Sanitizing Conditioning Formula

Abstract

1. An aqueous antimicrobial composition comprising or consisting of the following components: (a) polyhexanide (PHMB) or a salt thereof at a concentration ranging from 0.001% w / v to 0.2% w / v; (b) an organic or inorganic buffer different from (a) having at least one pKs value ranging from 8.5 to 11.5 at a concentration ranging from 0.01 M to 1 M; (c) a further additive at a concentration ranging from 0% w / v to 20% w / v; and (d) water, wherein the pH value of the composition is in the range of 8 to 11.5.

Description

[Technical Field]

[0001] The present invention relates to disinfecting formulations, in particular disinfecting conditioning formulations, as well as to the use thereof and to methods for producing the corresponding formulations. [Background technology]

[0002] Particularly during the pandemic, there has been increased interest in compositions that impart antimicrobial properties to products and surfaces. Some pathogenic bacteria have evolved to be resistant to most, if not all, of the antibiotics currently on the market. These drug-resistant bacteria pose a challenge to the healthcare industry. Furthermore, in the food industry, recalls related to bacterial infestations are becoming more prevalent due to the inadequacy of current cleaning methods. Consumers are also seeking solutions to this problem for products that impart antimicrobial properties to architectural coatings and home care and laundry products.

[0003] Before and after implant surgery, cleaning the implant and removing biofilm are important for preventing or reducing the risk of inflammation, respectively.

[0004] Antiseptic formulations are also used to rinse body parts, for example, for rinsing the mouth, treating wounds, disinfecting skin, and the like.

[0005] For this purpose, a variety of different disinfectant formulations are known to those skilled in the art, typical disinfectant formulations including aqueous or at least partially aqueous formulations of disinfectants such as octenidine (1,1'-(decane-1,10-diyl)bis(N-octylpyridin-4(1H)-imine)-hydrochloride), chlorhexidine (1,6-bis(4-chloro-phenylbiguanide)hexane) or polyhexanide (polyhexamethylenebiguanide), as well as strongly basic or acidic solutions or solutions based on inorganic disinfecting systems.

[0006] Patent Document 1 provides a disinfectant solution that is gentle on the skin and has the effect of inactivating norovirus. This disinfectant solution contains 0.05% to 0.5% by weight of a polyhexamethylene biguanide compound and has a pH in the range of 9 to 12.

[0007] US Patent No. 5,999,499 relates to an aqueous biguanide-containing disinfecting solution containing an improved buffer system that includes both a phosphate buffer and a borate buffer. Preferred embodiments include methods and compositions for simultaneously cleaning and disinfecting contact lenses. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Laid-Open No. 2007-045732 [Patent Document 2] European Patent Application Publication No. 1049763 Summary of the Invention

[0009] It is therefore an object of the present invention to provide improved disinfecting formulations, in particular for example for conditioning of implants, which use organic disinfecting compounds in the lowest possible concentrations, which are compatible with the body and / or surfaces to which the formulation is applied, and which show the highest possible disinfecting effect while at the same time showing the highest possible biocompatibility.

[0010] This object is achieved by the claimed subject matter, more particularly by the claimed compositions, the use of such compositions, and methods for producing such compositions.

[0011] According to a first aspect of the present invention, the present invention provides a composition comprising the following components: (a) polyhexanide (PHMB) or a salt thereof at a concentration ranging from 0.001% w / v to 0.2% w / v; (b) an organic or inorganic buffer different from (a) having at least one pKs value in the range of 8.5 to 11.5 at a concentration in the range of 0.01 M to 1 M; (c) a further additive at a concentration ranging from 0% w / v to 20% w / v; (d) water; 1. An aqueous antimicrobial composition comprising or consisting of: The aqueous antimicrobial composition described above, wherein the pH value of the composition is in the range of 8 to 11.5.

[0012] Polyhexanide is polyhexamethylene biguanide, and typically has a weight average molecular weight Mw in the range of 1500 g / mol to 4000 g / mol, preferably in the range of 2400 g / mol to 3000 g / mol.

[0013] Furthermore, typically, the polyhexanide (PHMB) of component (a) has a polydispersity index (PDI) in the range of 1.4 to 2.2, preferably in the range of 1.7 to 2.8.

[0014] Typically, the starting material for the preparation of the corresponding compositions is a salt of polyhexanide, in particular polyhexamethylene biguanide hydrochloride, the weight percentages being relative to the total weight of polyhexamethylene biguanide hydrochloride.

[0015] Generally speaking, when percentages are given in w / v, this means a measure of the weight (g) of the corresponding substance per 100 mL, and the units are g / cm 3 and this is 1kg / dm 3 is equal to 1000 kg / m 3 Therefore, 1% w / v is equivalent to 1 g / 100 mL, which is 0.01 g / cm 3 is equal to.

[0016] Furthermore, the pKs values ​​given are under standard laboratory conditions, i.e., in water at 20° C. and 101325 Pa.

[0017] Where pH values ​​are given, they are typically measured under standard laboratory conditions using calibrated pH / conductometers, e.g., Type 914 pH / conductometer (Metrohm) devices after calibration.

[0018] The water in the composition is typically nanopure water, ie, water according to ASTM Type I.

[0019] Indeed, as further demonstrated in the experimental section below, it has been unexpectedly found that the antimicrobial efficacy of polyhexanide can be significantly enhanced by adjusting the pH in the claimed range and by stabilizing the pH within that range by providing a corresponding buffer, preferably at the claimed concentration.

[0020] Without being bound by any scientific explanation, based on experimental evidence, it appears that this is not only a combination of the antibacterial effect of the high pH value and the activity of polyhexanide, but that the experimental evidence also indicates that there is a synergistic effect in the claimed concentration range of polyhexanide, making it possible to reduce the concentration of polyhexanide to achieve the same bactericidal or preventative effect, or to use the same concentration to achieve a more pronounced bactericidal or preventative effect.

[0021] Preferably, the aqueous antimicrobial composition is ethanol-free or contains less than 10% w / v or less than 5% w / v or less than 2% w / v ethanol.

[0022] Alternatively, and preferably, the aqueous antimicrobial composition does not contain any straight-chain or branched-chain alkyl or arylalkyl monohydric alcohols having 1 to 9 or 1 to 6 carbon atoms (in particular does not contain methanol, ethanol, propanol, 1-phenyl-1-propanol or combinations thereof), or contains less than 10% w / v, or less than 5% w / v, or less than 2% w / v, or less than 1% w / v of such straight-chain or branched-chain alkyl or arylalkyl monohydric alcohols.

[0023] As defined above, the composition can consist of components (a) to (d). However, it may also contain further components, and in particular, according to a preferred embodiment, it further comprises component (e), and preferably in this case it consists of components (a) to (e).

