HYDROGEL FOR BIOFILM REDUCTION

Description

Field of invention

[0001] The present invention relates to a hydrogel for reducing biofilms, containing an active ingredient embedded in the hydrogel and characterized by high moisture and active ingredient release. The hydrogel is suitable for medical applications. The invention further relates to a method for producing the hydrogel, the use of the hydrogel for medical purposes, and a wound dressing containing the hydrogel as a wound contact layer. Background and purpose of the invention

[0002] In wound care, it is generally known that a moist wound environment promotes healing. This is due to accelerated epithelialization, reduced scarring, and a diminished inflammatory response, all brought about by the moist environment. Moist wound care is particularly suitable for poorly healing, chronic, and infected wounds. Especially in the latter case, complications can arise from colonization of the wound by microorganisms. Wound infections are usually caused by bacteria. Measures to remove or kill the bacteria are not always successful, as the bacteria often adapt to the altered conditions. This includes, in particular, the development of resistance and the formation of biofilms.While modern wound care has already responded to the development of resistance and the topical application of classic antibiotics has declined, biofilms in wounds still pose a serious problem and are the subject of current research. WO2017191453 describes the use of metal complexes to combat biofilms in wounds. Furthermore, hydrogels containing such metal complexes are disclosed. These hydrogels were produced from a specific polyacrylic acid – brand name Carbopol®. Although Carbopol® is a popular raw material in polymer chemistry, it has disadvantages in practical application. For example, the use of Carbopol® leads to dust formation. Also, due to its low density, the powder is difficult to dissolve by stirring. This results in long mixing times, during which unwanted foaming can occur.Furthermore, lumps may form upon (intentional or unintentional) contact with moisture.

[0003] In animal models, Carbopol® has shown inhibitory effects on wound healing (Grip, Jostein, et al. "Sprayable Carbopol hydrogel with soluble beta-1, 3 / 1, 6-glucan as an active ingredient for wound healing—development and in-vivo evaluation." European Journal of Pharmaceutical Sciences 107 (2017): 24–31). Therefore, there is a need for hydrogels containing active ingredients against biofilms, which release these agents into the wound along with moisture to a high degree, and whose substrate does not impede wound healing. The object of the present invention is to meet this need. This object is achieved by a method according to claim 1, a hydrogel according to claim 9, and a wound dressing according to claim 15. Definitions

[0004] Within the scope of the present invention, the term hydrogel refers to a finely dispersed system consisting of at least one solid and one liquid phase. This solid phase forms a sponge-like, three-dimensional network whose pores are filled with a liquid (lyogel). Both phases permeate each other. Preferably, both phases permeate completely. By absorbing water, the three-dimensional network can expand its volume through swelling without losing its structural cohesion. The term hydrogel is also used synonymously in the following as hydrogel composition or hydrogel matrix. By varying the reaction parameters of the manufacturing process according to the invention, the resulting hydrogel can sometimes acquire a foam-like character. Such products are also referred to as hydrogels according to the invention. The crucial point is that they can be obtained by the manufacturing process according to the invention.

[0005] The term active ingredient can have the following meanings within the scope of the present invention: a) the complex compound Ag 2 Zn(EDTA), b) an aqueous solution of said complex compound or c) an aqueous solution of the starting substances silver nitrate, zinc sulfate or

[0006] Zinc sulfate monohydrate and tetrasodium EDTA combine to form the aforementioned complex. Unless otherwise stated, the term "active ingredient" primarily refers to the complex compound mentioned in a). The active ingredient has both biofilm-reducing and antibacterial properties and also promotes the release of moisture from the hydrogels according to the invention.

[0007] The term reaction mixture refers to a mixture of all components required for the inventive process to produce a biofilm-reducing hydrogel. This includes all reactants and may also contain optional excipients such as consistency enhancers, stabilizers, acids, alkalis, etc. Various embodiments of the inventive process are described below. The composition of the reaction mixture may vary depending on the specific embodiment.

[0008] The term biofilm refers to a thin, spreading layer of slime containing populations of microorganisms. This slime film is formed by the microorganisms and is a matrix of extracellular polymeric material that encloses them. Typically, the microbial populations are mixed. Biofilms form on surfaces, which can include wound tissue. The microorganisms organized within the biofilm exhibit increased resistance to conventional antibiotics, disinfectants, and the immune systems of higher organisms.

[0009] The term "biofilm reducing" encompasses both the killing of bacteria (disinfectant properties) and the breaking of chemical bonds and the removal of chemical bonding partners from the biofilm-forming extracellular matrix. The latter reduces the resistance of the microorganisms previously organized in the biofilm to influences such as disinfectants, antibiotics, the immune system, or environmental factors in general. Within the scope of the present invention, only those substances suitable for application to open wounds without causing significant harm to the individual being treated are considered biofilm reducing.

[0010] The term starting solution refers to a solution containing at least water, an amine-terminated prepolymer, and the active ingredient. Additional components, such as a polyhydric alcohol, preferably glycerol, or a base, preferably ammonia, may be included optionally.

[0011] The terms moisture release and moisture release mean the same thing.

[0012] The term colony-forming unit (CFU) refers to a single dividing cell of a single-celled organism, in particular a human-pathogenic single-celled organism or bacterium. Description of the invention

[0013] The hydrogels according to the invention have excellent properties with regard to their ability to store water and release it to a wound. It has been shown that the active ingredient content in the hydrogel, i.e., the concentration of the complex in the hydrogel, influences the extent to which moisture is released to the wound by the hydrogel. With increasing concentration of active ingredient in the hydrogel, the moisture release increases.

[0014] The increased moisture released from the hydrogel according to the invention by the active ingredient has the advantage that the active ingredient is delivered into the wound along with the moisture.

[0015] Surprisingly, measurements have shown that the adhesive strength of the hydrogel according to the invention can be increased by embedding the active ingredient. At the same time, the atraumatic nature of the hydrogel as a wound contact layer is maintained, since the hydrogel does not stick to the wound. Embedding the active ingredient in the hydrogel can therefore, under certain circumstances, allow for smaller additional adhesive layers or a surrounding adhesive border, or—depending on the intended use of the wound dressing—even eliminate them entirely. This simplifies the production of such a wound dressing according to the invention and saves costs. During the development of the present invention, it was found that the adhesive strength of the hydrogel increases with increasing proportion of the active ingredient in the hydrogel; that is, the hydrogel adheres more strongly to the skin or wound the more Ag₂Zn(EDTA) it contains.This is at least partially attributed to the fact that the degree of cross-linking within the hydrogel matrix decreases with increasing active ingredient content. In this sense, the invention also includes the use of an Ag₂Zn(EDTA) complex in a hydrogel to adjust or increase the hydrogel's adhesive strength. In particular, this can be used to adjust the hydrogel's adhesive strength to tissues such as skin or wound tissue.

