Oral mucosa treatment formulations

Abstract

Composition for use for the treatment and / or prevention of infections or lesions of the (oral) mucosa, in particular originating from at least one selected the group consisting of: perleche; scarlet fever; pharyngitis; acute necrotising ulcerative mucositis; impetigo contagiosa; chelitis glandularis apostem atosa; gingivostomatitis herpetica; herpes simplex; herpes stabistis recidivans; herpes zoster; hand-foot-mouth; human papilloma virus; HIV; oral candidiasis; oral lichen planus; lichen ruber planus; leukoplakia, erythroplakia; methicillin-resistant staphylococcus aureus; gingivitis / periodontitis; mucositis / peri- implantitis; alveolar osteolytis; wherein the composition comprises or consists of the following components: (a) polyhexanide (PHMB); (b) an organic or inorganic buffer different from a); (c) further additives; (d) optionally water.

Description

[0001] TITLE

[0002] ORAL MUCOSA TREATMENT FORMULATIONS

[0003] TECHNICAL FIELD

[0004] The present invention relates to compositions for use for the treatment and / or prevention of odontogenic or non-odontogenic infections or lesions of the mucosa, in particular of the oral mucosa.

[0005] PRIOR ART

[0006] There has been an increasing focus on compositions that impart antimicrobial properties to products and surfaces, in particular during the pandemic. Some pathogenic bacteria have evolved to become resistant to most, if not all, of the currently available antibiotics on the market. These drug-resistant bacteria present a challenge to medicine, dentistry and the healthcare industry. Furthermore, in the food industry, bacteria infestation related recalls have become more prevalent due to current cleaning methods being insufficient. Even consumers are seeking solutions to this issue with products that impart antibacterial properties to architectural paints and homecare and laundry products.

[0007] Before or after insertion , cleaning of implants and removing biofilms is important to prevent inflammation or reduce inflammation risks, respectively.

[0008] Also, antiseptic formulations are used for rinsing body parts, for example for mouth rinsing, wound treatment, skin disinfection and the like.

[0009] Various different antiseptic formulations are known to the skilled person, typical antiseptic formulations include aqueous or at least partly aqueous formulations of antiseptic agents such as octenidine (1 ,1'-(decane-1 ,10-diyl)bis(N-octylpyridin-4(1 H)-imine)-hydrogen chloride), chlorhexidine (1 ,6-bis(4-chloro-phenylbiguanido)hexane) or polyhexanide (polyhexamethylene biguanide), but also strongly basic or acidic solutions or solutions based on inorganic antiseptic systems.

[0010] JP-A-2007045732 provides a disinfection solution mild to the skin and having effects for inactivating Norovirus. The antiseptic solution contains 0.05-0.5 wt.% polyhexamethylene biguanide-based compound and has a pH within the range of 9-12.

[0011] EP-A-1049763 relates to aqueous biguanide-containing disinfecting solutions containing an improved buffer system comprising both a phosphate and borate buffer. Preferred embodiments include methods and compositions for simultaneously cleaning and disinfecting contact lenses.

[0012] WO-A-2019069298 describes a chewing gum composition comprising polyhexanide for the treatment and / or prevention of an infectious disease in the oral cavity. The disclosure also describes a chewing gum composition formulated for the controlled release of polyhexanide and optionally, at least one additional water-soluble antiseptic agent.

[0013] JP-A-2007045732 (JP-B-4975987) provides a disinfection solution mild to the skin and having effects for inactivating Norovirus, which antiseptic solution contains 0.05-0.5 wt.% polyhexamethylene biguanide-based compound and has a pH within the range of 9-12.

[0014] SUMMARY OF THE INVENTION

[0015] It is thus an object of the present invention to provide new uses and indications for compositions based on polyhexanide (PHMB) and an organic or inorganic buffer, which are compatible with the body and / or the surfaces to which the formulations are applied, and which show an as high as possible preventive and / or therapeutic effects on human or animal mucosa, while at the same time showing an as high as possible biocompatibility.

[0016] This object is achieved by the subject matter as claimed, more specifically by compositions for uses as claimed.

[0017] According to a first aspect of the present invention it relates to compositions for use for the treatment and / or prevention of infections or lesions of the animal or human mucosa.

[0018] According to a preferred embodiment, it relates to compositions for use for the treatment and / or prevention of odontogenic or non-odontogenic infections or lesions of the oral mucosa (in particular oral cavity), in particular originating from at least one selected the group consisting of:

[0019] Normally non-odontogenic, bacterial: perleche; scarlet fever; pharyngitis; mucositis (ulcerative gingivitis / periodontitis, including (acute) necrotising ulcerative mucositis (ANUM)); impetigo contagiosa; stomatitis gangraenose (noma), chelitis glandularis apostem atosa;

[0020] Normally non-odontogenic, viral: gingivostomatitis herpetica; herpes simplex; herpes stabistis recidivans; herpes zoster; hand-foot-mouth; human papilloma virus (HPV); HIV;

[0021] Normally non-odontogenic, fungal: oral candidiasis;

[0022] Normally non-odontogenic, autoimmune: oral lichen planus; lichen ruber planus;

[0023] Normally non-odontogenic, other: leukoplakia, erythroplakia;

[0024] Normally odontogenic, bacterial infections for example: methicillin-resistant staphylococcus aureus; gingivitis / periodontitis; mucositis / peri-implantitis; alveolar osteomyelitis osteolytis.

[0025] Within this document the mucosa is defined as including the mucous membrane. The mucosa is composed of one or more layers of epithelial cells that secrete mucus, and an underlying lamina propria of loose connective tissue. The type of cells and type of mucus secreted vary from organ to organ and each can differ along a given tract. Mucous membranes line the digestive, respiratory and reproductive tracts. Within this document mucosa is not restricted to mucous membrane it also includes epithel cells / tissue, which can be exposed due to burnings, in particular due to 2nddegree burnings, which epithel cells / tissue exposed due to burnings behaves the same or similarly to mucosa in that it secretes a protective fluid similar to mucus, a thick protective fluid secreted by mucosa in the narrow sense.

[0026] Within this document the oral mucosa is defined as the soft tissue lining of the oral cavity including the buccal and lingual mucosa, the gingivae, the tongue, the tonsils, the soft and hard palate, the inner and outer part of the lips.

[0027] Infections or lesions of the oral mucosa as to be understood in this application also include infections or lesions of the soft tissue lining of the oral cavity, so also the lips, including the inner parts of the lips and the outer parts and also the edge and transition region of the lips to the facial skin.

[0028] According to a preferred embodiment, the oral mucosa is restricted to the mouth and the inner parts of the lips or even just the inner parts of the mouth without the lips.

