Glass powders with increased metal-ion release rates of different metal-ion combinations for faster reduction of microorganisms and / or viruses and for supporting cell regeneration and / or cell proliferation, and method for producing such glass powders

Abstract

The invention relates to a glass powder for reducing microorganisms and / or viruses and for supporting cell regeneration and / or cell proliferation, wherein the glass powder has a plurality of glass particles and the glass particles have a particle size of less than 1.0 mm and are doped with first metal ions, wherein the first metal ions have an antimicrobial, antiviral and / or cell-regenerating effect, wherein the glass particles are doped with at least second metal ions in such a way that when the first metal ions and the second metal ions are released from the glass particles, greater release concentrations of both metal ions are present in comparison to glass particles doped with the first metal ions or the second metal ions alone, wherein the relative composition of the elements in the glass matrix is advantageously changed during thermal treatment and doping. The invention also relates to a method for producing glass powders having a plurality of doped glass particles.

Description

[0001] Glass powder with increased metal ion release rates of different metal ion combinations for faster

[0002] To reduce microorganisms and / or viruses and to support cell regeneration and / or

[0003] Cell proli feration and methods for producing such

[0004] Glass powder

[0005]

[0001] The invention relates to a glass powder for reducing microorganisms and / or viruses and for supporting cell regeneration and / or cell proliferation, wherein the glass powder comprises a plurality of glass particles and the glass particles have a particle size of less than < 1.0 mm and are doped with first metal ions, wherein the first metal ions have an antimicrobial, antiviral and / or cell-regenerating effect. Furthermore, the invention relates to a method for producing glass powder with a plurality of doped glass particles.

[0006]

[0002] It is generally known that some metal ions, such as silver, copper, and zinc ions, can exhibit antimicrobial and / or antiviral properties. The antimicrobial and / or antiviral effect typically depends on the dosage form, the concentration of the metal ion, and / or the conditions of use. Due to increasing antibiotic resistance, there is a general need for complementary or substitute antimicrobial substances and / or materials, for example, in the treatment of bacterial skin inflammations. Following COVID-19, there is a general increased need for new active ingredients with antiviral effects.

[0007]

[0003] DE 103 40 276 A1 discloses a personal care product for treating inflammation and / or infection, which contains metallic particles that release zinc ions and silver ions in the personal care product itself or upon contact with body moisture. The antimicrobial effect of both agglomerated silver and nanodispersed silver in the personal care product was enhanced when zinc and copper were also present in addition to silver. The personal care product (cream) contained 99.5% silver, 0.49% zinc, and 0.01% copper. Likewise, the antimicrobial effects of the various metallic mixtures in the cream are only presented based on the germ reduction rates. Furthermore, the long-term consequences of applying metallic nanoparticles to and / or in the body are currently being discussed.

[0008]

[0004] DE 10 2016 003 868 A1 discloses a color-stable, antimicrobial glass powder which is produced by partial ion exchange at a temperature of 300°C to 350°C and an exchange time of 1 to 120 minutes from a mixture of porous glass particles, the glass particles having previously been obtained by extruding continuously foamed borosilicate glass and subsequently grinding the resulting glass foam to average particle sizes of 1.0 to 8.0 μm, color stabilizers containing 0.1% to 0.2% ammonium ions, and antimicrobial metal ions from dissolved metal salts, the metal ions being silver, zinc, and / or copper ions. The color-stable, antimicrobial glass powder can be used, for example, in polymers, paints, or cosmetics to achieve an antimicrobial effect. However, release from the color-stable, antimicrobial glass particles was only shown for silver ions in eluate experiments.This results in a silver ion release rate of 0.42 mg / l to 0.49 mg / l.

[0009]

[0005] DE 10 2011 011 884 A1 discloses a process for producing doped, porous, amorphous glass particles, in which the solid containing the doping substance, or a solution, suspension, or emulsion contained therein, is mixed with the glass particles. This is followed by thermal treatment and, optionally, subsequent mechanical post-treatment to deagglomerate the doped glass particles. The porous, amorphous glass particles can be obtained by grinding and classifying continuously produced glass foam. No antimicrobial efficacy of the metal ion-doped glass particles is mentioned in this regard. Nor are combinations of doping with different metal ions, in particular doping with silver ions, disclosed.

[0010]

[0006] Furthermore, it is generally known that zinc ions, in addition to their antimicrobial effect, also have an effect on improving cell regeneration by supporting cell proliferation (Alan BG Lansdown, PhD, ERG Path; Ursula Mirastschi ski, MD, PhD; Nicky Stubbs, RN; Elizabeth Scanlon, RN, MSc; Magnus S. Agren, DMSci: "Zinc in wound healing: Theoretical, experimental, and clinical aspects", Wound Repair Regen. 2007, 15 (1) 2-16, doi: 10.1111 / j .1524- 475X.2006.00179.x).

[0011]

[0007] DE 102 13 632 A1 and DE 10 2004 011 520 A1 relate to antimicrobial, anti-inflammatory and / or wound-healing glass or a glass composition in which the metal ions are added during melting or by ion exchange of the glass after melting.

[0012]

[0008] The object of the invention is to improve the state of the art.

[0013]

[0009] The object is achieved by a glass powder for reducing microorganisms and for supporting cell regeneration and / or cell proliferation, wherein the glass powder has a plurality of glass particles and the glass particles have a particle size of < 1.0 mm and are doped with first metal ions, wherein the first metal ions have an antimicrobial, antiviral and / or cell regenerating effect, and the glass particles are doped with at least second metal ions such that when the first metal ions and the second metal ions are released from the glass particles, greater release concentrations of both metal ions are present compared to glass particles doped solely with the first metal ions or the second metal ions.

[0014]

[0010] Thus, a glass powder with glass particles doped with at least two different types of metal ions with an increased metal ion release rate is provided for improved antimicrobial, antiviral and / or cell regenerating action. It is particularly advantageous that the glass powder, due to its structure and / or size, can be easily used in different matrices, such as creams or gels, and / or aids, such as a wound dressing or bandage, in order to provide a rapid and improved antimicrobial and / or cell regenerating effect through the increased release concentrations of both types of metal ions. It is particularly advantageous that, in addition to a rapid reduction in unwanted microorganisms, the glass powder also simultaneously significantly supports cell regeneration and / or cell proliferation.Thus, for example, with the first metal ions, a metal ion release quantity of up to 240 times can be achieved compared to the ion release quantities mentioned in DE 103 40 276 Al and DE 10 2007 043 11 Al.