[0016] The inventive process for producing a hydrogel comprises the following steps: i. Providing an isocyanate-terminated prepolymer containing polyalkylene oxide units, ii. Providing an amine-terminated prepolymer containing polyalkylene oxide units, iii. Dissolving the substance provided under ii in a water-containing liquid to obtain an aqueous preparation, iv. Mixing the aqueous preparation and a solution, in particular an aqueous solution, containing an Ag₂Zn(EDTA) complex to obtain a starting solution, v. Combining the starting solution and the isocyanate-terminated prepolymer to form a reaction mixture, whereby these are converted to a hydrogel by polymerization. wherein the pH of the solution from step iv is at least 9, preferably 10 to 12, and wherein the reaction mixture from step v does not contain acrylic acid or polyacrylic acid.

[0017] In the final step v, the isocyanate-terminated prepolymer from step i and the amine-terminated prepolymer from step ii, contained in the starting solution, are reacted together. Other reactants, such as a polyol, may also be present. During the reaction, polymerization takes place, meaning that the two prepolymers form a cross-linked gel matrix. Water and the Ag₂Zn(EDTA) complex are incorporated into the gel matrix but can be released from it again. The resulting hydrogels according to the invention contain the active ingredient.

[0018] The starting solution and the isocyanate-terminated prepolymer can be combined successively – that is, gradually. It is possible to combine the starting solution and the isocyanate-terminated prepolymer in a mold. After the reaction is complete, the finished hydrogel can be removed from the mold and retain the shape defined by the mold.

[0019] The complex compound Ag 2 Zn(EDTA) represents the biofilm-reducing agent within the hydrogel and is obtained by dissolving the following compounds in a polar, preferably aqueous liquid, in particular water: Tetrasodium EDTA (also known as tetrasodium EDTA), silver nitrate and zinc sulfate, respectively.

[0020] Zinc sulfate monohydrate. To prepare Ag₂Zn(EDTA), it is possible to first react polar, preferably aqueous, solutions of tetrasodium EDTA (e.g., a 3.8% solution) and silver nitrate (e.g., a 6.8% solution) and filter out the precipitated solid. The filtrate can then be added to a polar, preferably aqueous, solution of zinc sulfate monohydrate (e.g., a 1.9% solution). After further filtration, the Ag₂Zn(EDTA) complex is obtained.

[0021] The process according to the invention and the associated chemical reactions can take place at room temperature. When adding alcohols to the reaction mixture, a lower temperature can sometimes lead to better results, which will be explained in more detail elsewhere.

[0022] The reaction mixture of the process according to the invention and the hydrogel according to the invention do not contain acrylic acid or polyacrylic acid. The addition of acrylic acid is not recommended, as it could have a negative impact on wound healing.

[0023] In the manufacturing process according to the invention, the mass ratio of the isocyanate-terminated prepolymer to the amine-terminated prepolymer can be between 1.3 and 3.2, preferably between 1.4 and 1.8, particularly preferably between 1.5 and 1.7 and most preferably between 1.55 and 1.65.

[0024] In the hydrogels mentioned, the solid phase does not necessarily have to be formed solely by a polymer resulting from the reaction between an amine-terminated prepolymer and an isocyanate-terminated prepolymer. A polyhydric alcohol can also participate in the reaction, as its free hydroxyl groups can react with isocyanate groups. The polyhydric alcohol component contributes to additional crosslinking, which, particularly in the case of polyhydric alcohols with more than two hydroxyl groups, leads to three-dimensional crosslinking of the prepolymers. The reaction between a polyhydric alcohol and an isocyanate group yields a carbamic acid ester, also known as urethane. This reaction can be accelerated by acids or bases as catalysts and reversed by the addition of thermal energy. The process according to the invention can be carried out at room temperature.If the reaction temperature is kept constant between 5°C and 30°C, preferably between 5°C and 20°C, this reaction can proceed in sufficient proportions to obtain hydrogels with covalently bound polyhydric alcohols that exhibit advantageous properties. In this context, the reaction mixture can contain at least one polyhydric alcohol. This can be selected from the group of dihydric, trihydric, tetrahydric, pentahydric, or hexahydric alcohols. In particular, the alcohol can be selected from the group of glycols, especially ethylene glycol, polyethylene glycols with a mass of 200 g / mol to 6000 g / mol, preferably polyethylene glycols with a mass of 300 g / mol to 2000 g / mol, as well as sorbitol or glycerin, or mixtures thereof. These alcohols are also excellent moisturizers and thus provide a conditioning component for the skin surrounding the wound.Hydrogels containing one or more of these alcohols as partners in the reaction described above exhibit high absorption capacity for wound exudate and reduced moisture loss. They possess an adhesive strength that allows for atraumatic dressing changes. Due to their low cytotoxicity, they are very well tolerated by wound tissue. Furthermore, such gels are able to concentrate growth factors in the wound exudate that are essential for wound healing, thus accelerating the healing process. The presence of multiple alcohols in the wound leads to slowed moisture evaporation, thereby keeping the wound moist for a longer period.

[0025] Therefore, according to a preferred embodiment of the process according to the invention, glycerin is added to the reaction mixture. The glycerin can be added to the water-containing liquid from step iii of the process. Accordingly, the process is preferably characterized in that the water-containing liquid in step iii contains glycerin.

[0026] The amount of glycerin added is preferably chosen such that the reaction mixture in step v of the process contains 10 to 30 wt% glycerin.

[0027] The hydrogels produced in this way exhibit particularly advantageous properties with regard to cell compatibility, fluid loss and adhesion.

[0028] In a particularly preferred embodiment, glycerol is used as the polyhydric alcohol in a concentration of 15-25 wt%. The hydrogels produced in this way also exhibit a particularly high absorption capacity.

[0029] According to another embodiment, ethylene glycol is used as the polyhydric alcohol in a concentration of 5-30 wt%, preferably 10-25 wt%, particularly preferably 15-20 wt%. Such hydrogels exhibit advantageous properties with regard to moisture loss, absorption capacity, and cell compatibility.

[0030] According to another embodiment, sorbitol is used as the polyhydric alcohol in a concentration of 5-30 wt%, preferably 10-25 wt%, particularly preferably 15-20 wt%. Such hydrogels exhibit advantageous properties with regard to absorption capacity and cell compatibility.

[0031] According to a further embodiment, the polyhydric alcohol PEG300 (polyethylene glycol with an average relative molecular mass of 300 g / mol) is used in a concentration of 5-30 wt%, preferably 10-25 wt%, particularly preferably 15-20 wt%. Such hydrogels exhibit advantageous properties with regard to moisture loss and absorption capacity.

[0032] According to a further embodiment, the polyhydric alcohol PEG2000 (polyethylene glycol with an average relative molecular mass of 2000 g / mol) is used in a concentration of 5-30 wt%, preferably 10-25 wt%, particularly preferably 15-20 wt%. Such hydrogels according to the invention exhibit advantageous properties with regard to cell compatibility.