[0029] According to the invention, the composition for such uses comprises or consists of the following components:

[0030] (a) polyhexanide (PHMB) or a salt thereof in a concentration in the range of 0.001- 0.2% w / v, preferably in the range of 0.005-0.1 % w / v;

[0031] (b) an organic or inorganic buffer (preferably glycine) different from a) with at least one pKs value in the range of 8.5-11 .5 in a concentration in the range of 0.01-1 M, preferably in the range of 0.05-0.2 M;

[0032] (c) further additives (different from (a), (b) and (d)) in a concentration in the range of 0-40% w / v or 0-30% w / v or preferably 0-20% w / v, or less than 10% w / v;

[0033] (d) optionally water; wherein preferably the pH value of the composition is in the range of 8 - 11.5, in particular in the range of 8.5 - 11.5 or preferably in the range of 8.5 - 10.5.

[0034] If the composition consists of the above components, the sum of (a)-(d) makes up 100% w / v.

[0035] Preferably, the formulation takes the form of an aqueous solution with a water content of at least 50% w / v, preferably of at least 70% w / v.

[0036] However, the composition can also be essentially free from water.

[0037] As for the w / v values of component (a), it is to be noted that the ranges given refer to the weight of the PHMB only, and if a PHMB salt is taken, the weight of the counter ion is not taken for the calculation of the w / v values of this component.

[0038] In fact, surprisingly these compositions, using assays as well as use with patients, showed a significant and lasting therapeutic effect for the above-mentioned infections or lesions of the mucosa, in particular of the oral mucosa, i.e. of corresponding oral mucosa infections or lesions which are in particular based on the above-mentioned origins. In particular, experimental and clinical evidence shows that there is a combined antimicrobial and antiviral and / or counter autoimmune deficiency effect provided by the proposed composition on mucosa, without impairing biocompatibility / tissue compatibility and / or inducing cytotoxicity, i.e. without negatively influencing the natural healing process. In fact, it was shown that the particular combination of using PHMB and in particular glycine as the organic or inorganic buffer provided this effect, for example when using the formulation as an aqueous tincture or rinsing solution / suspension or in the form of a gel locally applied to the corresponding infection / lesion of mucosa, so e.g. oral mucosa or to the whole mouth.

[0039] Polyhexanide is polyhexamethylene biguanide, which typically has a weight average molecular weight Mw in the range of 1000-4000 g / mol, or 1500-4000 g / mol, preferably in the range of 2000-2800 g / mol, or 2400-3000 g / mol.

[0040] Furthermore, the polyhexanide (PHMB) of component (a) typically has a polydispersity (PDI) in the range of 1.4-2.2, preferably in the range of 1.7-2.8.

[0041] Normally, the starting material for the preparation of the corresponding composition is a salt of polyhexanide, in particular polyhexamethylene biguanide hydrochloride, and the weight percent in terms of the total weight of polyhexamethylene biguanide hydrochloride.

[0042] Generally speaking, when giving percentages in w / v, this means the measure of weight of the corresponding substance in g per 100mL, and the unit is g / cm3which equals 1 kg / dm3which equals 1000 kg / m3. 1 % v / w thus corresponds to 1 g / 100mL which equals 0.01 g / cm3. Furthermore, the pKs values as given are in water under standard laboratory conditions, i.e. 20°C and 101 325 Pa.

[0043] Where pH values are given, they are typically measured using calibrated pH / conductometres, after calibration, under standard laboratory conditions for example using a device of the type 914 pH / Conductometer - Metrohm.

[0044] The water, if present in the composition, is typically nano pure water, i.e. water according to ASTM type I.

[0045] In fact, it was unexpectedly found as will be evidenced in the experimental section further below, that the preventive and therapeutic efficacy of polyhexanide can be greatly enhanced by adjusting the pH in the range as claimed and by stabilising it in that range by providing a corresponding buffer, preferably in the claimed concentration.

[0046] Without being bound to any scientific explanation, it seems based on the experimental evidence that this is not only a combination of an antibacterial and / or antiviral effect due to the high pH value and the polyhexanide activity, but the experimental evidence shows that there is a synergistic effect in the claimed concentration window for the polyhexanide, allowing, to achieve the preventive and treatment effect, a reduction of the concentration of the polyhexanide or, using the same concentration, to achieve a more pronounced effect. Preferably, the aqueous antimicrobial composition is free from alcohols, in particular free from ethanol, or comprises less than 10 % w / v or less than 5 % w / v or less than 2% w / v of alcohols, in particular of ethanol.

[0047] Alternatively and also preferably, the aqueous antimicrobial composition is free from linear or branched alkyl or arylalkyl monohydric alcohols with 1 - 9 or 1 - 6 carbon atoms (in particular free from methanol, ethanol, propanol, 1-phenyl-1 -propanol or a combination thereof) or 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 linear or branched alkyl or arylalkyl monohydric alcohols.

[0048] As defined above, the composition may consist of components (a)-(d). It may however also comprise further components, in particular according to a preferred embodiment it further comprises component (e), preferably in this case it then consists of components (a)-(e).

[0049] So according to a preferred embodiment, next to components (a) - (d) the composition further comprises the following component (preferably this component (e) is the only additional component, so the formulation consists of (a)-(e), further including the means to adapt the pH to the claimed value of in the range of 8 - 11.5, preferably in the form of NaOH): (e) at least one sugar alcohol having at least three carbon atoms.

[0050] Sugar alcohols (also called polyhydric alcohols, polyalcohols, alditols or glycitols) are to be understood as organic compounds, typically derived from sugars, containing one hydroxyl group (-OH) attached to each carbon atom. They are normally white, water-soluble solids that can occur naturally or can be produced industrially by hydrogenating sugars. Since they contain multiple -OH groups, they are classified as polyols. Sugar alcohols according to this disclosure are systems of this type having at least three carbon atoms, preferably 4-12 carbon atoms, particularly preferably 4-6 carbon atoms or exactly 6 carbon atoms. Sugar alcohols can be added to influence the taste and / or the viscosity of the composition and due to this effect may synergistically influence the efficacy of the other components, in particular of component (a) combined with (b).

[0051] Preferably the at least one sugar alcohol having at least three carbon atoms is present in the composition in a concentration of up to 75% w / v, preferably in a concentration of up to 70% w / v or in the range of 2-50% or 5-50% w / v or in the range of 3 - 40% or 10-40% w / v or 4-10% or 20-30%.

[0052] Preferably said 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, maltotetraitol, or a combination thereof. Correspondingly, according to a preferred embodiment, the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.002-0.15% w / v or 0.002-0.1% w / v, preferably in the range of 0.005-0.07% w / v or 0.005-0.05% w / v, in particular in the range of 0.007-0.03% w / v or 0.007-0.02% w / v or 0.007-0.015% w / v. A particularly high synergistic effect of the high pH value and of the polyhexanide presence can be achieved if the concentration of the pH and B is in the range of 0.01% w / v using polyhexanide hydrochloride as starting material.