[0015]

[0011] When the at least twice doped glass powder comes into contact with moisture and / or an aqueous medium, in particular a 3 to 250-fold, preferably a 3 to 25-fold or 5 to 25-fold, preferably a 3 to 10-fold or 5 to 20-fold release of first metal ions takes place with simultaneous release of the second metal ions compared to the sole doping, wherein the second metal ions have a release of 10 to 215 times the amount compared to the respective release amount in the case of glass particles doped solely with the second metal ions.

[0016]

[0012] It is particularly advantageous that the glass powder has a depot effect and thus also provides a multiple, increased release of the first metal ions and the second metal ions in the event of moisture, contact with water and / or an aqueous body secretion, in particular with sweat or wound secretion. Consequently, an increased mobilization of the first metal ions and also the second metal ions from the glass particles of the glass powder is possible, which leads to increased release concentrations of both types of metal ions and thus to an improved antimicrobial, antiviral and / or cell regenerating effect. Consequently, the glass powder can be used in many applications. For example, the glass powder can be used in cosmetic products to beautify the skin of humans and animals. The glass powder can also be used as a human medicinal and / or veterinary medicinal product.The glass powder can also be used to promote healing in acute wounds, chronic wounds and / or burns.

[0017]

[0013] A key concept of the invention is that the glass particles of a glass powder are or become doped simultaneously with at least two different types of metal ions, wherein at least the first metal ions have an antimicrobial, antiviral and / or cell-regenerating effect, so that upon contact of the glass particles with water or moisture, an increased amount of each of the two metal ions is released compared to glass particles doped solely with the first metal ions or the second metal ions. Advantageously, the relative composition of the elements in the glass matrix is ​​altered during thermal treatment and doping.Thus, a synergistic effect is achieved during the mobilization of at least two different types of metal ions from the glass particles and their release into the moist and / or aqueous environment, which leads to an improved antimicrobial and / or antiviral effect and / or also to an improvement in cell regeneration due to the two increased release amounts.

[0018]

[0014] The following terminology is explained:

[0019]

[0015] "Glass powder" is understood in particular to mean glass in the form of very small particles with a maximum particle size of < 1.0 mm. Glass powder is also understood in particular to mean glass powder with very fine glass particles with a particle diameter of < 100 pm. The glass powder has in particular a particle distribution curve with a percentile d50 of 1.5 pm to 3.0 pm, a percentile d99 of 7.5 pm to 12.0 pm, in particular a percentile d50 of 2.0 pm and a percentile d99 of 10 pm. The glass particles of the glass powder comprise in particular silicate glass, soda-lime glass, borate glass and / or borosilicate glass. The glass particles are produced in particular by comminuting and / or grinding glass foam made from borosilicate glass and / or soda-lime glass and / or coarse glass material. The glass powder and / or the glass particles are in particular porous, amorphous and / or foamed.The glass particles are in particular doped simultaneously with at least two types of metal ions or sequentially doped with at least two different metal ions. The glass particles in particular comprise 0.1 to 20.0 weight percent of a metal ion, preferably 0.25 to 3.0 weight percent, particularly preferably 0.3 to 1.8 weight percent. The glass particles can comprise the same amount of first metal ions and second metal ions or different amounts of both metal ions. The glass particles can comprise a larger amount of the first antimicrobial metal ions than the amount of the second metal ions in order to have more antimicrobially active agent present from the outset.Preferably, the glass particles contain a smaller amount of the first antimicrobial metal ions than the amount of the second metal ions, wherein the glass particles nevertheless exhibit, in particular, an improved antimicrobial and / or antiviral effect compared with glass particles doped solely with a higher amount of the first metal ions. A plurality of glass particles is understood, in particular, to mean that the glass powder is present in a volume of 1 cm. 3 in particular several hundreds , several thousands , several tens of thousands , several hundred thousands or even more glass particles .

[0020]

[0016] “Metal ions” are understood to mean, in particular, ions of metals. The metal ions are, in particular, positively charged cations. For doping, the metal ions are present, in particular, in aqueous solution as salts with anionic ions. The metal ions can be monovalent, divalent, trivalent or tetravalent metal ions. The metal ions comprise, in particular, elements of a heavy metal, semimetal, transition metal and / or light metal. The first metal ions and the second metal ions comprise, in particular, different elements. Thus, the first metal ions and the second metal ions are two different types of metal ions.

[0017] In principle, it should be emphasized that the terms “first”, “second”, “third”, “fourth”, etc. are merely for the purpose of differentiation.Thus, the first metal ions and the second metal ions differ in the type of metal ions, but the designation first and second does not, for example, specify a doping or mixing order.

[0021]

[0018] A "release concentration" is understood to mean, in particular, a concentration of the first metal ions or the second metal ions under defined conditions in an aqueous eluate. The release concentration is given, in particular, in mass of the respective metal ions per volume of the eluate. The elution takes place under defined and standardized conditions, as described, for example, below.

[0022]

[0019] The term "antimicrobial and / or antiviral effect" is understood in particular to mean that a chemical substance in low concentration acts against microorganisms and / or viruses. The antimicrobial and / or antiviral effect inhibits in particular the growth of the microorganisms and / or viruses, inactivates and / or destroys them. The antimicrobial and / or antiviral active ingredient is in particular at least the first metal ions and optionally the second, third, fourth and / or further metal ions. Thus, at least by the first metal ions, the reproductive capacity and / or infectivity of microorganisms and / or viruses is reduced and / or they are killed and / or damaged. The microorganisms can be any type of microorganism, such as bacteria, fungi, yeasts and / or algae.

[0023]

[0020] In a further embodiment of the glass powder, the second metal ions have an antimicrobial, antiviral and / or cell-regenerating effect or are free from an antimicrobial, antiviral and / or cell-regenerating effect.