[0024] Thus, according to a preferred embodiment, next to components (a) to (d), the composition further comprises the following components (preferably, this component (e) is the only additional component, so that the formulation consists of (a) to (e) and further comprises means for adapting the pH to the claimed value ranging from 8 to 11.5, preferably in the form of NaOH): (e) at least one sugar alcohol having at least 3 carbon atoms.

[0025] Sugar alcohols (also known as polyhydric alcohols, polyalcohols, alditols, or glycitols) are organic compounds typically derived from sugars, containing one hydroxyl group (-OH) attached to each carbon atom. They are usually white, water-soluble solids and can occur naturally or be produced industrially by hydrogenating sugars. Because they contain multiple -OH groups, they are classified as polyols. Sugar alcohols according to the present disclosure are those of this type having at least 3 carbon atoms, preferably 4 to 12 carbon atoms, particularly preferably 4 to 6 carbon atoms, or exactly 6 carbon atoms. Sugar alcohols can be added to affect the flavor and / or viscosity of the composition, and this effect can synergistically influence the effectiveness of other ingredients, particularly the combination of component (a) and component (b).

[0026] Preferably, the at least one sugar alcohol having at least 3 carbon atoms is present in the composition at a concentration of up to 75% w / v, preferably up to 70% w / v, or in the range of 2% w / v to 50% w / v or 5% w / v to 50% w / v, or in the range of 3% w / v to 40% w / v or 10% w / v to 40% w / v, or 4% to 10% or 20% to 30%.

[0027] Preferably, the sugar alcohol of component (e) is selected from the group consisting of glycerol, erythritol, threitol, arabitol, ribitol, mannitol, sorbitol, xylitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetriitol, or a combination thereof.

[0028] Thus, according to a preferred embodiment, the concentration of component (a) polyhexanide (PHMB) in the composition is in the range of 0.002% w / v to 0.15% w / v or 0.002% w / v to 0.1% w / v, preferably in the range of 0.005% w / v to 0.07% w / v or 0.005% w / v to 0.05% w / v, and particularly in the range of 0.007% w / v to 0.03% w / v or 0.007% w / v to 0.02% w / v or 0.007% w / v to 0.015% w / v. When polyhexanide hydrochloride is used as the starting material, a particularly high synergistic effect between the high pH value and the presence of polyhexanide can be achieved when the pH and the concentration of B are in the range of 0.01% w / v.

[0029] Preferably, the organic or inorganic buffer of component (b) is of the following system: amino acids selected from the group consisting of alanine, glycine, asparagine, isoleucine, leucine, serine, threonine, valine, or combinations thereof, in particular glycine; bicarbonate buffers, in particular selected from the group consisting of carbonate bicarbonate buffers, triethylammonium bicarbonate buffers, borate buffers, in particular sodium borate buffers; (Acetic acid)ethanolamine buffer, or any combination or mixture thereof; is selected from.

[0030] In particularly preferred cases, the organic or inorganic buffer of component (b) is selected from the group consisting of short chain amino acids, preferably glycine, alanine, valine, leucine, isoleucine, or combinations or mixtures thereof, which do not have side chains that impart a pKs value and have pKs values ​​in the claimed ranges.

[0031] Particularly preferably, the buffer is selected as a glycine buffer, in particular at a concentration ranging from 0.05 M to 0.2 M. That range is believed to be just sufficient to stabilize the pH in the desired range and to cooperate optimally with the other ingredients in the composition.

[0032] In general, it is preferred that the organic or inorganic buffer of component (b) has at least one pKs value in the range of 9-10.5, preferably in the range of 9.5-10.

[0033] Generally, the concentration of the organic or inorganic buffer solution of component (b) in the composition is in the range of 0.05M to 0.8M, preferably in the range of 0.08M to 0.5M, and particularly in the range of 0.1M to 0.2M.

[0034] The pH value of the buffer of component (b), or rather of the composition as a whole, is preferably adjusted to the claimed pH value in the range of 8 to 11.5, if necessary, preferably by adding a strong base, preferably an inorganic base, said base preferably being selected from the group consisting of NaOH, KOH, Ca(OH), NaClO, KClO, or combinations thereof. Typically, the concentration of the base in the composition is in the range of 0.001 M to 0.07 M, or 0.04 M to 0.06 M, or in the range of 0.045 M to 0.055 M, thus in particular about 0.05 M.

[0035] Preferably, buffer solution (b) is glycine at a concentration ranging from 0.05 M to 0.2 M, pH adjusted to a concentration ranging from 0.04 M to 0.06 M with an alkali metal hydroxide, selected in particular as NaOH, KOH or mixtures thereof.

[0036] It is further preferred that as component (c), the additive is selected from the group of poloxamers, polyethylene glycols, flavorings, coloring agents, sugar alcohols, calcium donors, or derivatives thereof or combinations thereof, at a concentration ranging from 0% w / v to 10% w / v.

[0037] Particularly preferred is when the additive of component (c) is 1% w / v to 3% w / v of a poloxamer, preferably of the structure EO n -PO m -EO n wherein n is in the range of 80 to 120 and m is in the range of 50 to 60; 1% w / v to 3% w / v of polyethylene glycol and / or ethoxylated vegetable oil, in particular both (preferably ethoxylated castor oil is used), 0.1% w / v to 0.4% w / v of a flavoring substance (preferably selected as a flavor oil), 2% w / v to 10% w / v of a sugar alcohol, preferably xylitol; 0.0% w / v to 0.05% w / v or 0.01% w / v to 0.05% w / v of a calcium donor; and wherein the composition is selected as follows: Preferably, the composition has a pH in the range of 9.5 to 10.

[0038] As pointed out above, the composition may contain additives / auxiliaries different from components (a) and (b) or components (a) to (e).

[0039] These additives of component (c) may be selected from the group consisting of surfactants, anticorrosives, flavor modifiers (different from the sugar alcohols mentioned above), fragrances, dyes, stabilizers, thickeners (different from the sugar alcohols mentioned above), complexing agents, organic solvents, in particular alcohols (different from the sugar alcohols mentioned above), further disinfectants, preservatives, flavor modifiers (different from the sugar alcohols mentioned above), thickeners (different from the sugar alcohols mentioned above), or mixtures or combinations thereof.

[0040] Examples of flavor modifiers (other than the sugar alcohols mentioned above) are one or a combination of natural or synthetic flavors, essential oils, tannic acid, menthol, sodium cyclamate, fructose, galactose, thymol, etc. The flavor modifiers (other than the sugar alcohols mentioned above) are typically present at a concentration in the range of 0.01% w / v to 10% w / v, preferably 0.1% to 5%, of the aqueous antimicrobial composition.

[0041] Examples of thickening agents (other than the sugar alcohols mentioned above) are one or a combination of gelatin, polyethylene glycols such as polyethylene glycol 1000, polyvinyl alcohol, silicon dioxide, starch, poloxamers (e.g., 188, 407), carrageenan, etc. The thickening agent (other than the sugar alcohols mentioned above) is typically present at a concentration ranging from 1% w / v to 20% w / v of the aqueous antimicrobial composition.