[0033] In the process according to the invention for producing a biofilm-reducing hydrogel, the reaction mixture can contain a polyalcohol, in particular glycerol. The reaction mixture preferably contains 10 to 30 wt% polyalcohol such as glycerol. Particularly preferably, the reaction mixture contains 15 to 25 wt% polyalcohol such as glycerol. Most preferably, the reaction mixture contains 18 to 23 wt% polyalcohol such as glycerol. The term polyalcohol also includes a mixture of different polyalcohols. In addition to glycerol, these include the previously mentioned alcohols ethylene glycol, sorbitol, PEG300, and PEG2000. Preferably, one of the aforementioned alcohols is combined with glycerol, such that the two alcohols constitute 10 to 30 wt% of the reaction mixture in the process according to the invention.During the development of the present invention, it was found that the active ingredient solution used in the inventive process for producing the hydrogel can be stabilized by an alkaline pH. At neutral and acidic pH values, however, precipitation can occur, leading to the chemical components precipitating out of the solution. The likelihood of precipitation can be reduced by adjusting the pH of the active ingredient solution to at least 9. Therefore, according to the invention, the pH of the active ingredient solution is at least 9, preferably 10 to 12. Furthermore, the likelihood of precipitation also depends on the concentration of the active ingredient in the solution. A higher concentration makes precipitation more likely.Preferably, a pH value of at least 9.5 is set for the active ingredient solution starting at an active ingredient concentration of 1% Ag 2 Zn(EDTA), a pH value of at least 10 for an active ingredient concentration of 1.5% Ag 2 Zn(EDTA), a pH value of at least 10.5 for an active ingredient concentration of 2% Ag 2 Zn(EDTA), and a pH value of at least 11 for an active ingredient concentration of 2.5% Ag 2 Zn(EDTA).

[0034] Ammonia and / or sodium hydroxide are preferably used to adjust the pH. The use of ammonia is preferred because it yielded the best and most stable hydrogels. It has been shown that when using NaOH, the sodium ions compete with the silver contained in the Ag₂Zn(EDTA). If necessary, acetic acid can be added to lower an excessively high pH.

[0035] Preferably, the active ingredient solution is aqueous. The water has the advantage that it is incorporated into the hydrogel matrix during the reaction and can then be released to the wound.

[0036] It is emphasized here that the pH value of the solution containing the active ingredient does not have to correspond to the pH value of the reaction mixture or of the hydrogel subsequently obtained according to the invention. The hydrogel can also have a neutral or slightly acidic pH value without precipitation of the active ingredient occurring.

[0037] It is generally known from the prior art to provide wound dressings for moist wound healing that deliver an isotonic solution to the wound. Within the scope of the present invention, it has been shown that most of these solutions are disadvantageous in conjunction with the hydrogel according to the invention. The reason for this is that these solutions generally contain chloride ions. As has been discovered, the chloride ions react with the silver contained in Ag₂Zn(EDTA) to form sparingly soluble silver chloride. According to a preferred embodiment of the process according to the invention, the reaction mixture contains no chloride ions or chloride salts—in particular, no NaCl. Accordingly, the hydrogel according to the invention, or the hydrogel obtainable by the process according to the invention, preferably also contains no chloride ions or chloride salts.

[0038] Preferably, the reaction mixture and / or the hydrogel according to the invention do not contain triethanolamine. The addition of triethanolamine is discouraged, as it could adversely affect the reaction of the process according to the invention. The triethanolamine could compete with the amine-terminated prepolymer contained in the reaction mixture. Therefore, it is also discouraged to use triethanolamine to adjust the pH of the hydrogel or the drug-containing solution.

[0039] The process according to the invention is typically characterized in that the amine-terminated prepolymer is at least partially covalently bonded during the reaction in process step v. According to one embodiment of the process according to the invention, at least 70 wt.% of the amine-terminated prepolymer used in the reaction mixture is covalently bonded during the manufacturing process according to the invention; preferably, at least 80 wt.% of the amine-terminated prepolymer used is covalently bonded; particularly preferably, at least 90 wt.% of the amine-terminated prepolymer used is covalently bonded; and most preferably, at least 95 wt.% of the amine-terminated prepolymer used in the reaction mixture is covalently bonded.

[0040] The reaction mixture can contain 0.5 to 4 wt% of the Ag₂Zn(EDTA) complex. The proportion of the complex in the reaction mixture influences the amount of active ingredient in the resulting hydrogel. Furthermore, different amounts of active ingredient in the hydrogel affect its efficacy against microorganisms and biofilms, as well as its moisture release from the hydrogel. Preferably, the reaction mixture contains 0.5 to 3.5 wt% of the Ag₂Zn(EDTA) complex. Particularly preferably, the reaction mixture contains 1 to 3 wt% of the Ag₂Zn(EDTA) complex. Most preferably, the reaction mixture contains 1 to 2 wt% of the Ag₂Zn(EDTA) complex.

[0041] According to a preferred embodiment, the sum of the masses of amine-terminated prepolymer and isocyanate-terminated prepolymer is 10 to 30 wt.% of the reaction mixture.

[0042] The reaction mixture can contain the isocyanate-terminated prepolymer in an amount of 10–25 wt.%. Preferably, the reaction mixture contains 11–23 wt.%, particularly preferably 12–20 wt.%, and most preferably 13–18 wt.% of the isocyanate-terminated prepolymer.

[0043] Furthermore, the reaction mixture can contain the amine-terminated prepolymer in an amount of 3 to 15 wt.%, preferably 5 to 15 wt.%, particularly preferably 6 to 12 wt.%, most preferably 7 to 10 wt.%.

[0044] The polyalkylene oxide units of the two previously mentioned prepolymers can be formed by polyethylene oxide and / or polypropylene oxide units, wherein the weight ratio of ethylene oxide to propylene oxide units is preferably 3:1 to 7:1. Furthermore, the isocyanate-terminated prepolymer is advantageously branched by at least three arms. In particular, the isocyanate-terminated prepolymer is branched by exactly three arms.

[0045] One possible isocyanate-terminated prepolymer with aliphatic isocyanate groups is, for example, a three-arm copolymer of propylene glycol and ethylene glycol units, each terminally reacted with a molecule of isophorone diisocyanate. It typically has a reactive isocyanate end group (NCO) content of 3.0% to 3.4%, preferably 3.2%, and a molar ratio of ethylene oxide units to propylene oxide units of 3:1 to 4:1. This isocyanate-terminated prepolymer could be Aquapol®. This chemical can be obtained from the manufacturer Carpenter (Richmond, USA) under the trade name Aquapol PI-13000-31.

[0046] One possible amine-terminated prepolymer is, for example, a triblock polymer consisting of two propylene glycol, ethylene glycol, and again propylene glycol units, wherein the polymer is terminally functionalized with 2-aminopropyl groups. It typically has a reactive amine end group content of 0.9554 mmol / g, an average molecular weight of approximately 2000 g / mol, and a dispersity of 1.08, as measured by gel permeation chromatography, and a molar ratio of ethylene to propylene units of 3:1 to 7:1, preferably 39:6. Such an amine-terminated prepolymer can be obtained from the manufacturer Huntsman (Everberg, Belgium) under the name Jeffamin® < ED-2003.

[0047] Furthermore, the invention comprises a hydrogel with biofilm-reducing properties obtainable or obtained by the inventive method.