[0053] Preferably, the organic or inorganic buffer of component (b) is selected from the following systems:

[0054] • amino acid, in particular selected from the group consisting of alanine, glycine, asparagine, isoleucine, leucine, serine, threonine, valine, or a combination thereof, in particular glycine;

[0055] • bicarbonate buffer, in particular selected from the group consisting of: carbonate bicarbonate buffer, triethyl ammonium bicarbonate buffer;

[0056] • borate buffer, in particular sodium borate buffer;

[0057] • (acetic acid) ethanolamine buffer; or a combination or mixture thereof.

[0058] With particular preference the organic or inorganic buffer of component (b) is selected from the group consisting of short-chain amino acids having no side-chain leading to a pKs value and having a pKs value in the claimed range, preferably glycine, alanine, valine, leucine, isoleucine, or a combination or mixture thereof.

[0059] Particularly preferably the buffer is selected as a glycine buffer, in particular in a concentration in the range of 0.05-0.2 M. It seems that range is just sufficient to stabilise the pH in the desired range and to optimally cooperate with the other components in the composition.

[0060] Generally speaking, preferably 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.

[0061] Also generally speaking, the concentration of the organic or inorganic buffer of component (b) in the composition is in the range of 0.05-0.8 M, preferably in the range of 0.08-0.5 M, in particular in the range of 0.1-0.2 M.

[0062] The pH value of the buffer of component (b) or rather of the whole composition is, if needed, adapted to the claimed pH value in the range of 8 - 11.5 preferably by adding a preferably strong, preferably inorganic base, said base preferably being selected from the group consisting of NaOH, KOH, Ca(OH)2, NaCIO, KCIO, or a combination thereof. Typically, the concentration of that base in the composition is in the range of 0.001-0.07 M or 0.04-0.06 M or in the range of 0.045 M - 0.055 M, so in particular around 0.05 M. Using Ca(OH)2 has the benefit of acting as a pH adjustment means as well as a calcium source.

[0063] Preferably the buffer (b) is glycine at a concentration in the range of 0.05-0.2 M adjusted in pH with an alkali metal hydroxide, in particular selected as NaOH, KOH or a mixture thereof, at a concentration in the range of 0.04-0.06 M.

[0064] The composition is preferably antimicrobial and antiviral.

[0065] The composition preferably takes the form of an aqueous suspension or solution, a gel, a foam, a tincture, a tablet, in particular coated tablet, a paste, a chewing gum, a stripe or plaster.

[0066] Water of component (d) is normally at least 2% w / v (e.g. for solid forms), or at least 40% w / v or at least 80% w / v (for gel forms), or at least 90% w / v or 95% w / v.

[0067] It is further preferred that as component (c) the additives are selected from the group: poloxamer, polyethylene glycol, flavouring agents, colouring agents, sugar alcohol, calcium donor or derivatives or combinations thereof, in a concentration in the range of 0-10 % w / v. Particularly preferred is a composition, wherein the additives of component (c) are selected as

[0068] 1-3 % w / v poloxamer, preferably poloxamer having the structure EOn-POm-EOn, wherein n is in the range of 80-120 and m is in the range of 50-60 (e.g. poloxamer 407, in which the approximate lengths of the two PEG blocks is 101 repeat units, while the approximate length of the propylene glycol block is 56 repeat units),

[0069] 1-3 % w / v polyethylene glycol and / or ethoxylated vegetable oil, in particular both, with ethoxylated castor oil preferably being used (e.g. PEG-40 and / or PEG-800, preferably PEG- 800 only),

[0070] 0.1 -0.4% w / v flavouring substances, preferably selected as flavouring oil

[0071] 2-10% w / v sugar alcohol, preferably xylitol and / or glycerol,

[0072] 0.0-0.05% w / v or 0.01-0.05% w / v calcium donor, preferably the composition having a pH in the range of 9.5-10.

[0073] As pointed out above, the composition may comprise additives / auxiliaries different from the components (a) and (b) or (a) - (e), in particular 0.01-1 % w / v, preferably 0.1-3% w / v (Pro- )0.01 -1 %, preferably 0.1-3% (Pro-)Vitamins such as panthenol.

[0074] One preferred formulation has the following composition (in each case w / v):

[0075] Water: >70 %; NaOH or KOH: 0.15-0.25 % (pH = 8-11.5, preferably 8-10); Glycerol: 0.5-3 %; Poloxamer (preferably Poloxamer 407): 1-3%; Glycine: 0.7 - 0.8 % (approx. 0.1 M); PHMB (Polyhexanide, preferably with Mw in the range of 2000-3000 g / mol): 0.01-0.1 %; Xylitol: 2-5 %; PEG (preferably PEG-800 and / or PEG-40, preferably PEG-800 only): 1-2%; aroma substances 0.1 -0.4%.

[0076] These additives of component (c) can be selected from the group consisting of: surfactants, anti-corrosion agents, taste modifiers (different from the above mentioned sugar alcohols), perfumes, dyes, stabilisers, thickeners (different from the above mentioned sugar alcohols), complexing agents, organic solvents, in particular alcohols (different from the above mentioned sugar alcohols), further disinfectants, preservatives, taste modifiers (different from the above mentioned sugar alcohols), thickeners (different from the above mentioned sugar alcohols), compatibilizers, phytopharmaca, vitamins, including provitamins, or mixtures or combinations thereof.

[0077] Examples for taste modifiers (different from the above-mentioned sugar alcohols) are one or a combination of: natural or synthetic fragrances, essential oils, tannic acid, menthol, sodium cyclamate, fructose, galactose, thymol. Taste modifiers (different from the above- mentioned sugar alcohols) are typically in a concentration in the range of 0.01-10 % w / v, preferably in the range 0.1-5%, with respect to the aqueous antimicrobial composition.

[0078] Examples for thickeners (different from the above-mentioned sugar alcohols) are one or a combination of: gelatin, polyethylene glycol, e.g. polyethylene glycol 1000, polyvinyl alcohol, silicon dioxide, starch, poloxamer (e.g. 188, 407), carrageenan, PVA, cellulose including HPMC, CMC, (corn) starch, gum Arabic, gellan gum, but also polymers based on vinylpyrrolidone and vinylacetate (e.g. acetic acid ethenyl ester, polymer with 1-ethenyl-2- pyrrolidinon such as poly(1-vinylpyrrolidone-co-vinyl acetate, in particular with a molecular weight Mw in the range of 30'000-70'000 or 40'000-50'000). Thickeners (different from the above-mentioned sugar alcohols) are typically in a concentration in the range of 1 - 30% w / v or 1-20 % w / v with respect to the aqueous antimicrobial composition.