[0042] The surfactant may be an ionic surfactant, a nonionic surfactant, or an amphoteric surfactant.

[0043] The anionic surfactants of these additives are in particular selected from alkyl sulfates, alkyl ether sulfates, alkyl sulfonates, alkyl benzyl sulfonates, α-olefin sulfonates, alkyl amido sulfonates, alkaryl polyether sulfates, alkyl amido ether sulfates, alkyl monoglyceryl ether sulfates, alkyl monoglyceride sulfates, alkyl monoglyceride sulfonates, alkyl succinates, alkyl sulfosuccinates, alkyl ether sulfosuccinates, alkyl sulfosuccinamates, alkyl amido sulfosuccinates; alkyl sulfoacetates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alkyl amido ether carboxylates, acyl lactylates, alkyl isethionates, acyl isethionates, carboxylates and amino acid-derived surfactants, such as N-alkylamino acids, N-acylamino acids, alkyl peptides, and mixtures thereof.

[0044] The amphoteric surfactants of these additives may be chosen in particular from alkylbetaines; alkylamidobetaines; alkylamidosultaines; alkylmonoamphocarboxylates and alkyldiamphocarboxylates; amine oxides; and mixtures thereof.

[0045] The nonionic surfactants of these additives can be chosen, for example, from ethoxylated fatty alcohols, ethoxylated alkylphenols, ethoxylated Guerbet alcohols, ethoxylated vegetable oils (e.g. ethoxylated castor oil, e.g. of the PEG-40 type; such compounds can, for example, help dissolve further ingredients), polypropylene glycols, polyethylene glycols, block copolymers of propylene glycol and / or ethylene glycol, ethoxylated sorbitan esters, sorbitan esters, alkyl polyglucosides, alkyl glucamides, and mixtures thereof.

[0046] The concentration of component (c) surfactant may range from 0 or greater than 0 to less than 10% w / v or less than 5% w / v of the total composition.

[0047] The concentration of the additive of component (c) may range from less than 10% w / v or less than 5% w / v.

[0048] As regards the dyes of component (c), these are typically present in the composition at a concentration of less than 0.2% w / v, preferably less than 0.1% w / v, particularly preferably in the range of 0.001% w / v to 0.05% w / v, based on the total composition.

[0049] More preferably, the additives other than the thickener (different from the sugar alcohols mentioned above) and the flavor adjuster (different from the sugar alcohols mentioned above) are present in a range of less than 0.2% w / v, preferably less than 0.1% w / v, particularly preferably in the range of 0.001% w / v to 0.05% w / v, for example in combination with a proportion of thickener (different from the sugar alcohols mentioned above) in the range of 1% w / v to 19.8% w / v of the total composition.

[0050] In some applications, it is preferred that no additives are present, so that the additive content is essentially 0.0 w / v of the total composition.

[0051] According to another preferred embodiment of the proposed composition, the composition has, either as an additional component or as part of component (c), a total calcium content in the range of 1 mmol / L to 5 mmol / L, preferably 2 mmol / L to 3 mmol / L, where the calcium can be in ionic or ion-bound form (in particular bound to albumin).

[0052] Typically, Ca 2+ is introduced into the composition as CaCl2, Ca citrate, Ca(OH)2, Ca lactate, calcium carbonate or calcium phosphate or a combination thereof.

[0053] As noted above, one important feature of the composition is a pH value that is compatible with the higher pKs of the polyhexanide system, which is in the range of 12. The pH value of the composition must be below that value.

[0054] According to a preferred embodiment, the composition has a pH value in the range of 8 to 11, preferably in the range of 8.5 to 10.5, in particular in the range of 9.5 to 10. An optimum effect is achieved when the pH is around 9.8.

[0055] According to a particularly preferred embodiment, the composition comprises (a) to (d) or (a) to (e), wherein the polyhexanide (PHMB) of component (a) has a weight-average molecular weight Mw in the range of 2400 g / mol to 3000 g / mol, and the polyhexanide (PHMB) of component (a) is in the form of polyhexamethylene biguanide hydrochloride, and the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.007% w / v to 0.015% w / v. Furthermore, the organic or inorganic buffer of component (b) is selected as glycine, and the concentration of the organic or inorganic buffer of component (b) in the composition is in the range of 0.1 M to 0.2 M. The concentration of the additional additive of component (c) is less than 0.01% w / v, preferably in the range of 0.001% w / v to 0.01% w / v.

[0056] According to a further aspect of the invention, it relates to a particular use of such a composition.

[0057] Therapeutic uses of such compositions (also formulated as "compositions for use as") include wound care (general), including use as a purification solution, a debridement solution, a wound cleansing solution, a wound care solution, wound management, promoting wound healing, particularly in the early healing stages in the oral cavity, priming / conditioning the wound / injured area, supporting the cleansing phase during the primary healing stage, cleansing and moistening wounds, or a combination thereof.

[0058] Therapeutic uses of such compositions (also formulated as "compositions for use as") also include wound irrigation (as wound irrigation solutions), antimicrobial decontamination and infection prevention, infection prophylaxis, and use to reduce the antimicrobial load of the oral cavity.

[0059] The therapeutic uses described may be for human or animal treatment and may be prophylactic or therapeutic use.

[0060] According to this aspect of the invention, a composition as defined above is proposed for the treatment or prevention of bacterial infections or bacterial colonization or both, in particular of the skin, wounds and preferably the oral cavity.

[0061] In other words, the present invention relates to the use of such compositions for the treatment or prevention of bacterial infections or bacterial colonization or both, in particular of the skin, wounds and preferably the oral cavity.

[0062] According to a first preferred embodiment, the composition is for the treatment and / or prevention of patients during and / or after implantation, in particular during and / or after dental implantation, including aftercare treatment for the days and even weeks after implantation, preferably in the form of a rinse or cleaning composition or instillation solution.

[0063] Non-therapeutic uses are intended to be applied to non-living things, such as hard surfaces or implants, and when applied to humans or animals, are purely for germicidal reasons and are applied to healthy humans or animals not in need of therapy or prophylaxis.

[0064] According to a further aspect of the invention, the invention relates to the use of the above-mentioned compositions for the disinfectant non-therapeutic treatment of surfaces, in particular non-living surfaces, preferably by dip-coating, spraying, dripping, or for the storage of biomaterials and / or preparation for implantation, as well as for devices, in particular implants for soft or hard tissue regeneration.

[0065] According to a first preferred aspect of this embodiment, the composition is used to store an implant or biomaterial, e.g. for soft or hard tissue regeneration, in particular a dental implant, in an immersed state before use or is packaged together or as a kit of parts with an implant or biomaterial, e.g. for soft or hard tissue regeneration, in particular a dental implant, in order to immerse or wet the implant or biomaterial with the composition immediately before implantation.

[0066] The present invention also relates to a method for cleaning and sanitizing and / or disinfecting a surface and providing residual inhibition of microorganisms, comprising: a) applying to the surface, article and / or substrate a composition as described above.