[0048] The hydrogels of the present invention can contain a polymer with polyurethane and polyurea groups as the solid phase. As the liquid phase, they can contain, in particular, water and optionally a polyhydric alcohol. Propylene glycol can be excluded from this, as this substance is less cell-compatible than, for example, glycerol.

[0049] Hydrogels are suitable for treating wounds. They can be applied in various ways. The gel can first be applied to the wound and then optionally covered with a dressing. The dressing helps to fix the hydrogel in place and protect it from external influences. Alternatively, the hydrogel can be left on the wound without a covering. This is particularly suitable for shorter application times and on skin areas where displacement of the hydrogel is unlikely. Applying it without a covering allows for particularly quick inspection of the wound and the healing process.

[0050] In connection with the present invention, hydrogels that form a continuous, discrete layer and do not release water under pressure occurring during intended use can be used as hydrogels. For this purpose, the water content in the reaction mixture of the manufacturing process should be adjusted accordingly. Depending on the proportions of the other reactants, the reaction mixture can contain a water content of 40 wt.% or more. Preferably, the reaction mixture contains a water content of 40 to 65 wt.%, more preferably 50 to 65 wt.%, and most preferably 50 to 60 wt.%. Accordingly, hydrogels according to the invention can have a water content of at least 40 wt.%, more preferably 40 to 65 wt.%, more preferably 50 to 65 wt.%, and most preferably 50 to 60 wt.%.

[0051] Hydrogels according to the invention generally have a pH value between 6.5 and 9.5, preferably between 6.5 and 8, and particularly preferably between 7 and 8, thus covering an optimal spectrum for the treatment of infected wounds. A particular advantage of the hydrogels according to the invention is that the hydrogels obtained by the manufacturing process according to the invention generally have an optimal pH value without any further intervention.

[0052] Although an acidic pH is often considered optimal for promoting wound healing, it is now known that this does not always apply to infected wounds. Depending on the pathogens present in the wound, a basic pH of the hydrogel or wound dressing used may be advantageous. If precise pH adjustment of the hydrogel according to the invention is desired, this can be achieved by adding suitable substances such as ammonia or acetic acid. A neutral or slightly acidic pH is recommended to prevent infections or in cases of only minor colonization of the wound. An alkaline pH (pH > 7) is recommended if significant colonization of the wound with pathogens has already occurred. There is evidence that numerous bacterial enzymes and toxins are inhibited in an alkaline environment. Should a combination of the wound dressing or dressing according to the invention be used...If the hydrogel is to be treated with antibiotics, an alkaline pH value is also recommended, as most antibiotics are inhibited by an acidic environment.

[0053] The hydrogel according to the invention can reduce biofilms containing gram-positive and / or gram-negative bacteria. In particular, the hydrogel is suitable for reducing biofilms of gram-positive pathogens. Staphylococcus aureus ( S. aureus ) and the gram-negative pathogen Pseudomonas aeruginosa ( P. aeruginosa ) to reduce. According to a preferred embodiment, a reduction in colony-forming units (CFU) or a reduction in the number of pathogens by at least log 10 = 2, particularly preferably at least log 10 = 3, and most preferably at least log 10 = 5, is achieved in a test according to ASTM E2871-13 or ASTM E2871-21 – particularly compared to S . aureus and / or P . aeruginosa.A surprisingly high efficacy is achieved in the reduction of biofilms containing only Gram-positive pathogens. According to ASTM E2871-13 or ASTM E2871-21, a reduction of CFU by at least log 10 = 7, preferably by at least log 10 = 8, and most preferably by at least log 10 = 9 can be achieved – particularly compared to S . aureus. The contact time between the hydrogel or wound dressing according to the invention and the biofilm can be 24 hours. A reduction of the biofilm by log 10 = 9 in a test according to ASTM E2871-13 can be equated with the complete killing of the organisms contained in the biofilm. Preferably, such a hydrogel has an active ingredient content of 0.5 to 2.5 wt%. Further details can be found in the exemplary embodiments.

[0054] In the context of the present invention, the complex or complex compound Ag₂Zn(EDTA) is typically embedded in the hydrogel. Compared to coating a hydrogel with an active ingredient, this results in more stable cohesion and a more uniform release of the active ingredient. Furthermore, the micropores in the hydrogel remain open and are not sealed, leading to improved mass transfer (release of moisture, absorption of exudate and pathogens). According to a preferred embodiment, 95 wt.% of the active ingredient used in the reaction mixture is embedded in the hydrogel, particularly preferably 98 wt.%, and most preferably 99 wt.%.

[0055] According to one embodiment, the hydrogel according to the invention contains 0.5 to 4 wt.% of the complex or complex compound Ag₂Zn(EDTA), preferably 0.5 to 2.5 wt.% Ag₂Zn(EDTA), particularly preferably 0.5 to 2 wt.% Ag₂Zn(EDTA), and most preferably 1 to 1.5 wt.% Ag₂Zn(EDTA). The concentration of Ag₂Zn(EDTA) in the hydrogel can be adjusted via the manufacturing process according to the invention.

[0056] Measurements have shown that the active ingredient is released from the hydrogel to the wound in a larger quantity than would have been expected. Surprisingly, it has been found that the active ingredient—in addition to its effectiveness against bacteria and biofilms—also enhances the release of moisture from the hydrogel layer according to the invention. This means that a hydrogel produced according to the inventive method but without the active ingredient releases less moisture to a wound than a hydrogel containing the active ingredient according to the invention. This effect is attributed to the fact that the active ingredient influences the cross-linking within the hydrogel matrix and thus also the hydrogel's tendency to release water or moisture.

[0057] According to one embodiment, the moisture release of the hydrogels according to the invention is at least 5 mg per square centimeter per day. The moisture release increases with increasing active ingredient content. Preferably, the moisture release is at least 8 mg per cm² per day, particularly preferably at least 15 mg per cm² per day, and most preferably at least 18 mg per cm² per day. Hydrogels that are structurally identical to the hydrogels according to the invention but do not contain an active ingredient exhibit a moisture release of less than 5 mg per cm² per day. The moisture release can be measured relative to a filter paper, meaning that the measured moisture is transferred to the filter paper. The filter paper can be a commercially available laboratory filter paper with a diameter of 5 cm.The laboratory filter paper can have an average pore diameter of 15-20 µm and / or an average filtration rate of 35 and 37 seconds. Moisture release is accompanied by a release of the active ingredient. The moisture release can be determined using the method described in this document (see Example 1.4). In this context, the invention comprises the use of an Ag₂Zn(EDTA) complex in a hydrogel to adjust or increase the moisture release of the hydrogel. Specifically, from an active ingredient content of 0.5 wt%, the moisture release is at least 5 mg per cm² per day; from an active ingredient content of 1 wt%, it is at least 15 mg per cm² per day; and from an active ingredient content of 1.5 wt%, it is at least 18 mg per cm² per day.

[0058] The active ingredient released in this way is capable of exerting multiple effects. It counteracts harmful effects caused by bacteria (infection, biofilms, inflammation) and, on the other hand, improves wound healing by moisturizing the wound and cleansing it. This cleansing effect allows harmful or excessively present substances to be removed from the wound bed or at least diluted and, optionally, absorbed into an absorbent layer of the wound dressing according to the invention.

