to DIN ISO 13320-1: 1999-11. As far as in the present description and in the claims particle sizes are given, these are to be understood as meaning that they are particle sizes as measured by laser diffraction, in particular according to DIN ISO 133320-1: 1999-11. A suitable meter is commercially available, for example, under the name "SYMPATEC HELOS (H2023) & SUCELL".

Preferably, 95% by weight, especially 98% by weight and most preferably 99% by weight of the particles have a size of less than 5 μm. This is the absolute size of the particles (and not averages).

The skilled person are different forms of

Particle size distribution known. The particle size distribution may be monomodal, bimodal or multimodal, that is, it may have a maximum or several maxima. Preferably, it is a normal distribution (Gaussian distribution) with a maximum or about a distribution that corresponds approximately to a normal distribution.

The term "aqueous suspension of silver orthophosphate" or even "suspension" is used in the context of the present invention is used so that it is compatible with all the information given in this description particle size of the silver orthophosphate.

The plastic product produced according to the invention may consist exclusively of antimicrobially finished plastic, as obtainable by a method according to the invention, and in particular of antimicrobially finished plastic containing plastic and partially reduced silver orthophosphate distributed therein.

The plastic product may also be constructed so that at least a part thereof consists of the antimicrobial plastic and at least one other part thereof consists of a different material. The other material may be selected from metals, glass, ceramics and plastics.

The KunstStoffprodukt can be constructed so that its surface is at least partially made of antimicrobial plastic and at least partially made of other material. Alternatively, the plastic product may be constructed so that the antimicrobially finished plastic encloses the other material, so that the surface of the product consists exclusively of this plastic.

In the broadest sense, stage g) of the method according to the invention also extends to the fact that the plastic precursor is applied as a coating composition or coating composition to a shaped body made of any desired material, so that the surface of the coated shaped body consists completely or partially of the antimicrobially finished plastic. The invention also relates to a process for the preparation of partially reduced silver orthophosphate with the steps a) to e) of claim 1 and preferred embodiments of this process according to claims 2 to 24. Furthermore, the invention relates to the use of the thus-produced partially reduced silver orthophosphate as antimicrobial agent, recordable in cosmetic preparations for external use, in medical preparations for external use, in medical preparations for use in body cavities, in medical preparations for use in and on wounds, in dressings for use on the injured and uninjured skin, in plastics for the production of threads and Spun as a semi-finished product for textile fabrics, in paints, in paints, in coatings, in solid and liquid preparations for addition to liquids (for germ removal and retention) and in ceramic bodies.

The invention will be explained in more detail by way of examples.

example 1

150 ml of deionized water were initially introduced into a reaction flask and 8.3 g of K ₂ HPO ₄ and 24.3 g of trisodium citrate dihydrate were dissolved therein. By adding 1.4 g of NaOH, a pH of 12.35 was set. The whole solution was heated to 25 ° C with stirring.

In 50 ml of water, 24.3 g of AgNC> 3 were dissolved and transferred to a dropping funnel. The silver nitrate solution was added slowly (about 30 minutes) to the reaction flask.

The resulting Ag ₃ P0 ₄ suspension was heated to 95-98 ° C. After reaching this temperature, the entire system was stirred for 90 minutes. The onset of reduction was evident in the color change. After 90 minutes the product showed a black-brown color.

Subsequently, the suspension was cooled to 25 ° C and measured the pH in the aqueous phase. He was 6.8.

From the cooled suspension, the solid was separated by centrifugation and resuspended in deionized water. The washing process was repeated four times. The specific electrical conductivity of the last washing solution was 50 S / cm. The separated solid was then dried at 105 ° C.

By chemical analysis, the following silver contents were determined in the solid.

Ag ⁺ content: 74.2%

Total Ag: 79.5%

In this example, the solids / liquid ratio to the end of the process is 1:10. Example 2

750 ml of deionized water were initially introduced into a reaction flask and 21 g of K ₂ HPO ₄ and 86 g of trisodium citrate dihydrate were dissolved therein. By adding 4.0 NaOH, a pH of 12.5 was set. The whole solution was heated to 25 ° C with stirring.

In 250 ml of water 60.8 g of AgN0 _{3 were} dissolved and transferred to a dropping funnel. The silver nitrate solution was added slowly (about 30 minutes) to the reaction flask.

Subsequently, the suspension was cooled to 25 ° C and measured the pH in the aqueous phase. He was 7.0.

From the cooled suspension, the solid was separated by centrifugation and resuspended in deionized water. The washing process was repeated four times. The specific electrical conductivity of the last washing solution was 31 S / cm.

The separated solid was then dried at 105 ° C.

Ag ⁺ content:% 72.7%

Ag total ehalt _g: 78.5% In this example, the solids / liquid ratio to the end of the process is 1:20.