[0079] The surfactants can be ionic, non-ionic or amphoteric surfactants.

[0080] Anionic surfactants of these additives are in particular selected from alkyl sulfates, alkyl ether sulfates, alkyl sulphonates, alkylbenzyl sulfonates, a-olefin-sulphonates, alkylamide sulphonates, alkarylpolyether sulphates, alkylamidoether sulfates, alkyl monoglyceryl ether sulfates, alkyl monoglyceride sulfates, alkyl monoglyceride sulfonates, alkyl succinates, alkyl sulfosuccinates, alkyl ether sulfosuccinates, alkyl sulfosuccinamates, alkyl amidosulfosuccinates; alkyl sulfoacetates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alkyl amidoethercarboxylates, acyl lactylates, alkyl isethionates, acyl isethionates, carboxylate salts and amino acid derived surfactants such as N-alkyl amino acids, N-acyl amino acids, alkyl peptides, and mixtures thereof.

[0081] Amphoteric surfactants of these additives can in particular be selected from alkyl betaines; alkylamido betaines; alkylamido sultaines; alkyl mono- and di-amphocarboxylates; amine oxides; and mixtures thereof.

[0082] Nonionic surfactants of these additives for example can be selected from ethoxylated fatty alcohols, ethoxylated alkylphenols, ethoxylated Guerbet alcohols, ethoxylated vegetal oils (e.g. ethoxylated castor oil, e.g. of the PEG-40 type, such compounds may e.g. help dissolving further components), polypropylene glycol, polyethylene glycol, block copolymers of propylene glycol and / or ethylene glycol, ethoxylated sorbitan esters, sorbitan esters, alkyl polyglucosides, alkyl glucamides, and mixtures thereof.

[0083] Vitamins can be vitamin A, vitamin B, vitamin C, provitamins, in particular panthenol, in particular panthenol in a concentration in the range of 0.1-5 %w / v.

[0084] Further additives can be film-formers, emulgators (such as coco-gluconate), foaming agents, resins, tannic acid.

[0085] The concentration of the surfactants of component (c) can be zero or more than zero and in the range of less than 15 % w / v or less than 10 % w / v or less than 5% w / v with respect to the total composition.

[0086] The concentration of the additives of component (c) can be in the range up to 30% w / v or up to 20% w / v of less than 15 % w / v or less than 10 % w / v or less than 5% w / v.

[0087] For solid forms of the composition (e.g. a coated tablet), where there is no water or less than 5% w / v water, as a separate invention, the proportion of (a) is as given above, the additives of component (c) can be up to 99% w / v or up to 95% w / v, and in this case the additives may also be fillers, and formulation agents. In this case the amount of component (b) is typically in the range of 0.025 - 3% w / v or of 0.05 - 2% w / v.

[0088] As for the dyes of component (c) these typically are present in the composition in a concentration of less than 0.2% w / v, preferably in the range of less than 0.1% w / v, particularly preferably in the range of 0.001-0.05% w / v with respect to the total composition. Further preferably, additives other than thickeners (different from the above mentioned sugar alcohols) and taste modifiers (different from the above mentioned sugar alcohols) are in the range of less than 0.2% w / v, preferably in the range of less than 0.1% w / v, particularly preferably in the range of 0.001-0.05% w / v, this for example in combination with a proportion of thickeners (different from the above mentioned sugar alcohols) in the range of 1-19.8% w / v with respect to the total composition.

[0089] For some applications it is preferred if there are no additives, so the additive content is essentially 0.0 w / v with respect to the total composition.

[0090] According to another preferred embodiment of the proposed composition, the composition has a calcium content as an additional component or as part of component (c) in the range of 1-5 mmol / L, preferably 2-3 mmol / L, which is the total, and the calcium can be in ionic form or in ionic bound form (in particular bound on albumin).

[0091] Typically, the Ca2+is introduced into the composition as CaCh, Ca citrate, Ca(OH)2, Ca lactate, calcium carbonate or Ca phosphate or combinations thereof.

[0092] As pointed out above, one important characteristic of the composition is the pH value which is adapted to the higher pKs of the polyhexanide system, which is in the range of 12. The pH value of the composition should be below that value.

[0093] According to a preferred embodiment, the composition contains water and has a pH value in the range of 8-11 , preferably in the range of 8.5-10.5, in particular in the range of 9.5-10. an optimum effect is achieved if the pH is somewhere around 9.8.

[0094] According to a particularly preferred embodiment the composition consists of (a) - (d) or (a) - (e), the polyhexanide (PHMB) of component (a) has a weight average molecular weight Mw in the range of 2400-3000 g / mol, the polyhexanide (PHMB) of component (a) takes the form of polyhexamethylene biguanide hydrochloride, and the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.007-0.015% w / v. Furthermore, the organic or inorganic buffer of component (b) is selected as glycine in a concentration of the organic or inorganic buffer of component (b) in the composition in the range of 0.1-0.2 M, and the concentration of the further additives of component(c) is less than 0.01% w / v, preferably in the range of 0.001-0.01% w / v.

[0095] Therapeutic uses of such a composition are preferably for the treatment or prevention of at least one of viral, fungal or autoimmune infection or at least one of viral, fungal or colonisation or both.

[0096] In particular the proposed composition is for the treatment and / or prevention of herpes simplex, aphthoid lesions or at least one of oral lichen planus and lichen ruber planus, or combinations thereof.

[0097] Therapeutic uses as described can be for the treatment of humans or animals, and can be preventive uses or curative uses.

[0098] Treatment can be by spraying, dripping, use of applicators such as brushes.

[0099] It is noted that the above composition can also be used for the treatment of at least one the following indications or uses, which are not necessarily affecting the oral mucosa, but preferably the mucosa in the broad sense as defined above and in particular using solid, semi-solid, liquid or other form, including e.g. for topical application, rinsing, as a chewing gum, or ingestion (e.g. in the form of a coated tablet or solution / suspension): herpes (such as blisters in the face e.g. lip); dental root canal treatment; pH value regulation (such as mouth, stomach, such as support for oral hygiene such as support for removing stubborn deposits, e.g. children's oral hygiene, caries prophylaxis); antiseptic tamponade and drainage of body cavities, fistulas and wound pockets after surgical infection treatment, aligner and denture cleaning; cleaning of orthodontic corrections (braces), disinfection of gingival / periodontal pockets, disinfection of peri-implant lesions, treatment of burnings, in particular of 2ndor 3rddegree burnings (preferably formulated in gel form for such applications). Further embodiments of the invention are laid down in the dependent claims.