[0059] Hydrogels according to the invention are preferably a component of a wound dressing. Within the scope of the present invention, a wound dressing is understood to be a product suitable for application to a wound and provided in ready-to-use form. Measurements have shown that hydrogels according to the invention with a water content of 60% by weight or higher exhibit a particularly effective release of the complex contained in the hydrogel as an active ingredient. Such hydrogels and the wound dressings containing them represent preferred embodiments of the invention and are particularly suitable for reducing or completely dissolving biofilms in wounds.

[0060] According to a preferred embodiment, wound dressings according to the invention comprise at least the hydrogel according to the invention as a wound contact layer and a carrier layer opposite the wound contact layer, which optionally comprises a circumferential adhesive area.

[0061] The wound contact layer offers several advantages. These include ensuring particularly gentle removal of the wound dressing according to the invention during dressing changes. Furthermore, the wound contact layer can disinfect the wound, prevent or reduce bacterial colonization, moisturize the wound, accelerate the healing process, have wound-edge care properties, reduce skin irritation, and have an anti-adherent effect. The hydrogels according to the invention are ideally suited as a wound contact layer. They do not stick to the wound and prevent granulation tissue from growing into the wound dressing.

[0062] The carrier layer serves, in particular, to prevent the hydrogel from drying out on the side facing away from the wound. However, a small amount of moisture or water vapor may still pass through the carrier layer. Wound dressings according to the invention can comprise the following layers: a carrier layer, a hydrogel layer according to the present invention, and preferably an absorbent layer arranged between the hydrogel layer and the carrier layer. Accordingly, the wound dressing advantageously further comprises an absorbent layer between the wound contact layer and the carrier layer, preferably in the form of an absorbent foam, particularly preferably in the form of an absorbent polyurethane foam. For example, a wound-facing side of the polyurethane foam can be coated with the hydrogel, while a side facing away from the wound is bonded to the carrier layer.Furthermore, in this embodiment, the hydrogel can be designed as a net-like wound contact layer. This improves the penetration of wound exudate into the additional absorbent layer.

[0063] The active ingredient prevents bacteria that have migrated into or been absorbed into the wound dressing from multiplying within it. Since bacteria originating from the wound must pass through the hydrogel layer (wound contact layer) before reaching an absorbent layer, they inevitably come into contact with the active ingredient. This prevents subsequent proliferation of germs within the absorbent layer.

[0064] Polymer films or polymer foams can be used as a carrier layer, preferably films or foams made of polyurethane, polyether urethane, polyester urethane, polyether-polyamide copolymers, polyacrylate, or polymethacrylate. In particular, a waterproof and water vapor-permeable polyurethane film or a waterproof and water vapor-permeable polyurethane foam is suitable as a carrier layer. In particularly preferred embodiments, these films have a moisture-proof, circumferential adhesive layer. This layer ensures that the wound system can be applied and fixed in its intended location. Furthermore, it ensures that no fluid can leak between the film and the skin adjacent to the wound. Possible adhesives are acrylic adhesives or acrylic-based adhesives. These ensure particularly strong adhesion.Other possible adhesives include silicone adhesives or silicone-based adhesives. These allow for atraumatic adhesion and are particularly suitable for damaged or sensitive skin, as well as for frequent dressing changes. The surrounding adhesive area can include the adhesives listed in this section as an adhesive layer.

[0065] Possible arrangements of the different layers in multilayer wound dressings according to the invention are described, for example, in WO 2010 / 000450, to which full reference is hereby made.

[0066] Furthermore, the wound dressing can also include additional layers besides the absorbent layer and the carrier layer, such as one or more barrier layers and / or one or more distribution layers.

[0067] It is standard practice to provide the wound dressing with a protective or peel-off film on the wound contact side. This protects the dressing from contamination during storage and prevents moisture loss. The protective film must be removed before use.

[0068] The wound dressing can have a rectangular or essentially square shape. A size range of 8 cm x 8 cm to 20 cm x 20 cm is preferred. The thickness of the wound dressing is preferably less than 2 cm, with any foam layer preferably having a thickness between 0.1 cm and 1.8 cm, more preferably between 0.3 cm and 0.8 cm.

[0069] Particularly advantageous embodiments have been found to be wound dressings comprising a hydrogel matrix or a hydrogel wound contact layer with a thickness of 0.1 to 5.0 mm. In particular, a wound dressing according to the invention thus has a wound contact layer with a thickness of 0.1 to 5.0 mm, more preferably 0.5 to 5.0 mm, and most preferably 0.5 to 3.0 mm. Wound dressings with such thicknesses are capable of absorbing wound exudate released from a wound and transferring it to the absorbent layer. These thicknesses can be the same at every point in the wound contact layer or can have different values ​​in different areas of the wound contact layer. The hydrogels according to the invention are suitable for the treatment of wounds. The present invention therefore also includes hydrogels according to the invention for the treatment of wounds.In particular, the present invention comprises hydrogels for the treatment of infected wounds, chronic wounds such as decubitus ulcers, pressure ulcers, venous leg ulcers, arterial leg ulcers, wounds resulting from diabetic foot syndrome, neuropathic ulcers, but also wounds resulting from autoimmune diseases or tumors (exulcing tumors) or radiation damage during tumor therapy.

[0070] In this sense, the invention also includes a method for treating wounds - in particular infected wounds - and biofilms in wounds, comprising the following steps: 1) Applying the hydrogel or wound dressing according to the invention to a wound or to an infected or biofilm-covered wound, 2) Optionally fixing or covering the hydrogel or wound dressing according to the invention, wherein the fixing or covering can be done using a circumferential adhesive area (in the case of a wound dressing), adhesive strips, a bandage and / or a compress, and 3) Optionally changing the hydrogel or wound dressing after 2 to 7 days, preferably after 3 to 6 days.

[0071] Hydrogels or wound dressings containing them according to the invention are suitable for phase-appropriate wound therapy, in particular for the therapy of wounds in the granulation phase and / or the epithelialization phase. Examples

[0072] The present invention is illustrated in detail by the following non-limiting examples. 1. Non-foaming hydrogels Example 1.1 Production of hydrogels without active ingredient

[0073] Hydrogel prototypes were produced in two different ways: manually or using a gel casting machine. The main sample preparation was carried out with the B100 gel casting machine distributed by bdtronic, which allows for dynamic control and combination of two components while setting a precise mixing ratio. Identical prototypes with the same thickness and weight-to-area ratio can be produced.

[0074] To optimize the product, hydrogels were also prepared manually under laboratory conditions. Due to the varying reaction rates at different mixing ratios, some samples had to be quickly combined and directly distributed into Petri dishes to prevent solidification during stirring. Unlike the gel machine, this method was more suitable for small quantities of hydrogels with varying concentrations.