Example 3

A 600 ml beaker is filled with 300 ml of deionized water. Therein, 8.3 g of K2HPO4, 24.3 g of trisodium citrate dihydrate and 1.5 g of NaOH are dissolved.

24.3 g of AgNO ₃ are separately dissolved in 100 ml of deionized water and the solution is placed in a dropping funnel.

The 600 ml beaker is tempered with the solution therein in a water bath at 25 ° C. An Ultraturrax mixer is inserted into the beaker. With stirring, the AgNC> 3 solution is slowly added dropwise from the dropping funnel.

After completion of the precipitation, the resulting suspension is heated to 95-98 ° C and held for 60 min. At this temperature.

After this time, the suspension is cooled to 25-30 ° C, the solid is separated and washed four times with deionized water until the filtrate conductivity is less than 50 pS / cm.

The solid is finally dried at 105 ° C for a period of 3 to 8 hours.

The solids / liquid ratio was 1:20. Measurement of particle size distribution

The parameters of the particle size distribution for the products of Examples 1 to 3 are summarized in Table 1 below. All particle size distributions were with a laser granulometer of the type SYMPATEC HELOS (H2023).

Table 1

χ (50): 50% by weight of the solids amount have a particle size up to x (90): 90% by weight of the solids amount have a particle size up to

Examples 1 to 3 show that a shift of the particle size distribution to smaller particle sizes, except by using a suitable dispersing agent, e.g. Tri-sodium citrate, also by using a mechanical intensive stirrer (high energy input) in combination with the dispersing agent and also by choosing a small solid / liquid ratio.

The difference between Example 1 and 2 is the solid / liquid ratio. In both cases, the same stirrer, a standard glass blade stirrer, was used. By choosing the lower solids / liquid ratio, a shift of the particle size distribution to smaller particle sizes, the proportion of particles with diameters <1 μιη increases.

Example 3 differs from Example 2 only by the use of another stirring device. In example 3, a so-called ULTRTURRAX type mechanical intensive stirrer with 8000 rpm was used. used. The consequence of the associated higher energy input is a further considerable increase in the proportion with particle sizes <1 pm and also one Shifting the frequencies of particle sizes to smaller particle sizes.

The same effects as with the mechanical Ultraturrax are achieved even when using ultrasound for dispersing.

Table 1 shows that according to the invention smaller particles are obtained than in the process according to WO 2009/013016.

Claims

claims

A process for producing an antimicrobial plastic product comprising a) silver orthophosphate precipitated by reacting a basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with an aqueous solution of a silver salt at a first temperature to form an aqueous suspension of silver orthophosphate with the hydroxycarboxylic acid or its salt as dispersant, b) the aqueous suspension thus obtained is heated to a second temperature and / or irradiated with UV light in order to reduce the silver orthophosphate as reducing agent by means of the hydroxycarboxylic acid or its salt dissolved in the suspension c) the partially reduced silver orthophosphate is separated as a solid from the aqueous solution, d) the solid is washed repeatedly with portions of deionized water until the specific Conductivity at 25 ° C of the last portion of washing water after separation from the solid has a value below 50 μΞ / οπι, e) the solid is dried, f) the dried solid is incorporated into a plastic precursor, which is not with a colloid Metal has been treated or contains such, and g) the plastic product is molded.

A method according to claim 1, characterized in that a first temperature in the range of 15 ° C to 35 ° C is used.

3. The method according to any one of the preceding claims, characterized in that a second temperature in the range of 70 ° C to 100 ° C is used.

4. The method according to any one of the preceding claims, characterized in that the obtained in step b) aqueous suspension of partially reduced silver orthophosphate is cooled to a temperature in the range of 15 ° C to 25 ° C, before in step c) the solid is separated.

5. The method according to any one of the preceding claims, characterized in that the solid is dried in step e) at a temperature in the range of 80 ° C to 105 ° C.

6. The method according to any one of the preceding claims, characterized in that based on the total in the

Procedure used amount of water the respective amounts of water are chosen so that the aqueous solution which is presented in the reaction of the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a), 60 to 90 vol , contains% of water, and the aqueous solution, which is added in the reaction of the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a) contains 10 to 40 vol.% Of the amount of water.

7. The method according to any one of the preceding Anprüche, characterized in that in step a) the aqueous solution of the hydrogen phosphate and the hydroxycarboxylic acid or the salt thereof before the reaction with the aqueous solution of the silver salt to a pH in the range of 10.5 to 13 is set.

8. The method according to claim 7, characterized in that the adjustment of the pH is effected by addition of an alkali metal hydroxide.

9. The method according to any one of the preceding claims, characterized in that a hydrogen phosphate is used which corresponds to the formula Me ₂ HP0 ₄ , in which Me means a metal ion in the oxidation state +1.

10. The method according to any one of the preceding claims, characterized in that is used as the hydrogen phosphate di-potassium hydrogen phosphate.