[0024]

[0021] Thus, the second metal ions can further enhance the antimicrobial and / or antiviral effect, since the second metal ions themselves have an antimicrobial and / or antiviral effect, or the simultaneous presence of second metal ions leads to the greater release concentration of the antimicrobial and / or antiviral first metal ions and / or to an improvement in the cell regenerating effect.

[0025]

[0022] In order to achieve targeted higher release concentrations of at least the first metal ions and the second metal ions, the first metal ions and / or the second metal ions comprise an element of a transition metal, a semimetal, a light metal and / or a heavy metal.

[0026]

[0023] A "transition metal" is in particular a chemical element with one of the atomic numbers from 21 to 30, 39 to 48, 57 to 80 and 89 to 112. Transition metals usually have an effect as a catalyst. A transition metal is, for example, Cr, Ni or Cu, although Zn is also often counted among the transition metals.

[0024] A "semi-metal" is in particular an element which is located between the metals and the non-metals in the periodic table. The semi-metal elements in particular have properties of metals as well as properties of classic non-conductors. A semi-metal is, for example, Si, Se or Ge.

[0027]

[0025] The term "light metal" refers in particular to metals and alloys whose density is below 4.5 g / cm 3 Examples of light metals include Li, Na, Mg, and Al.

[0028]

[0026] The term "heavy metal" is understood to mean, in particular, a metal whose density is at least greater than 5.0 g / cm 3 Heavy metals include, in particular, precious metals and base metals such as iron, copper, lead, zinc, tin, and nickel. Particularly in the case of heavy metals as metal ions, it is advantageous that the release concentration of the heavy metal ions from the glass particles is significantly lower than the release concentration of the first, microbially active metal ions and / or the toxic concentration of the heavy metal.

[0029]

[0027] In a further embodiment of the glass powder, the first metal ions are silver ions or zinc ions.

[0030]

[0028] In order to specifically adjust the increased release concentrations and / or to achieve an additional antimicrobial, antiviral and / or cell-regenerating effect, the second metal ions are aluminum ions, copper ions, tin ions, iron ions and / or zinc ions.

[0029] The second metal ions (and / or third and further metal ions) are preferably aluminum ions, copper ions and / or zinc ions. Advantageously, the first metal ions are zinc ions and the second metal ions are copper ions and / or aluminum ions or another metal ion. Furthermore, the first metal ions are particularly advantageously copper ions and the second and third metal ions are zinc ions and / or other metal ions.

[0031]

[0030] Advantageously, the first metal ions are also silver ions and the second metal ions are zinc ions. In this case, the glass particles have in particular between 5 and 50 mg / g Ag+, preferably between 2.50 and 30 mg / g Ag+, of their dry mass. As second metal ions, the glass particles have in particular between 5 and 50 mg / g Zn 2 + , especially between 10 to 30 mg / g Zn 2 + , on .

[0032]

[0031] By doping with zinc ions as one of the metal ions, the glass powder exhibits, in addition to the antimicrobial and / or antiviral effect, improved cell regeneration and / or cell proliferation and thus improved

[0033] Wound healing on .

[0034]

[0032] In order to further increase the antimicrobial, antiviral and / or cell regenerating effect and / or the release concentrations, the glass particles are doped with at least third metal ions and / or fourth metal ions and optionally with further metal ions or with ammonium ions.

[0035]

[0033] For at least the third metal ions, fourth

[0036] Metal ions and optionally further metal ions are in particular the metal ions mentioned and described above, which, however, differ in type from the first and second metal ions. Thus, for example, the first metal ions can be silver ions, the second metal ions can be zinc ions, and the third metal ions can be copper ions. However, the third metal ions can also be silicon or aluminum, for example.

[0037]

[0034] It has surprisingly been shown that a desired release amount of silver ions as the first metal ions can be achieved with a significantly lower amount of silver ions when doping the glass particles in the presence of at least second metal ions and optionally third and further metal ions, compared to doping with silver ions alone. In comparison to the weight percent of silver ions of 3 mass percent mentioned in DE 10 2007 043 311 A1, the combination with a second metal ion can achieve the same level of silver ion release with just 0.25 mass percent of silver ions as the first metal ion, as mentioned in DE 10 2007 043 311 A1, i.e. specifically with 1 / 12 of the doping amount.

[0038]

[0035] The additional addition of ammonium ions during doping further increases the release amounts of the first metal ions and the second metal ions compared to doping with the same weight percent of first metal ions and second metal ions free of ammonium ions. The ammonium ions are added during doping, in particular, as ammonium nitrate.

[0036] In order to provide a specifically large surface area both for doping and for the release of the metal ions, the glass particles are porous, amorphous, and / or foamed.

[0039]

[0037] If the glass particles are made from continuously foamed glass, they have a significantly higher specific surface area than solely porous and / or amorphous glass particles.

[0040]

[0038] In a further embodiment of the glass powder, the glass particles are mixed with a liquid, a gel or a cream.

[0041]

[0039] Thus, a liquid, aqueous and / or oil-containing phase is provided, so that at least the first metal ions and the second metal ions are released into this phase. Consequently, the glass powder can exert its antimicrobial and / or antiviral effect and / or its cell regeneration-supporting function from the second metal ion directly upon contact with a skin surface.

[0042]

[0040] The liquid can, for example, be a solution for ear drops, for nasal rinsing or wound rinsing. In the mixture of the glass particles with a gel or a cream and / or ointment, this mixture can be used for the cosmetic or medical treatment of humans and animals, for example as a skin ointment for wound healing, treatment of burns, nail and / or athlete's foot, mud fever, Mortellaro and the like.

[0041] In a further aspect of the invention, the object is achieved by an aid for application to a skin surface, wherein the aid comprises a glass powder as described above and optionally at least one fiber, a polymer and / or a coating.

[0043]

[0042] Thus, the glass powder can be used as an adjuvant in a galenic composition, in particular a medicament or cosmetic skin care product, and / or in a topically applicable dressing. In a galenic composition, the amount of glass powder used can be in particular between 0.01 and 5.0 wt.%, preferably between 0.5 and 3 wt.%, particularly preferably between 0.5 and 1 wt.% of the weight of the galenic composition.