[0100] BRIEF DESCRIPTION OF THE DRAWINGS

[0101] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0102] Fig. 1 shows results of early in vitro biofilm model set tests of the synergistic antimicrobial effect of testing reagents in alkaline buffers for low PHMB concentrations;

[0103] Fig. 2 shows results of early in vitro biofilm model set tests of the synergistic antimicrobial effect of testing reagents in alkaline buffers for medium PHMB concentrations;

[0104] Fig. 3 shows results of early in vitro biofilm model set tests of the synergistic antimicrobial effect of testing reagents in alkaline buffers for higher PHMB concentrations;

[0105] Fig. 4 in a) shows results of denser and older biofilm model tests of the synergistic antimicrobial effect of testing reagents in alkaline buffers for higher PHMB concentrations, and in b) shows the behaviour of Streptococcus sanguinis cultured in either neutral PBS (pH 7.2) or in alkaline T. buffer (pH 9.7) or in alkaline T. buffer spiked with 0.015% PHMB;

[0106] Fig. 5 shows the results of the biocompatibility tests of the different alkaline buffers;

[0107] Fig. 6 shows the results of the biocompatibility tests of PHMB and CHX for different concentrations;

[0108] Fig. 7 shows the cell viability of human primary cells after the treatment with various antiseptics at concentrations as used in products that are currently on the market;

[0109] Fig. 8 shows the effect of the additive ethanol at 10, 20 and 50% on the cell vitality of human primary cells;

[0110] Fig. 9 shows the cell viability of human gingival fibroblasts at day 1 after treatment;

[0111] Fig.10 shows the cell viability of human gingival fibroblasts at day 7 after treatment;

[0112] Fig. 11 shows the release of IL-6 of human gingival fibroblasts at day 1 after treatment;

[0113] Fig. 12 shows the release of IL-6 of human gingival fibroblasts at day 7 after treatment;

[0114] Fig. 13 shows the release of IL-6 of human gingival fibroblasts at day 1 after treatment and stimulation with Poly IC (HMW, 100 pg / ml);

[0115] Fig. 14 shows the release of IL-6 of human gingival fibroblasts at day 1 after treatment and stimulation with Poly IC (HMW, 10 pg / ml); Fig. 15 shows the release of IL-10 of human gingival fibroblasts at day 1 after treatment and stimulation with Poly IC (HMW, 10 pg / ml);

[0116] Fig. 16 shows the antiplaque assay of HSV-1 virus after the treatment with sample 1 (alkaline buffer without polyhexanide); note: "+" indicates that the number of plaques is too high to count accurately, while "0" indicates no plaques; the number of plaques in the sample group is significantly lower than that in the control group, showing that both sample 1 and sample 2 have an inhibitory effect on the HSV-1 virus;

[0117] Fig. 17 shows the antiplaque assay of HSV-1 virus after the treatment with sample 1 (alkaline buffer with polyhexanide at a concentration of 0.025%); note: "+" indicates that the number of plaques is too high to count accurately, while "0" indicates no plaques; the number of plaques in the sample group is significantly lower than that in the control group, showing that both sample 1 and sample 2 have an inhibitory effect on the HSV-1 virus;

[0118] Fig. 18 shows a patient with aphthousulcer; the left picture shows the clinical situation before treatment, the right picture shows the clinical situation after one week of treatment with alkaline buffer containing polyhexanide; patient reported after 2 days of treatment to be pain-free.

[0119] DESCRIPTION OF PREFERRED EMBODIMENTS

[0120] Preparation of testing reagents:

[0121] As testing reagents, different Chlorhexidine and Polyhexamethylene biguanide hydrochloride (PHMB) solutions were prepared with varying concentrations and buffers. Chlorhexidine-digluconate solution (CHX, 20 % w / v in water, CAS 18472-51-0) was purchased from Sigma-Aldrich, Switzerland (article number C9394). Glycine was purchased as solid substance from Honeywell Fluka, Switzerland (CAS: 56-40-6). Polyhexamethylene biguanide hydrochloride was purchased as solid substance from Biosynth, UK (article number FP76704, lot number: B20V06202). As stock solution, a 10% (by weight per volume) PHMB solution in water was prepared. All of the PHMB testing reagents were prepared based on the 10% stock solution.

[0122] Buffers, according to Table 1 below, were prepared using a 0.05M NaOH solution and adding solid Glycine in an amount to lead to the Glycine concentration as indicated, pH given as measured with a pH electrode (914 pH / Conductometer Metrohm, 3 point calibration).

[0123] Table 1: Solutions and Buffers as used (all concentrations are given for the final composition)

[0124] Polyhexanide (polyhexamethylene biguanide hydrochloride, PHMB, CAS Number 28757- 47-3, also 32289-58-0) testing reagents were prepared from 10% PHMB stock solution in ultrapure water (weight per volume, ASTM Type 1 as provided by a Sartorius Arium Pro Water System, e.g. ultrapure according to ASTM D1193-06(2018)) and using the solutions and buffers as given in Table 1 and tested in different experiments according to Table 2 below. Table 2: PHMB solutions as used in experiments (all concentrations are given for the final composition)

[0125] CHX testing reagents were prepared from a liquid 20% CHX stock solution in ultrapure water and using the solutions and buffers as given in Table 1 and tested in different experiments according to Table 3 below.

[0126] Table 3: CHX solutions as used in experiments (all concentrations are given for the final composition)

[0127] Moreover, a 0.9 % NaCI solution (weight per volume) in ultrapure water was used as state of the art rinsing solution.

[0128] Apart from the above-mentioned solutions used in the in vitro experiments reported further below, the following final formulation in Table 3a for in vivo use was prepared and found to be stable and efficacious: Table 3a: PH MB solution as used for in vivo testing (pH = 9.8 as measured)

[0129] Another formulation for in vivo use was prepared and found to be stable and efficacious and is given in Table 3b below.

[0130] Table 3b: PH MB solution as used for in vivo testing (pH = 9.8 as measured)

[0131] Determination of the antimicrobial effect of various testing reagents in an in vitro biofilm model:

[0132] In order to test the antimicrobial effect of various testing reagents, the oral strain Streptococcus sanguinis, purchased from ATCC, was used. All experiments started 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 with PBS to reach an optical density of 0.5, which is eguivalent to 108CFU / ml. For the antimicrobial experiments, a start inoculum of 103CFU / ml in BHI medium was used.

[0133] To model the early biofilm formation after setting of a dental implant, round shaped titanium discs (diameter of 16 mm, provided by Thommen Medical AG) were cleaned, heat- autoclaved and placed into a 24 well plate.