[0067] Furthermore, the present invention preferably relates to a method for producing the above-mentioned composition, which comprises the steps of preparing an aqueous sodium hydroxide solution, adding polyhexanide and a buffer solution thereto in required proportions, adding additives before or after the addition, if necessary, and subsequently mixing.

[0068] The composition can be stored in a container without requiring refrigeration, preferably a glass or plastic container, which may be combined with the object to which the composition is to be applied before use, e.g., a combined package including a container for the composition and a separate container for the object, e.g., an implant, is possible. Such a package may also be configured such that the container containing the composition can be opened by manipulation so that the composition flows into a package compartment of the object for direct wetting and / or immersion.

[0069] Further embodiments of the invention are also defined in the dependent claims.

[0070] Hereinafter, preferred embodiments of the present invention will be described with reference to the drawings. However, the drawings are intended to explain the preferred embodiments of the present invention and are not intended to limit the present invention. [Brief explanation of the drawings]

[0071] [Figure 1] FIG. 1 shows the results of an initial in vitro biofilm modeling study of the synergistic antimicrobial effects of test agents in alkaline buffer with low PHMB concentrations. [Figure 2] FIG. 2 shows the results of an initial in vitro biofilm modeling study of the synergistic antimicrobial effects of test agents in alkaline buffer with moderate PHMB concentrations. [Figure 3] FIG. 3 shows the results of an initial in vitro biofilm modeling study of the synergistic antimicrobial effects of test reagents in alkaline buffer at higher PHMB concentrations. [Figure 4a]FIG. 4a) shows the results of a denser and older biofilm model test of the synergistic antimicrobial effect of test reagents in alkaline buffer with higher PHMB concentrations. [Figure 4b] Figure 4b) shows the behavior of Streptococcus sanguinis cultured in either neutral PBS (pH 7.2), alkaline T. buffer (pH 9.7), or alkaline T. buffer supplemented with 0.015% PHMB. [Figure 5] FIG. 5 shows the results of a biocompatibility test of various alkaline buffer solutions. [Figure 6] FIG. 6 shows the results of a biocompatibility test of PHMB and CHX at various concentrations. [Figure 7] FIG. 7 shows cell viability of human primary cells after treatment with various disinfectants at concentrations used in current commercial products. [Figure 8] FIG. 8 shows the effect of added ethanol at 10%, 20% and 50% on cell vitality of human primary cells. DETAILED DESCRIPTION OF THE INVENTION

[0072] Preparation of test reagents: As test reagents, various chlorhexidine and polyhexamethylene biguanide hydrochloride (PHMB) solutions were prepared at various concentrations and buffer solutions. Chlorhexidine digluconate solution (CHX, 20% w / v in water, CAS 18472-51-0) was purchased from Sigma-Aldrich (Switzerland) (item number C9394). Glycine was purchased as a solid substance from Honeywell Fluka (Switzerland) (CAS: 56-40-6). Polyhexamethylene biguanide hydrochloride was purchased as a solid substance from Biosynth (UK) (item number FP76704, lot number: B20V06202). A 10% (weight per volume) aqueous PHMB solution was prepared as a stock solution. All PHMB test reagents were prepared based on the 10% stock solution.

[0073] Buffer solutions were prepared according to Table 1 below using 0.05 M NaOH solution with the addition of solid glycine in amounts to give the indicated glycine concentrations, and the pH was measured with a pH electrode (914 pH / Conductivity Meter (Metrohm), 3-point calibration).

[0074] [Table 1]

[0075] Polyhexanide (polyhexamethylene biguanide hydrochloride, PHMB, CAS No. 28757-47-3, also 32289-58-0) test reagents were prepared from a 10% PHMB stock solution in ultrapure water (weight per volume, ultrapure water according to ASTM Type 1, e.g., ASTM D1193-06 (2018), provided by Sartorius Arium Pro Water Systems) using the solutions and buffers shown in Table 1 and tested in various experiments according to Table 2 below.

[0076] [Table 2]

[0077] CHX test reagents were prepared from a 20% CHX stock solution (liquid) in ultrapure water using the solutions and buffers shown in Table 1 and tested in various experiments according to Table 3 below.

[0078] [Table 3]

[0079] Additionally, a 0.9% NaCl solution (weight per volume) in ultrapure water was used as the state of the art rinse solution.

[0080] Apart from the above solutions used in the in vitro experiments reported further below, the following final formulations in Table 3a were prepared for in vivo use and were found to be stable and effective.

[0081] [Table 4]

[0082] Alternative formulations have been prepared for in vivo use and found to be stable and effective, and are shown in Table 3b below.

[0083] [Table 5]

[0084] Determination of the antimicrobial efficacy of various test agents in an in vitro biofilm model: To test the antimicrobial effects of various test reagents, the oral strain Streptococcus sanguinis purchased from ATCC was used. All experiments began with the preparation of an overnight culture of S. sanguinis in brain heart infusion (BHI) medium at 37°C under aerobic conditions. After 16 hours, the bacterial suspension was centrifuged at 3000 rpm for 5 minutes. The supernatant was removed, and the pellet was resuspended in 1 ml of phosphate-buffered saline (PBS, Sigma-Aldrich, Switzerland). The bacterial suspension was adjusted in PBS and diluted to 10 ml. 8 The optical density of 0.5, which corresponds to CFU / ml, was adjusted to 10 3 A starting inoculum of CFU / ml was used.

[0085] To model early biofilm formation after dental implant placement, circular titanium discs (16 mm diameter, provided by Thommen Medical AG) were cleaned, heat autoclaved, and placed in 24-well plates.

[0086] In the next step, these titanium discs were preconditioned with the test reagents or BHI medium / 0.9% NaCl (control group).

[0087] The conditioned titanium discs were then plated with 1 ml / well of bacterial suspension (10 3 CFU / ml).

[0088] After 24 hours, the BHI medium was removed and the titanium discs were washed with the test reagent for 10 minutes at 37°C and 70 rpm.

[0089] Crystal violet staining was performed to quantify the amount of biofilm on the titanium discs. For this purpose, the test reagent was removed with a pipette, and 300 μl / well of crystal violet solution (0.1% in ultrapure water, purchased from Sigma-Aldrich, Switzerland) was added and incubated for 10 min at room temperature.

[0090] After the incubation period, the titanium disks were washed four times with distilled water (600 μl / well) and transferred to a new 24-well plate. To release the crystal violet stain from the titanium disks, 1 ml / well of acetic acid (33%) was added and incubated for 5 minutes at room temperature and 70 rpm. 100 μl of each solution was transferred in duplicate from each well to a new 96-well plate, and the absorbance at 590 nm was measured using a BioTek Epoch2 microplate reader.

[0091] To evaluate the antimicrobial effects of the test reagents not only on early biofilm formation but also on older, more dense biofilms, similar experiments as described in the above section were performed on 10 6 The experiment was repeated using a starting inoculum of CFU / ml and an incubation time of 72 hours.