[0044]

[0043] In the case of an auxiliary agent comprising the glass powder and at least one polymer, the polymer may in particular be PP, PS, PVE, and / or PTFE. In the case of a pharmaceutical composition, this comprises at least one polymer matrix, in particular comprising polyamide and / or a polyamide derivative and / or polyurethane and / or a polyurethane derivative.

[0045]

[0044] In the case where the auxiliary agent comprises a mixture of glass powder and polymer, the auxiliary agent comprises, depending on the water absorption of the polymer, glass powder in a range of 0.15 to 1 wt.% for a hydrophilic gel, a cream, polyamide and / or a suspension, or 1.0 to 3.0 wt.% of the glass powder in highly hydrophobic compositions such as PP, PS, PVE and / or PTFE. In principle, the amount of glass powder used is in particular in a range of 0.1 to 3 wt.% of the respective matrix and / or of the auxiliary agent. The glass particles can also be integrated into a coating of the auxiliary agent and / or arranged on and / or in a fiber structure. The glass particles can be bonded to a polymer and / or a polymer base, in particular chemically, for example in polyamide via OH groups.

[0046]

[0045] The glass powder and / or fibers can also be incorporated together in a polymer matrix. In this case, the glass powder has an average particle size and / or diameter that is or are equal to or smaller, in particular by a factor of 10 to 100, than the average size, in particular an average diameter, of a fiber of the polymer matrix.

[0047]

[0046] An "aid" can be, in particular, any agent that can be used for cosmetic and / or medical treatment. An aid can be an aqueous solution, a gel, a cream, an ointment, an emulsion, a dispersion and / or a suspension. However, an aid can also be a dressing, a bandage, a compress, a nonwoven fabric for use as a medical or veterinary dressing, or a wound dressing. Likewise, an aid can be a medical device, such as a cannula, a syringe, a port, a tube, a housing, an implant, a wire, a sensor, a surgical access, an artificial anus, a shunt and / or the like.In addition to at least two different types of metal ions, the auxiliary agent may also comprise and / or contain a conventional disinfectant, such as an alcohol. A fiber may be a textile, polymeric, and / or metallic fiber.

[0048]

[0047] In an additional aspect of the invention, the

[0049] The problem is solved by using the glass powder described above for cosmetic applications, human medical applications, veterinary medical applications and / or for preserving liquid materials, such as drop preservatives, paints, in particular water-based paints, or silicone joint material.

[0050]

[0048] In a further aspect of the invention, the object is achieved by a method for producing glass powder with a plurality of doped glass particles, comprising the following steps:

[0051] - optional extrusion of coarse glass material and / or glass powder with the addition of a blowing agent in an extruder to form a glass foam,

[0052] - crushing and / or grinding the glass foam and / or coarse glass material into ground glass particles,

[0053] - Mixing the ground glass particles with soluble salts of first metal ions and at least second metal ions and optionally with ammonium ions in water to form a mixture,

[0054] - Thermally treating and doping the ground glass particles in the mixture at a temperature in a range from 150 ° C to less than 300 ° C, so that a manufactured, previously described glass powder with a plurality of doped glass particles with an improved antimicrobial, antiviral and / or cell regenerating effect is present.

[0055]

[0049] Thus, a process is provided in which the produced and doped glass particles, upon subsequent contact with moisture and / or water, exhibit an increased release of at least the two different types of metal ions compared to doping with only one metal ion, thereby ensuring an improved antimicrobial and / or cell-regenerating effect of the produced glass powder.

[0056]

[0050] In the process, a high-temperature extrusion can optionally first be carried out to produce a glass foam from glass powder with the addition of a blowing agent in an extruder, wherein the glass foam produced comprises, in particular, borosilicate or soda-lime glass. The production of the doped glass particles, and thus of the glass powder, from glass foam has the advantage that the glass particles have greater porosity and consequently a larger specific surface area. The production of glass foam is described, for example, in DE 195 45 065 A1.

[0057]

[0051] Conventional, undoped glass powder is used in particular for extrusion. Coarse glass material can also be used for extrusion. Coarse glass material is, in particular, glass pieces with a particle size of > 1 mm. This can be glass fragments and / or pellets. Alternatively, the coarse glass material is not extruded, but directly crushed and / or ground so that the ground glass particles are available for subsequent mixing. Of course, the extruded glass foam can also be crushed and ground together with coarse glass material and then doped together.

[0058]

[0052] The at least two types of metal ions and optionally the ammonium ions are mixed in particular as salts in the water. The salts can be the corresponding nitrates, such as silver nitrate, copper nitrate, zinc nitrate and optionally ammonium nitrate, and / or the respective chlorides. In principle, metal salts which are soluble in solvents other than water and are then introduced into the water can also be used. When the corresponding metal salts are mixed in the water with the ground glass particles, the metal ions are incorporated into the pores of the glass particles. When using silver nitrate, zinc nitrate, copper nitrate, aluminum nitrate and / or ammonium nitrate, a partial ion exchange with the sodium ions of the glass particles also takes place.

[0059]

[0053] The thermal treatment and thus the doping of the ground glass particles in the mixture takes place at a temperature in a range from 150 ° C to less than 300 ° C, preferably in a range from 160 ° C to 280 ° C. In particular in the presence of ammonium ions, the thermal treatment and doping are carried out at a temperature in a range from 180 ° C to 210 ° C, in particular at 190 ° C. The doping can be carried out in the entire temperature range and in the sub-ranges in the presence of ammonium ions or in the absence of ammonium ions.

[0060]

[0054] Furthermore, it was found that the ions exchanged from the glass matrix at lower temperatures below 300 ° C cause a significant change in the elemental composition of the glass matrix compared to an ion exchange at high temperatures equal to or greater than 300 ° C. Accordingly, at the lower temperatures according to the invention, the percentages of the elements are changed differently than at high temperatures equal to or greater than 300 ° C according to the prior art.

[0061]

[0055] To demonstrate the influence of temperature and the difference in the chemical and elemental composition of the glass matrices, ICP-OES (optical emission spectroscopy with inductively coupled plasma) analyses were carried out on samples of the product TG. This is a glass powder made of borosilicate glass doped according to the invention with a grain size distribution in d50 of 2 pm. The various products were each doped the same way but treated at different temperatures (TG 81 at 190 °C and TG 56 at 300 °C).