[0075] The following table shows the percentage distribution of the components for hydrogel formation: Table 1 Solution component Percentage in hydrogel [wt%] Solution fraction [wt.%] A Glycerin 16,88 87 Jeffamin 7,58 Water 62,53 B Aquapol 13 13

[0076] The B100 gel system consists of a dynamic two-component mixing head with material feed via two pneumatically controlled needle valves, two reservoirs for the alcohol-amine mixture solution and Aquapol, and a control unit with a digital display. The system also includes a compressed air preparation unit. Solutions A and B (see table) were filled into the two cartridges. During this filling process, there is a risk of air becoming trapped in the solutions. To prevent this from disrupting the casting process, both solutions were allowed to stand for twelve hours to degas. The components were pumped by external pumps through separate hoses to needle valves attached to the mixing head. Since the two components react with each other here, the mixing time must be kept shorter than the gel formation time; otherwise, hardening would occur within the mixing head.To ensure a constant mass flow rate, regardless of the medium's viscosity, the cartridges were pressurized with compressed air. The pressure was set to 1.5 bar on both sides. To prevent moisture in the system, the compressed air was first dried in a silica gel filter. The resulting gel was expelled through the outlet nozzle on the mixing head and placed into plastic Petri dishes. The maximum dosing rate was 3.50 g / s.

[0077] Since the system is a two-component mixture, a batch solution of Jeffamine, glycerin, and water (solution A) was prepared prior to gel production. Because the weight ratio between Jeffamine and Aquapol is responsible for gel formation, precise adjustment of the correct mixing ratio is essential. Empirical analyses determined that a mass ratio of Aquapol to Jeffamine of 1.7 is optimal for drug-free gels. Mass ratios of 1.3 to 1.8 also yielded satisfactory results.

[0078] Furthermore, it was found that when adding the active ingredient to the hydrogels, the aforementioned weight ratio had to be adjusted to obtain optimal results. This will be explained in more detail in the following section. Example 1.2 Production of gels with different active ingredient concentrations

[0079] Hydrogels were produced according to the procedure described in Example 1, but with varying drug concentrations. For this purpose, a 2.5 wt% stock solution of the drug in water was prepared and added to the gels in different proportions. Unexpectedly, it was found that the added drug reduced the degree of cross-linking of the resulting hydrogels. Further analyses revealed that with increasing drug concentration, a progressive increase in the proportion of isocyanate-terminated prepolymer relative to the amine-terminated prepolymer improved the results. By increasing the proportion of the isocyanate-terminated prepolymer, hydrogels with excellent stability could be obtained. The composition of the different hydrogels is given in Table 2 below, which also includes the drug-free gel from Table 1 for comparison.The proportion in the reaction mixture is given in weight percent. Table 2 Solution component Proportion in the reaction mixture of a gel without active ingredient Proportion in the reaction mixture of a gel with 0.5 wt% active ingredient Proportion in the reaction mixture of a gel with 1 wt% active ingredient Proportion in the reaction mixture of a gel with 1.5 wt% active ingredient A Glycerin 16,88 14,57 13,36 11,16 Jeffamine 7,58 7,58 7,58 7,58 H₂O 62,53 42,54 22,49 0 Aqueous active ingredient strain 2.5% 0 19,99 40,08 62,53 B Aquapol 13 15,31 16,52 18,72 Aquapol / Jeffamine relationship 1,7 2,02 2,18 2,47

[0080] To prepare solution A, the required amount of Jeffamine was heated in a water bath at 50°C for 30 minutes. The specified amount of water was then added. The components were mixed using a magnetic stirrer, and the necessary amount of the active ingredient stock solution was added during this process. Solutions A and B were placed in the B100 system, and the gels were prepared by mixing the two solutions using this system.

[0081] The hydrogels from Tables 1 and 2 were used for the experiments described below. Example 1.3 Kinetics of hydrogel production

[0082] It has been shown that the reactions for producing the hydrogels exhibit different reaction rates. The respective reaction rates depended on the active ingredient content. The reaction was considered complete as soon as the so-called gelling point was reached and a non-sticky, gel-like surface formed. The results are Fig. 1 depicted.

[0083] While a reference gel without active ingredient (composition according to Table 1) took about 2 minutes to reach the gelling point, it took about 10 minutes with an active ingredient content of 0.5%, about 30 minutes with 1% and about 75 minutes with 1.5%. Example 1.4 Moisture release of hydrogels

[0084] The moisture release onto filter paper for hydrogels according to the invention with different active ingredient concentrations was measured. A gel without active ingredient (composition according to Table 1) was included in the measurement as a reference.

[0085] For the measurement, samples with a diameter of 2.5 cm were punched out and their initial weight determined. The samples were then placed in Petri dishes lined with filter paper. The Petri dishes and filter paper had a diameter of 5 cm and were also weighed beforehand. The Petri dishes were sealed and incubated at a temperature of 37°C. After 24 hours, the samples, filter paper, and Petri dish were weighed separately. The moisture loss was determined using the following formula: Feuchtigkeitsabgabe = mt − m 0 × 1000 A mt = Weight of Petri dish and filter paper after 24 h [g] m0 = Initial weight of Petri dish and filter paper [g] A = Area of ​​the filter paper [cm²]

[0086] The results are shown in the table below and also as a bar chart in Fig. 2 shown: Table 3 Active ingredient concentration [%] Moisture release [mg / cm²< ] 0 < 5 0,5 6,1 1 18,5 1,5 20,8 Example 1.5 Drug release from hydrogels Release of silver and zinc

[0087] Gel samples with an active ingredient concentration of 1.5% were tested to determine the release. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used for the analysis of trace elements in the concentration range of mg / L to µg / L.

[0088] This method allows the simultaneous determination of all metals and some non-metals from acidified aqueous solutions up to a concentration of about 10 g / L.

[0089] To determine the ion release of silver and zinc, one-gram hydrogel samples were transferred to a sample container and 10 mL of demineralized water was added. Fifteen samples were prepared and incubated at 180 rpm at room temperature on a shaker. After 4, 24, 48, 72 hours, and 7 days, 3 mL of the solution from each sample were pipetted into vials. These samples were analyzed according to EN ISO 17294-2 (E29). The samples underwent pressure digestion with nitric acid in Teflon tubes.

[0090] The resulting clear solution was diluted to a final concentration of 10–50 g / L and analyzed. For ICP-OES analysis, the sample solution was introduced into an inductively coupled argon plasma via a pneumatic nebulizer system. At a plasma temperature of 5000–7000 K, the elements were atomized and excited to emit light. The emitted light was simultaneously analyzed using a polychromator split into element-specific wavelengths. To quantitatively determine the elemental content of a solution, the instrument was calibrated using synthetic solutions of known concentration. Analysis of the migration of zinc ions in 1.5% hydrogels in H₂O showed an almost linear increase from 0.07 g / L after 24 hours to 0.13 g / L after 7 days. Therefore, a constant release of the ions can be assumed.

[0091] In contrast, analysis of the released silver ions in the same medium showed a sharp decline in release after about one day, until a consistently low level was reached after approximately 72 hours. While the values ​​remained constant at 0.19 g / L over a 24-hour period, the detectable amount of silver ions dropped to 0.02 g / L after 7 days.