[0134] In a next step, these titan discs were pre-conditioned with the testing reagents or BHI medium 10.9 % NaCI (control group).

[0135] The conditioned titanium discs were afterwards incubated with 1 ml / well of bacterial suspension (103CFU / ml) in BHI medium.

[0136] After 24 hours, the BHI medium was removed and the titanium discs were washed with the testing reagents for 10 minutes at 37°C and 70 rpm.

[0137] To guantify the biofilm mass on the titanium discs, a crystal violet staining was performed. To this end, the testing reagents were removed with a pipette and 300 p / well of crystal violet solution (0.1 % in ultrapure water, purchased from Sigma-Aldrich Switzerland) were added and incubated for 10 minutes at room temperature.

[0138] After the incubation time, titanium discs were washed four times with distilled water (600 pl / well) and transferred to a new 24 well plate. In order to liberate the crystal violet stain from titan discs, 1 ml / well of acetic acid (33%) was added and incubated for 5 minutes at room temperature and 70 rpm. Duplicates of 100 pl respectively were transferred from every well to a new 96 well plate and the absorbance at 590 nm was measured, using a BioT ek Epoch2 microplate reader.

[0139] In order to evaluate the antimicrobial effect of the testing reagents not only on the early biofilm formation but also on an older and denser biofilm, a similar experiment as described in the upper section was repeated using a start inoculum of 106CFU / ml and an incubation time of 72 hours.

[0140] To study the effect of alkaline pH on bacterial growth, a bacterial suspension of S. sanguinis with an optical density (600 nm) of 0.2 has been prepared either in PBS medium with a pH of 7.2 or in T. buffer (0.05M NaOH / 0.1 M glycine, 0.03% CaCI2) with a pH of 9.7 ± addition of 0.015% PHMB. Next, 100 pl of the bacterial suspension was transferred to a 96 well plate and placed into a preheated (37°C) Biotek reader. The optical density at 600 nm has been measured in 2h intervals over 24 hours in order to assess bacterial behaviour in variable buffers.

[0141] Cell culture and cytocompatibility tests of testing reagents and alkaline buffers:

[0142] Mouse fibroblasts (L929 cell line) were used in this study as recommended cell line for cytotoxicity testing in accordance with EN ISO 10993-5.

[0143] The fibroblasts were purchased from ATCC and cultured in Dulbecco’s Modified Eagle Medium-high glucose, supplemented with 10% fetal bovine serum and 1 % penicillinstreptomycin (Sigma-Aldrich, Switzerland) in T75 flasks at 37°C and 5% CO2. For the performance of the cytotoxicity experiments, L929 cells were seeded onto 96-well cell culture plates, 100 p / well, at a density of 1x106cells / mL to reach about 80% confluence after 24 hours. At the next day, 100 pl of fresh medium spiked with varying concentrations (0.001 , 0.005, 0.01 , 0.05 and 0.1 %) of CHX or PHMB were added.

[0144] As a control, cells were incubated with fresh medium without antiseptic agent.

[0145] Six replicate wells per concentration were tested.

[0146] After 60 minutes of incubation at 37°, the medium was removed and the wells were washed once with 100 pl of the fresh medium.

[0147] Thereafter, cells were incubated with 100 pL of the fresh medium containing 0.015 mg / ml AlamarBlue dye, for 2 hours at 37°C.

[0148] Finally, 100 pL of the media were 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).

[0149] In order to test the cytocompatibility of alkaline buffers, a similar experiment was performed. However, the alkaline buffers were incubated for 10 minutes instead of 60 minutes.

[0150] The following alkaline buffers were tested: a) 0.025 M NaOH, 0.025 M NaOH I 0.05 M glycine, 0.025 M NaOH I 0.05 M glycine / 0.03% CaCh (weight per volume in the final composition); b) 0.05 M NaOH, 0.05 M NaOH 10.05 M glycine, 0.05 M NaOH 10.05 M glycine / 0.03% CaCh (weight per volume in the final composition); c) 0.1 M NaOH, 0.05 M NaOH I 0.1 M glycine, 0.05 M NaOH I 0.1 M glycine / 0.03% CaCh (weight per volume in the final composition); d) 0.05 M NaOH / 0.1 M glycine; e) 0.05 M NaOH / 0.1 M glycine I 0.03% CaCh (weight per volume in the final composition).

[0151] Human primary cells and the effect of antiseptic substances and ethanol on cell vitality:

[0152] Human periodontal ligament fibroblasts (HPDLF) were used in this study as test system, imitating closer the in vivo situation. The fibroblasts were purchased from ATCC and cultured in ScienCell FM medium, supplemented with 2% fetal bovine serum, 1% fibroblast growth factor and 1 % penicillin-streptomycin (Sigma-Aldrich, Switzerland) in T75 flasks at 37°C and 5% CO2.

[0153] To study the effect of antiseptic substances, at concentrations that are currently used in marketed products, the vitality of HPDLF cells was assessed. For this purpose, cells were seeded onto 24-well cell culture plates, 1 ml / well, at a density of 3x104cells / mL to reach about 80% confluence after 48 hours. At a next step, 300 pl T. buffer (0.05M NaOH / 0.1 M glycine, 0.03% CaCh) spiked with varying concentrations (0.06 and 0.12 %) of CHX or (0.015, 0.025, 0.05 and 0.15%) PHMB were added. As a control, cells were incubated with T. buffer without antiseptic agent. Three replicate wells per concentration were tested. After 1 minute of incubation at 37°, the supernatant was removed and the wells were washed once with 600 pl of the fresh medium. Thereafter, cells were incubated with 600 pL of the fresh medium containing 0.015 mg / ml AlamarBlue dye, for 4 hours at 37°C. Finally, 100 pL of the medium were 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).

[0154] To evaluate the effect of ethanol on cell vitality, HPDLF cells were seeded onto 96-well cell culture plates, 100 p / well, at a density of 6x103 cells / mL to reach about 80% confluence after 24 hours. At the next day, 100 pl of fresh medium spiked with varying concentrations (10, 20 and 50 %) of ethanol were added. Additionally, the developed T. buffer was spiked with 10, 20 and 50% ethanol. As a control, cells were incubated with fresh medium without ethanol. Three replicate wells per concentration were tested. After 5 minutes of incubation at 37°, the medium was removed and the wells were washed once with 100 pl of the fresh medium. Thereafter, cells were incubated with 100 pL of the fresh medium containing 0.015 mg / ml AlamarBlue dye, for 2 hours at 37°C. Finally, 100 pL of the medium were 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).