[0062]

[0056] The results of the analyses for the elements examined are shown in Table 0 below. It is clearly evident that for approximately 80% of the elements listed, there are relevant changes between the low-temperature and high-temperature doped glass particles. For example, the TG 81 glass particles doped at 190°C exhibit a higher proportion of the elements copper (II) oxide (CuO), zinc oxide (ZnO), and silver (I) oxide (Ag2<3), at +100%, +9%, and +7%, respectively, than the TG 56 glass particles doped at 300°C.

[0063] Table 0: Comparison of the composition between glass powders doped at 190 °C (TG 81) and 300 °C (TG 56)

[0057] The invention will be explained in more detail below with reference to exemplary embodiments.

[0064] Figure 1 is a highly schematic representation of a

[0065] Wound dressing with glass powder with doped glass particles in a contact layer and with a carrier layer in cross section, and

[0066] Figure 2 is a flow diagram of a process for producing doped glass powders with associated process steps.

[0067]

[0058] A wound dressing 101 has a contact layer 103 for application to a skin surface and a carrier layer 105 arranged underneath. Distributed within the contact layer 103 is a glass powder 107 with a plurality of doped glass particles 109 (Figure 1 is not to scale with respect to the glass powder 107 and the doped glass particles 109). The doped glass particles 109 have been simultaneously doped with silver and zinc ions.

[0068]

[0059] The wound dressing 101 is applied by a user with the contact layer 103 to a skin surface (not shown) and secured by means of skin adhesive strips. Due to moisture released from the skin surface, which penetrates into and through the permeable contact layer 103, the silver ions and zinc ions are released from the doped glass particles 109, mix in the moisture and pass with the moisture through the contact layer 103 to the skin surface, where they bring about an improved antimicrobial, antiviral and cell-regenerating effectiveness due to their synergistic effects.

[0060] The doped glass particles 109 are produced in a method 201 for producing doped glass powder 107 with the following work steps. First, conventional glass powder made of borosilicate glass (see composition below) is extruded into a glass foam in a high-temperature extruder at 880 ° C (step 203).Subsequently, the extruded glass foam is crushed and ground 205 into ground glass particles. The ground glass particles are mixed, based on their weight, with 1.0 wt. % each of silver nitrate and zinc nitrate in distilled water (step 207). This is followed by thermal treatment at a temperature of less than 300°C, thus doping the ground glass particles for 20 minutes, so that the glass powder 107 with the glass particles 109 doped with silver and zinc is present.

[0069]

[0061] The mixing of the ground glass particles with the metal ions and optionally ammonium ions takes place in particular for a period of 10 to 60 minutes. The thermal treatment and thus the doping takes place in particular for a period of 1 to 150 minutes.

[0070]

[0062] Optionally, the heat-treated mixture can be cooled after the thermal treatment and doping 209. Likewise, dry grinding can optionally be carried out subsequently to deagglomerate the doped, ground glass particles.

[0071]

[0063] Using the method 201 described above, various glass powders 107 were prepared as samples under standardized conditions and the subsequent release of metal ions was investigated. For the production of the porous glass particles, the following borosilicate glass and sodium-lime

[0072] Glass used .

[0073] Table 1 : Chemical composition of borosilicate glass and soda-lime glass

[0074]

[0064] The determination of the chemical composition of the glass (ISO 52340) is carried out by means of atomic absorption spectroscopy or X-ray fluorescence analysis. Borosilicate glass with the described chemical composition was processed in a high-temperature extruder (according to patent DE 195 45 065 C2) into porous, amorphous foam glass. The same applies to glass powder, which is produced from coarse glass material by complex grinding. Subsequently, the glass foam is pre-crushed in a

[0075] Roller crusher with 7 mm perforated screen for glass foam particles < 7 mm.

[0076] In a subsequent combined grinding and classifying process (ball mill), the material is reduced to an average particle size of 2.0 pm (particle size distribution: dlO = 0.8 pm; d50 = 2.2 pm; d90 = 5.6 pm and d99 < 9.1 pm) or 3.0 pm (particle size distribution: dlO = 0.9 pm; d50 = 2.9 pm; d90 = 7.2 pm and d99 < 12.0 pm). The particle size distribution is determined using laser diffraction (equipment: Sympatec Heios; DIN ISO 1332-1). The d50 is the particle size at which 50 percent of the particles are smaller than or equal to the specified value.

[0077]

[0065] The pH of the porous glass particles is determined in a 10% aqueous suspension at room temperature according to DIN EN ISO 787-9. Deviating from the standard, the eluate is prepared from 20 g of glass powder and 180 g of distilled water. The glass particles are then filtered off, and the pH and conductivity of the filtrate are measured using the pH laboratory kit with conductivity electrode (Hach Lange GmbH).

[0078]

[0066] The moisture content of the glass particles is determined according to ISO 787-2 after 2 hours of drying in a circulating air cabinet at 105 °C.

[0079]

[0067] For the porous borosilicate glass powder used in the examples with a d50 of 2.2 pm, the following values ​​were determined: pH: 10.8, conductivity: 0.7 mS / cm and residual moisture: 0.3%.

[0080]

[0068] For example, the detailed production of antimicrobial, porous glass particles (sample 18) is described below. For the batch solution, 157.5 g of silver nitrate (pure, for synthesis, silver content 63.5%), 455 g of zinc nitrate, and 400 g of ammonium nitrate are dissolved in 500 ml of distilled water. This is done using a heatable magnetic stirrer, as the dissolution process is highly endothermic. 9.39 kg of glass powder with a d50 of 2.2 μm are filled into a VM 60A universal mixer. The glass powder in the mixer is wetted with the batch solution via a spray device at low speed (approx. 75 rpm), while mixing continues. After the complete solution has been added, mixing is continued for a further 10 minutes.