[0092] The results are in Fig. 3 depicted. Release of EDTA

[0093] The release of EDTA was determined by UV / VIS spectroscopy. To investigate the migration of the EDTA contained in the hydrogel into an aqueous solution, the eluate was analyzed using a photoLab® < S6 photometer. For this purpose, the absorption maximum of sodium EDTA in an aqueous solution was estimated. To develop a calibration curve, a serial dilution of NaEDTA concentrations was prepared within the range of the calculated maximum exposure limits of hydrogels. This covered the concentration range from 0 to 1 g / L.

[0094] To first determine the absorption maximum of the EDTA complex present in the hydrogels, a UV / VIS measurement of a 1 molar sodium EDTA complex solution (NaEDTA) was performed. This yielded a maximum at a wavelength of ṽ = 605 nm.

[0095] To determine the release, 1 g hydrogel samples were transferred to sample vials, and 10 ml of demineralized water was added to each. The samples were incubated at 180 rpm at room temperature on a shaker. After 4, 24, 48, 72 hours, and 7 days, 3 mL of the eluates were pipetted into polystyrene cuvettes, and the absorbance (in %) was measured at a wavelength of 605 nm.

[0096] Absorption measurements of the hydrogels according to the invention at a wavelength of 605 nm showed a trend towards increasing absorption proportional to the increasing active ingredient concentration. While the hydrogels with a concentration of 0.5% exhibited an absorption of 0.034% after 24 hours, this value almost doubled to 0.064% within 7 days. A doubling of the absorption was also observed in hydrogels with 1% active ingredient, from 0.077% after 24 hours to 0.134% after 7 days. 1.5% hydrogels showed an absorption of 0.072% after 24 hours and 0.249% after 7 days.

[0097] Using the previously established calibration curve (absorption as a function of EDTA concentration), the maximum EDTA concentration transferred into the medium after 7 days was 0.194 g / L for 0.5% hydrogels, 0.406 g / L for 1% hydrogels, and 0.754 g / L for 1.5% hydrogels. The measured values ​​are presented as curve diagrams in the Fig. 4a(0.5% active ingredient content), 4b (1% active ingredient content) and 4c (1.5% active ingredient content) are shown.

[0098] As can be seen from the figures, the concentration of the released EDTA complexes was proportional to the active ingredient content in the hydrogels. Example 1.6 Antimicrobial effect of hydrogels against biofilms

[0099] To determine the antimicrobial effect of the hydrogels according to the invention, the effectiveness against biofilms of the two human pathogenic bacterial germs was tested. S . aureus (Corn as deposited at ATCC 6538) and P . aeruginosa (Tribe as deposited at ATCC 15442) analyzed. This represented S . aureus the gram-positive bacteria and P . aeruginosaThe gram-negative bacteria were tested. The test was performed according to the publicly available standard protocol ASTM E2871-13. CDC (Centers for Disease Control and Prevention) bioreactors were used to generate the biofilms. Several rods are embedded in the lid of these bioreactors, which are immersed in the nutrient solution during use. The rods have recesses that can hold special discs—so-called coupons. Biofilms form on the coupons during incubation of the bioreactor. The anti-biofilm activity of the hydrogels according to the invention was tested on these biofilms.

[0100] First, a single colony of each species was inoculated in 10 mL of TBS (Tris-buffered saline) and incubated overnight at 37°C and 125 rpm on a vibrating plate.

[0101] The overnight culture of P . aeruginosaThe concentration was adjusted to 108 CFU (colony-forming units) per ml. It was then used to inoculate a CDC bioreactor by adding 1 ml to 300 ml TSB. The bioreactor was incubated in batch mode at 37°C and 80 rpm on a vibrating plate for 24 hours.

[0102] The overnight culture of S . aureus The pellet was centrifuged for three minutes, the supernatant discarded, and resuspended in 1 ml of TSB. The resuspended pellet was used to inoculate the CDC bioreactor by adding it to 300 mL of TSB. The bioreactor was incubated in batch mode at 37°C and 80 rpm on a vibrating plate for 24 h.

[0103] After 24 hours, biofilms had formed. The rods were removed from the bioreactor and washed twice with PBS. The coupons were wrapped in hydrogels that had previously been cut to a size of 2.5 x 5 cm. Three coupons were used per batch. The wrapped coupons were placed in 12-well plates and incubated for 24 hours at room temperature ( P . aeruginosa ) or 37°C ( S. aureus ) incubated.

[0104] The following day, the coupons were removed from the wells, added to 10 mL of Dey Engley neutralising broth, and treated with ultrasound for 30 minutes.

[0105] The samples were then vortexed and dispensed onto 96-well plates. Each sample was serially diluted 1:10 with PBS, and 20 µl of each dilution were dispensed in duplicate onto TSA (tryptone soy agar) plates. The samples were incubated overnight at 37°C, and colony counts were recorded the following day. This determined the total number of viable colonies. The results for hydrogels with drug concentrations of 0.5%, 1%, and 1.5% are presented as a graph in [reference missing]. Fig. 5 depicted.

[0106] Compared to biofilms of S . aureusHydrogels with all three tested drug concentrations showed a reduction in colony-forming units (CFU) of log 10 = 9, indicating extremely high efficacy. Since a higher drug concentration did not result in a further reduction in colony-forming units, it can be assumed that even the lowest drug concentration of 0.5% resulted in the complete elimination of all bacteria present in the biofilm.

[0107] Compared to biofilms of P . aeruginosa The antimicrobial effect increased with increasing active ingredient concentration. Hydrogels with an active ingredient content of 0.5% showed a logarithmic reduction of log 10 = 2, with an active ingredient content of 1% a reduction of log 10 = 3, and with 1.5% a reduction of log 10 = 5. Thus, it can be assumed that the effect of the hydrogels according to the invention against P . aeruginosa(and possibly against gram-negative bacteria in general) is dose-dependent and increases further with increasing drug concentration. 2. Hydrogels on polyurethane foam Example 2.1 Production of active ingredient-containing hydrogels on PU foam

[0108] Hydrogels with an active ingredient content of 0.5% and 1% by weight were combined with a polyurethane foam during their production. A hydrogel without the active ingredient served as an additional reference. The experiments showed that the timing of the hydrogel application to the PU foam is crucial. When the hydrogels are brought into contact with the PU foam, the hydrogel matrix must still have sufficient crosslinking potential. On the other hand, the reaction mixture must not be applied to the foam too early, as it will otherwise be absorbed by the foam. Although the optimal time for the reference gel was after the gelation point, it was found that the gelation point is the optimal time for the gels containing the active ingredient. The results are presented in Fig. 6As shown: The hatched area of ​​the graph bars represents the time from the start of the reaction until the gel was brought into contact with the PU foam. The black area of ​​the graph bars represents the time it took for the gels to bond with the PU foam. For this purpose, foams of appropriate size were added to the gel in the mold. The bonding process was considered complete as soon as the gel-foam composite could be removed from the mold without separating or being damaged. With an active ingredient content of 0.5 wt%, 10 minutes were required, and with an active ingredient content of 1 wt%, 15 minutes were required for the gel and foam to bond. The result was PU foams that were stably coated with hydrogels according to the invention and could be removed from the mold. Example 2.2 Absorption capacity of hydrogels on PU foam