[0092] To study the effect of alkaline pH on bacterial growth, bacterial suspensions of S. sanguinis with an optical density (600 nm) of 0.2 were prepared in PBS medium at pH 7.2 or in T. difficile buffer (0.05 M NaOH / 0.1 M glycine, 0.03% CaCl2) at pH 9.7 with or without the addition of 0.015% PHMB. Next, 100 μl of the bacterial suspension was transferred to a 96-well plate and placed in a preheated (37°C) Biotek reader. Optical density at 600 nm was measured at 2-hour intervals over 24 hours to assess bacterial behavior in various buffers.

[0093] Cell culture and cytocompatibility testing of test reagents and alkaline buffers: Mouse fibroblasts (L929 cell line) were used in this study as the recommended cell line for cytotoxicity testing according to EN ISO10993-5.

[0094] Fibroblast cells were purchased from ATCC and cultured in Dulbecco's modified Eagle's medium (high glucose) supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin (Sigma-Aldrich, Switzerland) at 37°C and 5% CO in T75 flasks. For cytotoxicity experiments, L929 cells were plated on 96-well cell culture plates at 100 μg / well, 1 × 10 6 Cells were seeded at a density of 0.001%, 0.005%, 0.01%, 0.05%, and 0.1% to reach approximately 80% confluence after 24 hours. The following day, 100 μl of fresh medium containing various concentrations of CHX or PHMB (0.001%, 0.005%, 0.01%, 0.05%, and 0.1%) was added.

[0095] As a control, cells were incubated in fresh medium without disinfectant.

[0096] Six replicate wells were tested per concentration.

[0097] After 60 minutes of incubation at 37°C, the medium was removed and the wells were washed once with 100 μl of fresh medium.

[0098] The cells were then incubated with 100 μL of fresh medium containing 0.015 mg / ml Alamar Blue dye at 37° C. for 2 hours.

[0099] Finally, 100 μL of medium was removed from each well and transferred to a new 96-well plate, and the absorbance was measured using a BioTek microplate reader (test wavelength: 570 nm, reference wavelength: 630 nm).

[0100] To test the cytocompatibility of alkaline buffer, a similar experiment was performed, except that the alkaline buffer was incubated for 10 minutes instead of 60 minutes.

[0101] The following alkaline buffers were tested: a) 0.025M NaOH, 0.025M NaOH / 0.05M glycine, 0.025M NaOH / 0.05M glycine / 0.03% CaCl2 (weight per volume in final composition); b) 0.05M NaOH, 0.05M NaOH / 0.05M glycine, 0.05M NaOH / 0.05M glycine / 0.03% CaCl2 (weight per volume in final composition); c) 0.1M NaOH, 0.05M NaOH / 0.1M glycine, 0.05M NaOH / 0.1M glycine / 0.03% CaCl2 (weight per volume in final composition); d) 0.05M NaOH / 0.1M glycine; e) 0.05M NaOH / 0.1M glycine / 0.03% CaCl2 (weight per volume in final composition).

[0102] Human primary cells and the effects of disinfectants and ethanol on cell vitality: In this study, human periodontal ligament fibroblasts (HPDLFs) were used as a test system that more closely mimics in vivo conditions. Fibroblasts were purchased from ATCC and cultured in T75 flasks at 37°C and 5% CO in ScienCell's FM medium supplemented with 2% fetal bovine serum, 1% fibroblast growth factor, and 1% penicillin-streptomycin (Sigma-Aldrich, Switzerland).

[0103] To study the effect of disinfectants at concentrations currently used in commercial products, the vitality of HPDLF cells was evaluated. For this purpose, cells were plated in 24-well cell culture plates at 1 ml / well, 3 × 10 4 Cells were seeded at a density of 1000 cells / mL and reached approximately 80% confluence after 48 hours. In the next step, 300 μl of T buffer (0.05 M NaOH / 0.1 M glycine, 0.03% CaCl2) containing various concentrations of CHX (0.06% and 0.12%) or PHMB (0.015%, 0.025%, 0.05%, and 0.15%) was added. As a control, cells were incubated in T buffer without disinfectant. Three replicate wells per concentration were tested. After 1 minute of incubation at 37°C, the supernatant was removed and the wells were washed once with 600 μl of fresh medium. The cells were then incubated in 600 μL of fresh medium containing 0.015 mg / mL Alamar Blue dye for 4 hours at 37°C. Finally, 100 μL of medium was removed from each well and transferred to a new 96-well plate, and the absorbance was measured using a BioTek microplate reader (test wavelength: 570 nm, reference wavelength: 630 nm).

[0104] To assess the effect of ethanol on cell vitality, HPDLF cells were plated onto 96-well cell culture plates at 100 μl / well, 6 × 10 3Cells were seeded at a density of 1000 cells / mL and reached approximately 80% confluence after 24 hours. The next day, 100 μL of fresh medium containing various concentrations of ethanol (10%, 20%, and 50%) was added. Additionally, 10%, 20%, and 50% ethanol was added to the developed T. buffer. As a control, cells were incubated in fresh medium without ethanol. Three replicate wells per concentration were tested. After 5 minutes of incubation at 37°C, the medium was removed, and the wells were washed once with 100 μL of fresh medium. The cells were then incubated in 100 μL of fresh medium containing 0.015 mg / mL Alamar Blue dye for 2 hours at 37°C. Finally, 100 μL of medium was removed from each well and transferred to a new 96-well plate. The absorbance was measured using a BioTek microplate reader (test wavelength: 570 nm, reference wavelength: 630 nm).

[0105] Results and Discussion Compatibility of test reagents in alkaline buffer solutions: Polyhexamethylene biguanide hydrochloride (polyhexanide, PHMB) is a chemical biocide. Six different PHMB product types have been identified, each with a combination of amine, guanidine, and cyanoguanidine end groups.

[0106] The antibacterial activity of PHMB depends on its molecular structure.

[0107] The minimum requirement is met by more than two biguanide moieties and five to seven methylene groups as spacers.

[0108] The biguanide moiety of PHMB is a strong base and becomes monoprotonated at pH 7 (pKa1≦2-3, pKa2≦10.5-11.5), resulting in a polycation with a positive charge on each biguanide moiety.

[0109] The positively charged moieties are thought to bind to the negatively charged phosphate head groups of phospholipids in the bacterial cell wall, leading to increased loss of fluidity, permeability and integrity and subsequent death of the organism.

[0110] The molecular structure of the PHMB monomer closely resembles that of the CHX molecule, except for the terminal NH group of CHX, which consists of 4-chloroaniline (4-CA). PHMB can essentially be viewed as a detoxified version of CHX. Like PHMB, the biguanide moiety of CHX has a pKa of ≤ 10.8, making it a strong base.