[0155] Human primary cells and the effect of buffer additives on cell viability and interleukin-6 release:

[0156] Human gingival fibroblast (HuGF) cells were used in this study as test system, imitating closer the in vivo situation. The fibroblasts were purchased from ScienCell (Cat.2620) and cultured in DM EM - high glucose medium (Sigma-Aldrich, Switzerland), supplemented with 10% FBS, and 1 % penicillin-streptomycin (P / S, Sigma-Aldrich, Switzerland) in T75 flasks at 37°C and 5% CO2.

[0157] To study the effect of (buffer) additives and constituents such as glycine, dexpanthenol and polyhexanide, cell viability has been measured over 7 days as indirect measure of cellular growth. For this purpose, cells were seeded onto 48-well cell culture plates, 300 pl / well, at a density of 3x104cells / mL to reach about 80% confluence after 24 hours. The next day, medium was changed to DM EM high glucose 0.5% FBS and 1% P / S spiked with either glycine in (10 mM), polyhexanide at low concentration (0.0001 %) or dexpanthenol (0.1 %), or with the cocktail of all three additives (which means glycine (10 mM), polyhexanide (0.0001 %), with or without dexpanthenol (0.1 %) depending on the experiment as indicated). It was decided to use a 20-fold lower concentration of the buffer additives and constituents for the in vitro studies, since the substances are in direct contact with the target cells in vitro and do not have to overcome any pharmacokinetic barriers such as tissue. In addition, there is no further distribution, metabolism, or dilution in vitro. In vivo, the substances are distributed and diluted by saliva and tissue volume. In contrast, the medium volume in vitro is small and localized, which requires an adjustment of the concentration. Therefore, the following concentrations have been used for the experiments: polyhexanide with 0.0001 %, dexpanthenol with 0.1 % and glycine in the range of 1 mM to 100 mM. As a control, cells were incubated with DM EM high glucose medium with 0.5% FBS and 1% P / S. Three replicate wells per condition were tested. After 1 day and 7 days of incubation at 37°, the supernatant was removed and the cells were incubated with 300 pL of the fresh medium containing 0.015 mg / ml AlamarBlue dye, for 2 hours at 37°C. Finally, 100 pL of the medium were 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).

[0158] To evaluate the effect of (buffer) additives and constituents (glycine, polyhexanide and dexpanthenol) on the release of lnterleukin-6, HuGF cells were seeded onto 48-well cell culture plates, 300 p / well in DM EM high glucose medium with 10% FBS and 1 % P / S, at a density of 6x103 cells / mL to reach about 80% confluence after 24 hours. On the next day, 300 pl of fresh medium (DMEM high glucose, 0.5% FBS, 1 % P / S) spiked with varying concentrations of glycine (1 mM, 2 mM, 10 mM, 20 mM or 100 mM, depending on the experiment), or polyhexanide (0.0001%), or dexpanthenol (0.1%), or with a mixture of polyhexanide (0.0001 %) and glycine (10 mM), designated as G10 / P, or with the cocktail of all three additives (the cocktail being defined as a solution containing polyhexanide (0.0001 %), dexpanthenol (0.1%) and glycine (10 mM); note in Fig. 9-12 the cocktail does not contain dexpanthenol, in Fig. 13, 14 and 16 it further contains dexpanthenol) were added to the cells. As a control, cells were incubated with fresh medium without additives. For cell stimulation, Poly IC HMW (TLR3 agonist purchased from InvivoGen, Switzerland) has been added to the HuGF cells at a concentration of 10 pg / ml or 100 pg / ml, depending on the experiment. Three replicate wells per condition were tested. After 1 day of incubation at 37°, the supernatant was collected and analyzed for interleukin-6 release using a human lnterleukin-6 ELISA Kit purchased from Abeam, UK.

[0159] Proof of antiviral efficacy using a plaque reduction assay:

[0160] Cell preparation: Suspended Vero cells (from ATCC) were cultured in DMEM medium (BioChannel) supplemented with 10 % FBS (Bio-Channel). The cells were seeded in a 12-well plate and incubated at 37 °C in a 5 % CO2atmosphere until reaching approximately 90 % confluence.

[0161] Virus Dilution:

[0162] Herpes simplex virus type 1 was diluted from the stock solution as follows:

[0163] Sample #1: 10,000 TCI D50

[0164] Sample #2: 20,000 TCIDso

[0165] Sample Incubation:

[0166] According to the publication from Manato Seguchi et al (Viruses 2024, 16(10), 1636; https: / / doi.org / 10.3390 / v16101636), 450 pL of the sample solutions were mixed with 50 pL of the corresponding diluted virus solution. The mixtures were thoroughly mixed and incubated at room temperature for 1 minute.

[0167] Simultaneously, 450 pL of 2 % FBS-supplemented DMEM was mixed with 50 pL of the corresponding virus dilution to serve as the virus control group. This control mixture was also incubated at room temperature for 1 minute.

[0168] The final concentrations of the samples were as follows:

[0169] • Sample #1 : 0.045 M sodium hydroxide, 0.031 M glycine, 0.54 % dexpanthenol, final pH of 10.2

[0170] • Sample #2: 0.045 M sodium hydroxide, 0.031 M glycine, 0.54 % dexpanthenol, 0.0225 % polyhexanide, final pH of 10.2

[0171] After the sample incubation a serial dilution of the mixtures and controls were done to determined concentrations.

[0172] • Sample #1 : 3-fold dilution of the virus-incubated mixture

[0173] • Sample #2: 81 -fold dilution of the virus-incubated mixture Infection:

[0174] The wells of the 12-well plate were rinsed with phosphate-buffered saline (PBS; Merck). Then, 350 pL of each diluted mixture or control was added to the wells. The plates were incubated at 37 °C for 2 hours with periodic shaking.

[0175] Agarose Overlay, Fixation, Staining, and Plaque Counting:

[0176] After the infection, an agarose overlay (Merck) was prepared and added to each well. After solidification at 4 °C, the plates were incubated at 37 °C for at least 48 hours. The cells were then fixed with 4 % paraformaldehyde (Merck), stained with crystal violet (MACKLIN), and rinsed. Clear plaques with a diameter > 1 mm were counted.

[0177] Results and discussion

[0178] Furthermore, using assays as well as use with patients, the formulation as an (oral) rinsing solution showed a significant and lasting therapeutic and / or preventive effect for the above- mentioned infections or lesions of the oral mucosa or more generally the mucosa as defined above, including freed tissue after 2ndor 3rddegree burnings, i.e. of corresponding oral mucosa infections or lesions which in particular are based on the above-mentioned origins. In particular, experimental and clinical evidence showed that there is a combined antimicrobial and antiviral and / or anti- or pro-inflammatory effect and / or counter autoimmune deficiency effect provided by the proposed composition, without impairing biocompatibility, i.e. without negatively influencing the natural healing process, by contrast positively enhancing the natural healing process.