[0109] To determine the absorption capacity of the coated PU foam, samples measuring 2.5 x 2.5 cm were punched out of the hydrogel-coated foams. Each sample was weighed and placed in a glass beaker containing demineralized water. After 24 hours, the samples were removed, dried using cellulose paper, and weighed again. The following formula was used to determine the absorption capacity for each sample: Absorptionskapazität = Endgewicht nach 24 h − Ausgangsgewicht / Ausgangsgewicht

[0110] After 24 hours, hydrogels with an active ingredient concentration of 0.5% on PU foam showed an absorption of 9.47 g / g, whereas an absorption of 9.17 g / g was measured at an active ingredient concentration of 1%. A reference gel on PU foam without active ingredient measured 10 g / g. A higher active ingredient concentration therefore appears to be associated with lower absorption. However, other measurements showed that a higher active ingredient concentration also promotes the release of moisture from the gel, suggesting that the increased moisture release is associated with lower absorption capacity. The results are presented in Fig. 7 presented as a diagram. Example 2.3 Adhesive strength of hydrogels on PU foam

[0111] The adhesion strength of hydrogels bonded to PU foam was tested on steel. A tensile testing machine conforming to DIN EN ISO 7500-01 was used. All measurements were performed under standardized conditions of 23°C and 50% relative humidity. Samples measuring 5 x 5 cm were punched out. The samples were attached with the foam side facing down to a horizontally movable support using double-sided adhesive tape. A metal weight with a force of 0.245 N and a glass base was used for the measurement. The base was cleaned with an ethanol-soaked pad before the measurement. The weight was placed on the hydrogel with the base facing down, and the measurement was carried out according to the following parameters: Table 4 Initial velocity [mm / min] Pull-off speed [mm / min] Contact time [s] 100 400 2

[0112] After the contact time had elapsed, the force required to pull off the weight at a 90° angle was measured using the tensile testing machine. Five measurements were taken for each active ingredient concentration, and the following average values ​​were determined: Table 5 Active ingredient content [%] Adhesive force [N] 0 0.767 0,5 0.834 1 0.867

[0113] As can be seen, the adhesion strength surprisingly increased with increasing drug concentration. Example 2.4 Antimicrobial effect of hydrogels on PU foam against biofilms

[0114] The test for the antibacterial efficacy of hydrogels against biofilms, described above, was repeated. This time, hydrogels with an active ingredient concentration of 0% and 0.5%, applied as a coating to PU foam, were tested. The results are presented in Fig. 8 depicted.

[0115] As the results show, hydrogels on PU foam without active ingredients have no effect against biofilms of S . aureus or P . aeruginosa. However, at an active ingredient concentration of 0.5%, an antibacterial effect against the biofilms is measurable. Thus, the biofilm of S . aureus reduced by a logarithm of log 10 = 4. In the case of biofilm of P . aeruginosa A reduction of log 10 = 9 even occurred. As discussed in the previously presented results on the antibacterial effect of non-foaming hydrogels, a reduction of log 10 = 9 indicates that all bacteria within the biofilm were killed.

[0116] Based on the results presented here, it can be assumed that hydrogels according to the invention, when used as a coating for PU foam, exhibit particularly high efficacy against biofilms of gram-negative bacteria such as P . aeruginosa The hydrogels according to the invention exhibit particularly high efficacy against biofilms of gram-positive bacteria without foaming. S . aureus achieve. Preferably, the invention further comprises:

[0117] Hydrogel according to the invention, wherein the moisture release of the hydrogel in a period of 24 h is at least 5 mg per square centimeter, preferably 10 mg per square centimeter, particularly preferably 15 mg per square centimeter and most preferably 20 mg per square centimeter.

[0118] The use of an Ag 2 Zn(EDTA) complex in a hydrogel to adjust or increase the adhesion strength of the hydrogel.

[0119] The use of an Ag 2 Zn(EDTA) complex in a hydrogel to adjust or increase the moisture release of the hydrogel.

Claims

1. Process for producing a biofilm-reducing hydrogel for medical purposes, especially for wound treatment, comprising the following steps: i. providing an isocyanate-terminated prepolymer containing polyalkylene oxide units, ii. providing an amine-terminated prepolymer containing polyalkylene oxide units, iii. dissolving the substance provided in ii in a water-containing liquid in order to obtain an aqueous formulation, iv. mixing the aqueous formulation and a solution, especially an aqueous solution, containing an Ag2Zn(EDTA) complex, in order to obtain a starting solution, v. combining the starting solution and the isocyanate-terminated prepolymer to give a reaction mixture, whereby these are converted by polymerization to the hydrogel, wherein the pH of the solution from step iv is at least 9, preferably 10 to 12, and wherein the reaction mixture from step v does not contain any acrylic acid or polyacrylic acid.

2. Process according to Claim 1, characterized in that the mass ratio of the isocyanate-terminated prepolymer to the amine-terminated prepolymer is between 1.3 and 3.2.

3. Process according to Claim 1 or 2, wherein the water-containing liquid in step iii contains glycerol.

4. Process according to any of the preceding claims, wherein the reaction mixture contains 10% to 30% by weight of glycerol.

5. Process according to any of the preceding claims, wherein the pH of the solution from step iv is adjusted by means of ammonia, sodium hydroxide or acetic acid.

6. Process according to any of the preceding claims, wherein the reaction mixture does not contain any triethanolamine, any chloride ions and / or chlorine salts, in particular any NaCl.

7. Process according to any of the preceding claims, wherein the reaction mixture from step v contains 0.5% to 4% by weight of the Ag2Zn(EDTA) complex.

8. Process according to any of the preceding claims, wherein the sum total of the masses of amine-terminated prepolymer and isocyanate-terminated prepolymer is 10% to 30% by weight of the reaction mixture.

9. Hydrogel having biofilm-reducing properties, obtainable by the process according to any of the preceding claims.

10. Hydrogel according to Claim 9, wherein the hydrogel has a water content of 40% to 65% by weight.

11. Hydrogel according to Claim 9 or 10, wherein the hydrogel has a pH of 6.5 to 9.5, preferably 6.5 to 8.

12. Hydrogel according to any of Claims 9 to 11, wherein the hydrogel reduces the number of bacterial cells of S. aureus or P. aeruginosa within a biofilm during a test according to ASTM E2871-13 and over a contact time of 24 h by at least log10 = 2.

13. Hydrogel according to any of Claims 9 to 12, wherein the hydrogel contains 0.5% to 4% by weight of the Ag2Zn (EDTA) complex.

14. Hydrogel according to any of Claims 9 to 13, wherein the release of moisture from the hydrogel is at least 5 mg per square centimetre and day.

15. Wound dressing comprising a hydrogel according to any of Claims 9 to 14 as wound contact layer, and a carrier layer opposite the wound contact layer, wherein the carrier layer optionally comprises a circumferential adhesive region.

16. Wound dressing according to Claim 15, further comprising an absorbing foam between the wound contact layer and the carrier layer, preferably an absorbing polyurethane foam.