[0111] Generally, inorganic bases such as sodium hydroxide will result in precipitation of PHMB and CHX at pH > pka values, for example 0.05 M NaOH at pH 12.7.

[0112] On the other hand, sodium hydroxide is known to induce an alkaline saponification reaction with bacterial phospholipid membranes, resulting in membrane destruction and ultimately cell death.

[0113] Surprisingly, there is a synergistic effect between PHMB and sodium hydroxide, resulting in increased bacterial kill or allowing the active concentration to be reduced to achieve the same effect.

[0114] However, to achieve this in practice, a buffer must be added that prevents PHMB precipitation while still allowing sufficient hydroxyl ions to be available to achieve alkaline saponification.

[0115] Therefore, various buffer compositions were tested for precipitation of PHMB and CHX, as shown in Table 1.

[0116] The results of these precipitation tests were as follows (precipitation was determined by visual inspection / visible turbidity and pH was measured): 0.05M NaOH / 0.05M glycine / CHX 0.06%, pH 11.06: Precipitation 0.05M NaOH / 0.1M glycine / CHX 0.06%, pH 9.9: no precipitation 0.05M NaOH PHMB 0.05%, pH 12.51: Precipitation 0.05M NaOH / 0.05M glycine / PHMB 0.05%, pH 11.06: No precipitation 0.05M NaOH / 0.1M glycine / PHMB 0.05%, pH 9.9: no precipitation.

[0117] The CHX concentrations of 0.06% and 0.12% w / v were based on common oral rinse solutions (e.g., Chlorhexamed products), and the 0.05% PHMB was based on wound rinse solutions with concentrations ranging from 0.04% w / v.

[0118] Based on the pKa value of 10.8 of the strongest base in the CHX molecule, precipitation occurs using a 0.05 M NaOH / 0.05 M glycine buffer at pH 11.2 (pH ≥ pKa).

[0119] Increasing the glycine concentration to 0.1 M, and therefore lowering the pH, does not result in precipitation of CHX.

[0120] In contrast to CHX, the pKa value of the strongest base in the PHMB molecule is in the range of 10.5–11.5. Therefore, precipitation of PHMB was not observed using a 0.05 M NaOH / 0.05 M glycine buffer (pH 11.06). However, a 0.05 M NaOH solution (pH 12.5) without the addition of glycine also induces PHMB precipitation.

[0121] Therefore, it can be concluded that a minimum of 0.05 M glycine is suitable for PHMB. Because 0.05 M NaOH / 0.05 M glycine, at pH 11.06, is close to the pKa value of PHMB's strongest base, for some applications it may be desirable to use a 0.05 M NaOH solution with 0.1 M glycine, i.e., a solution with a pH in the range of about 10 or less.

[0122] Synergistic antimicrobial effect of test reagents in alkaline buffer: In a study by Ojan Assadian et al. (2011) (Assadian O, Wehse K, Huebner NO, Koburger T, Bagel S, Jethon F, Kramer A. Minimum inhibitory (MIC) and minimum microbicidal concentration (MMC) of polihexanide and triclosan against antibiotic sensitive and resistant Staphylococcus aureus and Escherichia coli strains. GMS Krankenhhyg Interdiszip. 2011;6(1)), minimum inhibitory concentrations (MIC) ranging from 1 μg / ml to 2 μg / ml (0.002% w / v) were reported for Streptococcus aureus and Escherichia coli treated with PHMB solution.

[0123] To detect a possible synergistic effect between PHMB and alkaline buffer, initial biofilms of Streptococcus sanguinis were cultured on titanium disks for 24 hours, after which the disks were rinsed with various PHMB solutions containing 0.002% PHMB, similar to the reported MIC. As a control, biofilms were cultured in BHI medium.

[0124] There was no reduction in bacterial load with PHMB solution (0.002% in nanopure water), suggesting that 0.0002% is below the MIC for Streptococcus sanguinis in this assay.

[0125] However, when PHMB (0.002%) was prepared in 0.05 M NaOH / 0.05 M glycine buffer at pH 11.06, a significant decrease in absorbance and therefore bacterial load was observed.

[0126] Similar results are obtained for PHMB (0.002%) prepared in 0.05 M NaOH / 0.2 M glycine buffer at pH 9.27.

[0127] In contrast, when PHMB (0.002% in distilled water) was added to a 0.05 M NaOH solution at pH 12.5 (no precipitation was observed, likely due to the low concentration of PHMB used), the bacterial load did not decrease because the PHMB molecule could not be positively charged at pH ≥ pKa.

[0128] FIG. 1 graphically illustrates the absorbance results for low PHMB concentrations, with higher absorbance indicating less effect on biofilms.

[0129] In the next experiment, a higher concentration of PHMB (0.01% in ultrapure water) was tested against the early biofilm formation of Streptococcus sanguinis cultured on titanium discs.

[0130] In this experiment, a synergistic effect between 0.01% PHMB and NaOH / glycine buffer was also observed.

[0131] The best results for bacterial load reduction were obtained using 0.05 M NaOH / 0.05 M glycine (pH 11.06) and 0.05 M NaOH / 0.2 M glycine (pH 9.27) buffers. Higher concentrations of glycine, such as 0.4 M (pH 8.9), did not result in significant reductions in bacterial load compared to lower concentrations of glycine, such as 0.05 M to 0.2 M.

[0132] FIG. 2 graphically illustrates the absorbance results for low PHMB concentrations, with higher absorbance indicating less effect on biofilms.

[0133] As can be seen from the results shown in Figure 3, in the primary biofilm model, no significant synergistic effect is observed when 0.05% PHMB is added to alkaline buffer.

[0134] To verify whether an earlier in vitro biofilm model set up with a low concentration of bacterial starting inoculum and a short incubation time could potentially inhibit the potential synergistic effect of a higher PHMB concentration in alkaline buffer, e.g., 0.05%, experiments were performed on a higher density and older biofilm model (starting inoculum 10 6 The results were repeated using the same 0.05% PHMB in 0.05 M NaOH / 0.1 M glycine buffer (Figure 4a).

[0135] To assess the effects of pH and disinfectants on bacterial behavior, bacterial suspensions of S. sanguinis were measured for optical density at 600 nm and at 37°C over 24 hours. Incubation in neutral PBS showed significant growth of S. sanguinis over time, whereas growth in T. sanguinis buffer at pH 9.7 showed a significant inhibitory effect. Addition of 0.015% PHMB to alkaline T. sanguinis buffer at pH 9.7 resulted in bacterial death over time (see results in Figure 4b).

[0136] Biocompatibility of test reagents: L929 mouse fibroblast cells were used to test the biocompatibility of various alkaline buffers.

[0137] Cells were plated in a 96-well plate at 1 x 10 6 After seeding at a density of 1000 cells / ml and culturing for 24 hours, they were treated with various alkaline buffers for 30 minutes.

[0138] As a control, cells were cultured in fresh medium.