[0081]

[0069] The mixture is evenly distributed among five stainless steel sheets, with a layer thickness of < 2 cm. A charging trolley is loaded with the filled sheets and pushed into the low-temperature furnace preheated to 190°C. After reaching the target temperature of 190°C, the sheets remain in the furnace at 190°C for a further 150 minutes. The charging trolley is removed from the furnace, and after a cooling period of approximately 30 minutes, the antimicrobial, antiviral, and / or cell-regenerating, porous glass particles are removed from the sheet. The dried antimicrobial, porous glass powder is subsequently deagglomerated in a KK 100 toothed colloid mill.

[0082]

[0070] Eluates are then prepared from these (and from other antimicrobial, antiviral, and / or cell-regenerating, porous glass particles produced under different conditions as specified below). Deviating from the DIN EN ISO 787-14 standard, 20 g of the glass particles are eluted in 180 g of distilled water. The glass particles are then filtered off and centrifuged to remove suspended matter prior to analysis. The pH and conductivity of the filtrate are measured using the sensION™+ MM374 pH laboratory kit (Hach Lange GmbH). The pH of the filtrate for sample 18 was 7.2, and the conductivity was 8.7 mS / cm.

[0083]

[0071] The silver ion content in the eluate is determined using the DR 2800 photometer (manufacturer: Hach-Lange GmbH) and the powder packet test (silver reagent set) from Hach-Lange. The silver content in the eluate of sample 18 was 1.2 mg / l. The zinc ion content in the eluate is determined using the DR 2800 photometer (manufacturer: Hach-Lange GmbH). The LCK 360 cuvette test according to Hach-Lange is used. The zinc content in the eluate was 109 mg / l.

[0084] Table 2: Composition (recipe) of samples 16, 17, 18

[0085] (Borosilicate glass particles, d50 = 2.2 pm)

[0086]

[0072] The copper ion content in the eluate was determined using the DR 2800 photometer (manufacturer: Hach-Lange GmbH) and the LCK 329 copper cuvette test from Hach-Lange. The copper content in the eluate of sample 31 was 7.5 mg / l. Table 3 Composition (Formulation) of Samples 16, 30, 31

[0087] (Borosilicate glass particles, d50 = 2.2 pm)

[0073] The aluminum ion content in the eluate was determined using a DR 2800 spectrophotometer (manufacturer: Hach-Lange GmbH). The Hach-Lange aluminum reagent set was used. The aluminum content in the eluate of sample 26 was 17.4 mg / l. Table 4: Composition (recipe) of samples 16, 25, and 26

[0088] (Borosilicate glass particles, d50 = 2.2 pm)

[0089]

[0074] The iron ion content in the eluate was determined using a DR 2800 spectrophotometer (manufacturer: Hach-Lange GmbH) and the iron (II / III) cuvette test LCK 320 from Hach-Lange. The iron content in the eluate of sample 42 was 0.75 mg / l.

[0090] Table 5: Composition (recipe) of samples 41, 39, 42

[0091] (Borosilicate glass particles, d50 = 2.2 pm)

[0092]

[0075] For the eluate results presented below, the glass powders used, which are made from glass foams produced by an extruder, are designated as follows:

[0093] - B Glass K2 : Glass powder made of borosilicate glass with a

[0094] Grain size distribution in d50 of 2 pm,

[0095] - B Glass K3 : Glass powder made of borosilicate glass with a

[0096] Grain size distribution in d50 of 3 pm,

[0097] - K Glass K2 : glass powder made of soda-lime glass with a grain size distribution in d50 of 2 pm,

[0098] - K Glass K3: Glass powder made of soda-lime glass with a grain size distribution in d50 of 3 pm.

[0076] The following table shows results for differently doped glass powder (samples) with ion release values ​​from the eluate tests described above.

[0099] Table 6: Ion release values ​​of a 3% doped B glass K2 at 330 °C for 5 min

[0100]

[0077] In the case of sample 3 of B Glass K2, which is doped simultaneously with 3 wt.% silver and 3 wt.% zinc, a 12.38-fold greater release of silver is shown compared to sample 1 doped only with silver, and a 2.25-fold greater release of zinc is shown compared to sample 2 doped only with zinc.

[0101]

[0078] Similar conditions are shown in Table 7 for B Glass K3, which was doped at 330 °C for 45 minutes. The release values ​​for B Glass K3 are somewhat lower than the release values ​​shown in Table 6 for B Glass K2 due to the larger glass particles and thus the lower specific surface area.

[0102] Table 7: Ion release values ​​of a 3% doped B glass K3 at 330 °C for 45 min

[0103]

[0079] Both Table 6 and Table 7 show the significantly increased silver and zinc release rates for the simultaneously doped glass particles (samples 3 and 6) with the same doped weight amounts of 3.00%. These higher clay release rates directly lead to a stronger antimicrobial effect.

[0104]

[0080] In Table 8, the doped B glass K3 is again shown with the ion release values ​​as shown in Table 7, whereby this was additionally doped with ammonium nitrate (400 g).

[0105] Table 8: Ion release values ​​of a 3% doped B glass K3 additionally with ammonium nitrate at 330 ° C for 45 min

[0106]

[0081] Even with the addition of ammonium nitrate, the release rates for the combined doping with silver and zinc ions (sample 9) increase at the same amount of 3.00 wt.% each by a factor of 1.37 with respect to silver compared to sample 7 with sole doping with silver ions and by a factor of 1.67 with respect to zinc compared to sample 8 with sole doping with zinc ions. The release rate of the zinc ions in sample 8 with the use of ammonium nitrate during the thermal treatment and doping is significantly higher than the value of sample 5 without the use of ammonium nitrate.

[0107]

[0082] Even when using doped glass powder B Glass K2 with additional use of ammonium nitrate in the thermal treatment and doping, a significant increase in silver ion release (sample 12 compared to sample 10) and a slight increase in zinc ion release

[0108] (Sample 12 compared to Sample 11) can be seen (see Table 9). Table 9: Ion release values ​​of a 3% doped B glass K2 additionally treated with ammonium nitrate at 330 ° C for 5 min

[0083] As the release values ​​in the following table

[0109] 10 in comparison to Table 9, a reduction of the temperature from 330 ° C to 190 ° C during the thermal treatment and doping under otherwise identical conditions again leads to a significant increase in the release concentration of the silver ions in sample 15 with the simultaneous doping compared to sample 13 with the sole doping and to only a slightly increased zinc release in the simultaneously doped sample 15 compared to sample 13.