11. The method according to any one of the preceding claims, characterized in that with at least two carboxyl groups and at least one hydroxyl substituted ethane or propane is used as a polybasic hydroxycarboxylic acid.

12. The method according to any one of the preceding claims, characterized in that a polybasic hydroxycarboxylic acid or a salt thereof which is selected from citric acid, tartaric acid, malic acid or their salts.

Process according to Claim 12, characterized in that the salt of the polybasic hydroxycarboxylic acid trisodium citrate is used.

Method according to one of the preceding claims, characterized in that silver nitrate is used as the silver salt.

Method according to one of the preceding claims, characterized in that the first temperature and the time for the reaction of the basic aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof with the aqueous solution of a silver salt in step a) are selected so that during the precipitation of silver orthophosphate less than 0.1% of the silver ions are reduced to metallic silver.

Method according to one of the preceding claims, characterized in that in step b) the second temperature for the thermal treatment and / or the intensity of the irradiation and the duration of the thermal treatment and / or the irradiation are chosen such that 5 to 45% of the Silver ions are reduced to metallic silver.

Method according to one of claims 1 to 16, characterized in that presented in step a) the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof and the aqueous solution of a silver salt is added.

18. The method according to claim 17, characterized in that in step a) the aqueous silver salt solution is added in portions or continuously over a period of 15 to 45 minutes.

19. The method according to any one of claims 1 to 16, characterized in that presented in step a) the aqueous solution of a silver salt and the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof is added.

20. The method according to claim 19, characterized in that in step a) the aqueous solution of a hydrogen phosphate and a polybasic hydroxycarboxylic acid or a salt thereof is added in portions or continuously over a period of 15 to 45 minutes.

21. The method according to any one of the preceding claims, characterized in that in step b), the second temperature for the thermal treatment at 70 ° C to 100 ° C is set and the thermal treatment is carried out for 60 to 180 minutes.

22. The method according to any one of the preceding claims, characterized in that in step a) the aqueous suspension of silver orthophosphate is prepared using a dispersing device.

23. The method according to claim 22, characterized in that a stirrer or an ultrasonic probe is used as the dispersing device.

24. The method according to any one of the preceding claims, characterized in that a partially reduced silver orthophosphate having such a particle size distribution according to measurement by laser diffraction, that at least 15% by weight have a particle size of less than 1.0 μm and at least 90% by weight have a particle size of less than 5 μm.

25. The method according to any one of the preceding claims, characterized in that in step a) a suspension having a ratio at room temperature of solid fraction to liquid fraction of 1: 5 to 1:15 is prepared and at least 15 wt.% Of Silberorthophosphat- Particles have a particle size of less than 1.0 m.

26. The method according to any one of the preceding claims, characterized in that in step a) a suspension having a ratio at room temperature of solid fraction to liquid fraction of less than 1:15 to 1:25 is prepared and at least 30 wt.% Of Silver orthophosphate particles have a particle size of less than 1.0 μιη.

27. The method according to any one of the preceding claims, characterized in that a partially reduced silver orthophosphate is prepared with a weight ratio of silver ions of the silver orthophosphate to silver atoms of the metallic silver in the range of 95: 5 to 55:45.

28. The method according to any one of the preceding claims, characterized in that a plastic selected from polyurethane, polycarbonate, silicone, polyvinyl chloride, polyacrylate, polyester, polyolefin, polystyrene and / or polyamide is used.

29. The method according to any one of the preceding claims, characterized in that the dried solid in an amount of 0.1 wt.% To 10 wt.%, Based on the total Weight of the plastic product, is incorporated in the plastic pre-product.

30. The method according to claim 29, characterized in that the dried solid in an amount of 0.5 wt.% To 5 wt.% Is incorporated into the plastic pre-product.

31. The method according to claim 30, characterized in that the dried solid in an amount of 1 wt.% To 3 wt.% Is incorporated into the plastic precursor.

32. The method according to any one of the preceding claims, characterized in that a plastic product is produced, which consists of plastic, in which the partially reduced silver orthophosphate is distributed.

33. The method according to any one of the preceding claims, characterized in that a plastic product is produced, wherein at least a part thereof consists of plastic, in which the partially reduced silver orthophosphate is distributed, and at least one other part thereof consists of a different material.

34. The method according to claim 33, characterized in that a plastic product is produced in which at least one part consists of a material which is selected from metals, glass, ceramics and plastics.

35. The method according to any one of the preceding claims, characterized in that a plastic product is produced, whose surface is at least partially made of plastic, in which the partially reduced silver orthophosphate is distributed, and at least partially made of other material.

Method according to one of the preceding claims, characterized in that a plastic product is produced, in which the plastic, in which the partially reduced Silberrorthophosphat is distributed enclosing the other material, so that the surface of the product consists exclusively of this plastic.

37. The method according to any one of the preceding claims, characterized in that a plastic product is produced, which is a catheter.