[0139] After the incubation period, metabolic activity, used as an indirect marker of cytotoxicity, was measured using the Alamar Blue assay. Viable cells were able to convert the dye into a fluorescent product through a redox reaction. Therefore, the highest metabolic activity was observed in the control. A decrease in metabolic activity was associated with possible toxic effects.

[0140] Incubation with pure sodium hydroxide (0.025M, 0.05M and 0.1M) resulted in a significant decrease in metabolic activity.

[0141] Additionally, alkaline buffers containing 0.05 M NaOH / 0.05 M glycine (pH 11.06) and 0.1 M NaOH / 0.05 M glycine showed clear toxic effects.

[0142] Compared to the aforementioned buffers, alkaline buffers containing 0.025 M NaOH / 0.05 M glycine or 0.05 M NaOH / 0.1 M glycine resulted in metabolic activity comparable to the control.

[0143] Furthermore, it was observed that the addition of 0.03% CaCl2 to the alkaline buffer may have an additional beneficial effect on metabolic activity.

[0144] Figure 5 graphically shows the results of biocompatibility testing of various alkaline buffers. The pH values ​​of the samples in this figure are listed in Table 4.

[0145] [Table 6]

[0146] To evaluate the biocompatibility of PHMB compared with that of CHX, L929 mouse fibroblasts were treated with various concentrations of PHMB and CHX added to the culture medium for 60 minutes.

[0147] After incubation with disinfectants, metabolic activity was measured using the Alamar Blue assay. Data were normalized to the control (cells in fresh medium), which was therefore set to 100% metabolic activity. To compare the two disinfectants, IC represents the concentration allowing 50% cell viability. 50 The IC values ​​(thick horizontal lines) were calculated for each compound. The calculations showed that the IC values ​​for PHMB were less than 0.1% and for CHX were less than 0.01%. 50The values ​​were revealed (see Figure 6).

[0148] To evaluate the cell viability of the disinfectants PHMB and CHX, human primary cells (HPDLF) were treated with various concentrations of PHMB and CHX in T. buffer for 1 minute. After incubation with the disinfectants, metabolic activity was measured using the Alamar Blue assay (4 hours later). Low cell viability was observed in cells treated with CHX at test concentrations of 0.06% and 0.12% in T. buffer. For PHMB, low cell viability was observed in cells treated with PHMB at a concentration of 0.15%, while 0.05% PHMB only resulted in a decrease in cell viability. 0.025% and 0.015% PHMB revealed cell viability in the range of the T. buffer control. Cells treated with the negative control (5% DMSO) showed low cell viability. See Figure 7.

[0149] It should be noted that this is effective for disinfecting applications. If the application is rather anti-inflammatory (e.g., in the form used against mucositis), higher concentrations of PHMB, up to 0.2%, can also be used. A further advantage compared to the use of CHX is that application of PHMB formulations does not have a staining effect on the teeth, as opposed to the use of CHX-based formulations, and PHMB exhibits greater biocompatibility than CHX.

[0150] Finally, we investigated the effect of ethanol on cell vitality. HPDLF cells were grown in FM cell culture medium as a control. The effect of ethanol addition was examined by adding 10%, 20%, and 50% ethanol to the cell culture medium, or the developed T. Buffer and the corresponding amount of ethanol. After 5 minutes of incubation with the various test substances, cell vitality was measured by the AlamarBlue assay performed as described above. Addition of ethanol to the cell culture medium at concentrations of 20% and 50% showed a significant decrease in cell vitality. Ethanol added to the T. Buffer also had a negative effect on cell vitality (see Figure 8).

[0151] Key findings: Some of the main findings of the experimental evidence can be summarized as follows:

[0152] A particularly remarkable synergistic effect between PHMB and alkaline buffer was observed in an early biofilm formation model using Streptococcus sanguinis (starting inoculum 10 3 Results (CFU / ml, 24-h incubation time) were obtained for PHMB concentrations ranging from 0.002% to 0.04%. In experiments using the initial biofilm formation setup, little synergistic effect of PHMB with alkaline buffer was observed at PHMB concentrations above 0.05%.

[0153] Alkaline buffers containing 0.05 M NaOH and 0.05 M or less glycine tend to have too high a pH, pH ≥ pKa, resulting in reduced antimicrobial activity. Buffers containing 0.05 M NaOH and 0.4 M or more glycine also resulted in reduced antimicrobial activity. The best performance in terms of synergy (antimicrobial activity) was achieved with buffers containing 0.05 M NaOH and 0.05 M to 0.2 M glycine (pH range 11.06 to 9.8).

[0154] The synergistic effect of PHMB (0.05%) and alkaline buffer (0.05 M NaOH / 0.1 M glycine) was observed in the control of higher bacterial loads (10 6 CFU / ml) and a longer incubation time (72 h) in an in vitro biofilm model.

[0155] Biocompatibility studies using L929 mouse fibroblast cells showed good resistance to alkaline buffer solutions containing 0.025 M NaOH / 0.05 M glycine or 0.05 M NaOH / 0.1 M glycine + 0.03% CaCl (pH 9.78), indicating that alkaline buffer solutions composed of NaOH / glycine at pH 10 or less can be considered biocompatible.

[0156] Biocompatibility tests using L929 mouse fibroblast cells, PHMB, and CHX showed the following IC 50 The values ​​were: PHMB ≦ 0.1%, CHX ≦ 0.01%. These data indicate that PHMB is more biocompatible than CHX.

[0157] The cell vitality after exposure to the proposed formulation is very good compared to other products. The presence of ethanol has a negative effect on cell vitality, so alcoholic ingredients should rather be avoided.

[0158] The present proposal provides an optimal balance between high antimicrobial activity and biocompatibility with oral tissue cells.

Claims

1. Ingredients: (a) polyhexanide (PHMB) or a salt thereof at a concentration ranging from 0.001% w / v to 0.2% w / v; (b) an organic or inorganic buffer different from (a) having at least one pKs value in the range of 8.5 to 11.5 at a concentration in the range of 0.01 M to 1 M; (c) a further additive in a concentration ranging from 0% w / v to 20% w / v; (d) water; 1. An aqueous antimicrobial composition comprising or consisting of: The aqueous antimicrobial composition, wherein the pH value of the composition is in the range of 8 to 11.

5.

2. The polyhexanide (PHMB) of component (a) has a weight average molecular weight Mw in the range of 1500 g / mol to 4000 g / mol, preferably in the range of 2400 g / mol to 3000 g / mol; and / or said polyhexanide (PHMB) of component (a) has a polydispersity index (PDI) in the range of 1.4 to 2.2, preferably in the range of 1.7 to 2.8; And / or the composition according to claim 1, wherein the polyhexanide (PHMB) of component (a) is in the form of polyhexamethylene biguanide hydrochloride.