[0110] Table 10: Ion release values ​​of a 3% doped B glass K2 additionally with ammonium nitrate at 190 ° C for 150 min

[0084] As Table 11 shows, even with a

[0111] Reducing the doping weight fractions of silver and zinc from 3% to 1 wt.% each in the combined doping of sample 18 resulted in significantly higher release values ​​of silver and zinc than in the singly doped samples 16 and 17.

[0112] Table 11: Ion release values ​​of a 1% doped B glass K2 additionally with ammonium nitrate at 190 ° C for 150 min

[0085] It can also be shown for various samples of soda-lime glass that the release values ​​of silver ions are increased when doped with zinc ions at the same time, compared to doping with silver ions alone (compare sample 21 and sample 19 in Table 12). Likewise, a 5.25-fold higher release of zinc was found in sample 21 compared to sample 20 doped with zinc alone. However, the release values ​​for soda-lime glass are generally significantly lower than for borosilicate glass, which has also been shown in other samples not shown here, for example, when doped at 330°C.

[0113] Table 12: Clay release values ​​of a 3% doped K

[0114] Glass K3 at 190 ° C for 150 min

[0115]

[0086] As Table 13 shows, the simultaneous release values ​​of silver ions and zinc ions in a soda-lime glass also increase most strongly when the doping is carried out in the presence of ammonium nitrate. Table 13: Ion release values ​​of a 3% doped K glass K3 additionally with ammonium nitrate at 190 °C for 150 min

[0116]

[0087] All release values ​​shown for the respective samples demonstrate that simultaneous doping of the borosilicate glass and the soda-lime glass with silver and zinc ions results in a significantly higher release of silver and zinc ions from the produced and doped glass particles compared to doping of the glass particles with silver or zinc alone. The simultaneous addition of ammonium ions to the mixture before thermal treatment and doping leads to further increased simultaneous release of silver and zinc ions.

[0117]

[0088] As Tables 14 and 15 show, an increased release of silver ions is also achieved when doping with aluminum ions (Table 14) or copper ions (Table 15) occurs simultaneously. Table 14: Ion release values ​​of a 1% doped B glass K2 additionally with ammonium nitrate at 190 °C for 150 min Table 15: Ion release values ​​of a 1% doped B glass K2 additionally with ammonium nitrate at 190 °C for 150 min

[0118]

[0089] As can be seen from Table 16, a desired release amount of silver ions is also achieved during simultaneous doping when the glass particles were doped with a significantly lower weight fraction of 0.5 wt.% silver compared to 3 wt.% zinc. Analogous results were achieved when simultaneous doping was carried out with 0.25 wt.% silver and 1.0 wt.% aluminum. As Table 16 shows, despite a lower silver weight fraction of 0.50%, a higher silver release concentration is achieved in the eluate with the simultaneous doping with 3 wt.% zinc in sample 27 than with doping alone with 3 wt.% silver.

[0119] Table 16 : Clay release values ​​of a 0 , 5 % silver and

[0120] 3% zinc doped B glass K2 at 330 ° C for 5 min

[0121]

[0090] Comparative tests in Table 17 show release values ​​from the foamed and ground B glass K3 and a GB glass K3 ground from solid glass. The silver ion release rates are almost identical, while the zinc ion release is 30% lower for the B glass ground from solid glass. In principle, it can be shown that even finely ground solid glass can be doped with metal ions.

[0122] Table 17: Ion release values ​​of a B Glass K3 doped with 3.0% silver and 3% zinc and a GP B Glass K3 ground from solid glass (from solid glass) additionally treated with ammonium nitrate at 330 °C for 45 min

[0123]

[0091] As can be seen from Table 18, an increased release of metal ions is also achieved with simultaneous doping with iron and zinc ions. Both release values ​​of the metal ions increase significantly.

[0124] Table 18: Ion release values ​​of a 1% doped B glass K2 with iron (II) nitrate and zinc nitrate at 190 °C for 150 min

[0092] As can be seen from Table 19, an increased release of metal ions is also achieved with simultaneous 1% doping with copper and zinc ions and ammonium nitrate. Both release values ​​of the metal ions increase.

[0125] Table 19 : Ion release values ​​of a 1 % doped B glass K2 with ammonium nitrate, copper (II) nitrate and zinc nitrate at 190 ° C for 150 min

[0126]

[0093] Table 20 shows that an increased release of metal ions is also achieved with simultaneous 1% doping with copper and aluminum ions and ammonium nitrate. Both release values ​​of the metal ions increase with the simultaneously doped glass particles.

[0127] Table 20 : Ion release values ​​of a 1 % doped B glass K2 with ammonium nitrate and copper (II) nitrate and aluminum nitrate at 190 ° C for 150 min

[0094] Table 21 shows that an increased

[0128] The release of metal ions with simultaneous doping with copper and zinc ions is achieved at 3%. In particular, the release values ​​of the zinc metal ions increase significantly. An approximate doubling of the release values ​​of the zinc ions leads to the highest zinc ion release value in the series.

[0129] Table 21 : Ion release values ​​of a 3 % doped B glass K2 with ammonium nitrate and copper (II) nitrate and zinc nitrate at 190 ° C for 150 min

[0095] Thus, differently manufactured glass powders 107 with doped glass particles 109 are provided, in which at least one simultaneous doping of a first metal ion and a second metal ion has occurred. This leads, upon subsequent elution in an aqueous medium, to increased releases of both metal ions compared to dosing with only one metal ion. Accordingly, due to the increased release of both metal ions, the antimicrobial efficacy against a wide variety of microorganisms is improved.

[0130]

[0096] The higher antimicrobial efficacy against the test germ Klebsiella pneumoniae DSM 789 of the metal ion combination compared to a glass powder doped only with silver ions and ammonium nitrate, as described in patent EP 3 440 024 B1, was demonstrated in a hydrophobic base gel with an admixture of 1% of each of the two glass powders. The determination of the antibacterial activity was carried out according to a modified version of ISO 22196:2011 using inoculum (CFU / cm 2 ) 1 . 25 x 10 5 instead of 1 x 10 4 The antimicrobial results are summarized in Table 22 below.