3. 3. A composition according to claim 1 or 2, wherein the concentration of component (a) polyhexanide (PHMB) in the composition is in the range of 0.002% w / v to 0.15% w / v or 0.002% w / v to 0.1% w / v, preferably in the range of 0.005% w / v to 0.07% w / v or 0.005% w / v to 0.05% w / v, in particular in the range of 0.007% w / v to 0.03% w / v or 0.007% w / v to 0.02% w / v or 0.007% w / v to 0.015% w / v.

4. The organic or inorganic buffer of component (b) is amino acids selected from the group consisting of alanine, glycine, asparagine, isoleucine, leucine, serine, threonine, valine, or combinations thereof, in particular glycine; bicarbonate buffers, in particular selected from the group consisting of carbonate bicarbonate buffers, triethylammonium bicarbonate buffers, borate buffers, in particular sodium borate buffers; (acetic acid)ethanolamine buffer, or any combination or mixture thereof; is selected from the group consisting of 4. The composition of any one of claims 1 to 3, wherein the organic or inorganic buffer of component (b) is selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, or combinations or mixtures thereof.

5. 5. The composition according to any one of claims 1 to 4, wherein the organic or inorganic buffer of component (b) has at least one pKs value in the range of 9 to 10.5, preferably in the range of 9.5 to 10.

6. 6. The composition according to any one of claims 1 to 5, wherein the concentration of the organic or inorganic buffer of component (b) in the composition is in the range of 0.05M to 0.8M, preferably in the range of 0.08M to 0.5M, in particular in the range of 0.1M to 0.2M.

7. The additives of component (c) are surfactants, including ionic surfactants and nonionic surfactants, thickeners, compatibilizers, in particular anionic surfactants, in particular selected from alkyl sulfates, alkyl ether sulfates, alkyl sulfonates, alkyl benzyl sulfonates, α-olefin sulfonates, alkyl amido sulfonates, alkaryl polyether sulfates, alkyl amido ether sulfates, alkyl monoglyceryl ether sulfates, alkyl monoglyceride sulfates, alkyl monoglyceride sulfonates, alkyl succinates, alkyl sulfosuccinates, alkyl ether sulfosuccinates, alkyl sulfosuccinamates, alkyl amido sulfosuccinates; alkyl sulfoacetates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alkyl amido ether carboxylates, acyl lactylates, alkyl isethionates, acyl isethionates, carboxylates and amino acid-derived surfactants, such as N-alkyl amino acids, N-acyl amino acids, alkyl peptides, and mixtures thereof; amphoteric surfactants, in particular selected from alkylbetaines; alkylamidobetaines; alkylamidosultaines; alkylmonoamphocarboxylates and alkyldiamphocarboxylates; amine oxides; and mixtures thereof; non-ionic surfactants or thickeners or compatibilizers, in particular chosen from ethoxylated fatty alcohols, ethoxylated alkylphenols, ethoxylated Guerbet alcohols, ethoxylated vegetable oils, polypropylene glycols, polyethylene glycols, block copolymers of propylene glycol and / or ethylene glycol, ethoxylated sorbitan esters, sorbitan esters, alkyl polyglucosides, alkyl glucamides, and mixtures thereof; Anticorrosives, fragrances, dyes, stabilizers, complexing agents, organic solvents, especially alcohols, disinfectants, preservatives, or any mixture or combination thereof; The composition of any one of claims 1 to 6, selected from the group consisting of:

8. 8. The composition according to any one of claims 1 to 7, wherein the concentration of the additive of component (c) is in the range of less than 10% w / v or less than 5% w / v, and wherein the dye as part of component (c) is preferably present in a concentration in the range of less than 0.2% w / v, preferably less than 0.1% w / v, particularly preferably in the range of 0.001% w / v to 0.05% w / v or 0.0 w / v.

9. The composition according to any one of claims 1 to 8, wherein the composition has a pH value in the range of 8 to 11, preferably in the range of 8.5 to 10.5, in particular in the range of 9.5 to 10.

10. the polyhexanide (PHMB) of component (a) has a weight average molecular weight Mw in the range of 2400 g / mol to 3000 g / mol, the polyhexanide (PHMB) of component (a) is in the form of polyhexamethylene biguanide hydrochloride, and the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.007% w / v to 0.015% w / v; the organic or inorganic buffer of component (b) is selected as glycine, and the concentration of the organic or inorganic buffer of component (b) in the composition is in the range of 0.1 M to 0.2 M; 10. The composition of any one of claims 1 to 9, wherein the concentration of the further additive of component (c) is less than 0.01% w / v, preferably in the range of 0.001% w / v to 0.01% w / v.

11. A composition according to any one of claims 1 to 10 for the treatment or prevention of bacterial infections or colonisation or both, in particular of the skin, wounds and preferably of the oral cavity.

12. 12. A composition according to claim 11, preferably in the form of a rinse or cleaning composition or instillation solution, for the treatment and / or prevention of patients during and / or after implant surgery, in particular during and / or after dental implant surgery, including an aftercare treatment for several weeks after implant surgery.

13. Next to components (a) through (d), the composition further comprises the following components: (e) at least one sugar alcohol having at least 3 carbon atoms, preferably in a concentration of up to 75% w / v, preferably up to 70% w / v, or in the range of 5% w / v to 50% w / v, or in the range of 10% w / v to 40% w / v, or 20% to 30%; Further comprising:

13. The composition of any one of claims 1 to 12, wherein the sugar alcohol of component (e) is selected from the group consisting of glycerol, erythritol, threitol, arabitol, ribitol, mannitol, sorbitol, xylitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetritoitol, or combinations thereof.

14. 14. A composition according to any preceding claim, which is ethanol-free or contains less than 10% w / v or less than 5% w / v or less than 2% w / v of ethanol.

15. 15. The composition of any one of claims 1 to 14, which is free of straight or branched chain alkyl or arylalkyl monohydric alcohols having 1 to 9 or 1 to 6 carbon atoms, in particular free of methanol, ethanol, propanol, 1-phenyl-1-propanol or combinations thereof, or which comprises less than 10% w / v, or less than 5% w / v, or less than 2% w / v, or less than 1% w / v of such straight or branched chain alkyl or arylalkyl monohydric alcohols.

16. Use of a composition according to any one of claims 1 to 15 for the disinfectant non-therapeutic treatment of surfaces, in particular non-living or biomaterial surfaces, preferably by dip-coating, spraying, dropping, or for the storage and / or implantation preparation of devices, in particular implants or biomaterials, in particular for soft or hard tissue regeneration.

17. 17. Use according to claim 16, wherein the composition is used to store an implant or biomaterial, in particular for soft or hard tissue regeneration, in particular a dental implant, in an immersed state before use, or is packaged together or as a kit of parts with an implant or biomaterial, in particular for soft or hard tissue regeneration, in particular a dental implant, in order to immerse or wet the implant or material with the composition immediately before implantation.

18. 18. A method of cleaning and sanitizing and / or disinfecting a surface and providing residual inhibition of microorganisms, said method comprising: a) applying to the surface, article and / or substrate a composition according to any one of claims 1 to 17.

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