[0131] Table 22 : Antimicrobial test results (the live microbial counts per cm averaged from the multiple determinations are given 2

[0097] The calculation is based on the viable bacterial count as the geometric mean of the active samples at time t24 in comparison to the corresponding reference sample:

[0132] R (Effectiveness in log levels) = Log (CFU reference t24 / CFU active sample t24.

[0098] As an assessment criterion for the existence of antimicrobial

[0133] Tests require a logarithmic reduction in the number of bacteria in the antimicrobial sample compared to the corresponding reference sample of > 3 log levels.

[0134]

[0099] In addition to the higher antimicrobial efficacy and effectiveness against viruses, a low probability of resistance development is also to be expected. By increasing the zinc ion release rate, support for cell regeneration is simultaneously improved.

[0100] It can be assumed that the simultaneous doping of glass powder with several metal ions is the basis for the development of a variety of active ingredient combinations as an alternative to conventional antibiotic and antiseptic applications. This is clearly demonstrated by the results of the efficacy kinetics studies against Staphylococcus aureus and E. coli in a 0.1% additive solution in 0.9% NaCl.

[0135]

[0101] In this test, the following samples achieved a log reduction of CFU (Colony Forming Units) after 3 hours and 6

[0136] Hours as in Table 23 against Staphylococcus and in Table

[0137] 24 against E-Coli.

[0138] Table 23: Kinetic efficacy test against Staphylococcus aureus

[0139]

[0102] It turns out that the 3% copper-zinc

[0140] Combinations have a faster efficacy against Staphylococcus aureus than the 3% silver-zinc combination, which only achieves an efficacy of > 99.99% after 12 hours. However, the efficacy of the 3% silver-zinc combination is significantly higher than that described in patent EP 3 440 024 B1, in which a log reduction of one level was only achieved after 24 hours (Table 1 in the patent specification).

[0141]

[0103] It is further shown that even with low copper and aluminum and copper-zinc combinations a high effectiveness of 4 log steps reduction can be achieved after 6 hours.

[0142] Table 24 : Kinetic efficacy test against E. coli

[0143]

[0104] In the kinetic efficacy test, the copper-zinc combinations showed the same high efficacy against E. coli as the silver, copper, and silver-zinc combinations. Sample 46 showed a 99.99% log reduction after 12 hours.

[0105] Compared to the efficacy of the B glass types doped with only 3% silver, described in patent EP 3 440 024 B1, sample 15 showed a significantly faster efficacy than the efficacy of 99.99% log reduction after 24 hours stated in patent EP 3 440 024 B1.

[0144] Reference symbol list

[0145] 101 wound dressing

[0146] 103 Contact layer

[0147] 105 Carrier layer 107 Glass powder

[0148] 109 doped glass particles

[0149] 201 Process for producing doped glass powder

[0150] 203 Extrusion of coarse glass material and / or glass powder

[0151] 205 Crushing and / or grinding 207 Mixing the ground glass particles

[0152] 209 Thermal treatment and doping of the ground glass particles

Claims

Patent claims:

1. Glass powder (107) for reducing microorganisms and / or viruses and for supporting cell regeneration and / or cell proliferation, wherein the glass powder (107) comprises a plurality of glass particles and the gas particles have a particle size of less than 1.0 mm and are doped with first metal ions, wherein the first metal ions have an antimicrobial, antiviral and / or cell-regenerating effect, characterized in that the gas particles (109) are doped with at least second metal ions such that when the first metal ions and the second metal ions are released from the glass particles (109), greater release concentrations of both metal ions are present compared to glass particles doped solely with the first metal ions or the second metal ions.

2. Glass powder (107) according to claim 1, characterized in that the second metal ions have an antimicrobial, antiviral and / or cell-regenerating effect or are free from an antimicrobial, antiviral and / or cell-regenerating effect.

3. Glass powder (107) according to claim 1 or 2, characterized in that the first metal ions and / or the second metal ions comprise an element of a transition metal, a semimetal, a light metal and / or a heavy metal.

4. Glass powder (107) according to one of the preceding claims, characterized in that the first metal ions are silver ions or zinc ions.

5. Glass powder (107) according to one of the preceding claims, characterized in that the second metal ions aluminum ions, copper ions, tin ions, iron ions and / or zinc ions.

6. Glass powder (107) according to one of the preceding claims, characterized in that the gas particles (109) are doped with at least third metal ions and / or fourth metal ions and optionally with further metal ions and / or with ammonium ions.

7. Glass powder (107) according to one of the preceding claims, characterized in that the gas particles (109) are porous, amorphous and / or foamed.

8. Glass powder (107) according to one of the preceding claims, characterized in that the gas particles (109) are mixed with a liquid, a gel and / or a cream.

9. A tool (101) for application to a skin surface, the tool (101) comprising a glass powder (107) according to any one of claims 1 to 8 and optionally at least one fiber, a polymer and / or a coating.

10. A method (200) for producing glass powder (107) with a plurality of doped glass particles (109), comprising the following steps: optionally extruding (203) glass coarse material and / or glass powder with the addition of a blowing agent in an extruder to form a glass foam, Crushing and / or grinding (205) the glass foam and / or coarse glass material to form ground glass particles, mixing (207) the ground glass particles with soluble salts of first metal ions and at least second metal ions and optionally with ammonium ions in water to form a mixture, Thermal treatment and doping (209) of the ground Glass particles in the mixture at a temperature in a Range from 150 °C to less than 300 °C, so that a manufactured glass powder (107) according to one of claims 1 - 8 with a plurality of doped glass particles (109) with an improved antimicrobial, antiviral and / or cell-regenerating effect is present.

11. The method (200) according to claim 10, characterized in that the thermal treatment and doping (209) of the ground glass particles in the mixture are carried out at a temperature in a range of 160 °C to 280 °C.

12. The method (200) according to claim 10 or 11, characterized in that the thermal treatment and doping (209) of the ground glass particles in the mixture are carried out at a temperature in a range of 180 °C to 210 °C.

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