[0179] In fact, it was shown clinically that the particular combination of using PHMB and glycine as the organic or inorganic buffer, preferably combined with dexpanthenol, in the claimed concentrations, provided this effect, when using the formulation e.g. as an aqueous tincture or rinsing solution / suspension or in the form of a spray or gel locally applied to the corresponding infection / lesion of the mucosa or to the whole mouth.

[0180] Compatibility of testing reagents in alkaline buffers:

[0181] Polyhexamethylene biguanide hydrochloride (Polyhexanide, PHMB) is a chemical biocide. There are six different PHMB product types identified, possessing combinations of amine, guanidine and cyanoguanidine end-groups.

[0182] The therapeutic activity of PHMB depends on the molecular structure.

[0183] Minimum requirements are met by more than 2 biguanide moieties and 5-7 methylene groups as a spacer.

[0184] The biguanide moieties of PHMB are strong bases and monoprotonated at a pH value of 7 (pKa1 < 2-3; pKa2 < 10.5-11.5) resulting in a polycation with a positive charge at each biguanide moiety.

[0185] The positively charged moieties are believed bind to the negatively charged phosphate head groups of phospholipids at bacteria cell walls, leading to increased fluidity, permeability and loss of integrity, followed by the death of the organism.

[0186] PHMB can be seen as virtually detoxified CHX, as the molecular structure of PHMB monomers closely resembles the structure of CHX molecules, except for the terminal NH- group of CHX consisting of 4-chloroaniline (4-CA). Similar to PHMB, the biguanide moiety of CHX with a pKa < 10.8 makes it to a strong base.

[0187] In general, inorganic bases as sodium hydroxide lead to a precipitation of PHMB and CHX in case of pH > pka value, for example for 0.05 M NaOH with a pH of 12.7.

[0188] Sodium hydroxide on the other hand is known to induce an alkaline saponification reaction with the phospholipid membrane of bacteria, causing a disruption of the membrane and finally cell death.

[0189] Surprisingly, there is a synergistic effect of PHMB and sodium hydroxide, leading to a therapeutic / preventive effect and / or allowing for a reduced active concentration for achieving the same effect.

[0190] To implement this in practice, however also further a buffer has to be formulated that prevents the precipitation of PHMB but still allows sufficient hydroxyl ion availability to achieve an alkaline saponification.

[0191] Therefore, different buffer compositions were tested for the precipitation of PHMB and CHX, as given in Table 1.

[0192] The results of these precipitation tests were as follows (precipitation determined by visual inspection / visible clouding, pH as measured):

[0193] 0.05 M NaOH I 0.05 M glycine I CHX 0.06 %, pH 11 .06 : Precipitation

[0194] 0.05 M NaOH / 0.1 M glycine I CHX 0.06 %, pH 9.9: No precipitation

[0195] 0.05 M NaOH PHMB 0.05 %, pH 12.51 : Precipitation

[0196] 0.05 M NaOH I 0.05 M glycine I PHMB 0.05 %, pH 11 .06: No precipitation

[0197] 0.05 M NaOH / 0.1 M glycine I PHMB 0.05 %, pH 9.9: No precipitation.

[0198] The concentrations of 0.06 % and 0.12 % w / v CHX were based on standard care mouth rinse solutions, and 0.05% PHMB was based on wound rinsing solutions with concentrations in the range of 0.04 % w / v.

[0199] Based on the pKa value of 10.8 for the strongest base within the CHX molecule, precipitation occurs using a 0.05 M NaOH / 0.05 M glycine buffer with a pH of 11.2 (pH > pKa).

[0200] By increasing the glycine concentration to 0.1 M and thus decreasing the pH, no precipitation of CHX occurs.

[0201] In contrast to CHX, the pKa value of the strongest base within the PHMB molecule is in the range of 10.5-11.5. Thus, no precipitation of PHMB was observed using a 0.05M NaOH / 0.05 M glycine buffer (pH 11.06). However, a 0.05 M NaOH solution (pH 12.5) without the addition of glycine induces also precipitation of PHMB.

[0202] Therefore, it can be concluded that for PHMB and glycine a minimum of 0.05 M glycine is appropriate. As the pH of 11.06 for a 0.05 M NaOH / 0.05 M glycine is close to the pKa value of the strongest base of PHMB, for some applications it is advisable to use a 0.05 M NaOH solution spiked with 0.1 M glycine, so a solution having a pH in the range around or below 10.

[0203] Synergistic therapeutic / preventive effect of testing reagents in alkaline buffers:

[0204] In a study of Ojan Assadian et al.2011 (Assadian O, Wehse K, Hubner 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 )), a minimal inhibitory concentration (MIC) in the range of 1-2 pg / ml (0.002 % w / v) was reported for Streptococcus aureus and Escherichia coli treated with PHMB solutions.

[0205] To detect a possible synergistic effect of PHMB and an alkaline buffer, an early biofilm of Streptococcus sanguinis was cultured on titan discs for 24 hours, before the discs were rinsed with different PHMB solutions, containing 0.002% PHMB similar to the reported MIC. As a control, the biofilm was cultured in BHI medium.

[0206] The PHMB solution (0.002% in nanopure water) did not lead to a reduced bacterial amount, suggesting that 0.0002 % is below the MIC for Streptococcus sanguinis in this assay.

[0207] However, if PHMB (0.002% was prepared with 0.05 M NaOH / 0.05 M glycine buffer with a pH of 11.06, a significant reduction in absorbance and thus in bacterial amount was observed.

[0208] Similar results are obtained for PHMB (0.002%) prepared with a 0.05 M NaOH / 0.2 M glycine buffer with pH of 9.27.

[0209] In contrast, PHMB (0.002% in distilled water) spiked to a 0.05 M NaOH solution with a pH of 12.5 (no precipitation visible likely due to low PHMB concentration used) did not achieve a reduced bacterial amount, as the pH > pKa did not allow a positively charged PHMB molecule.

[0210] Fig. 1 graphically illustrates the results of the absorbance for the situation of low PHMB concentrations, a higher absorbance indicating a lower effect on the biofilm.

[0211] In a next experiment, a higher concentration of PHMB (0.01 % in ultrapure water) was tested on early biofilm formation of Streptococcus sanguinis, cultured on titan discs.

[0212] Also in this experiment, a synergistic effect of 0.01 % PHMB and NaOH / glycine buffer was observed.

[0213] The best results, in terms of reduced bacterial amount, were achieved using a 0.05 M NaOH I 0.05 M glycine (pH 11.06) buffer and a 0.05 M NaOH / 0.2 M glycine (pH 9.27) buffer. Higher concentrations of glycine e.g. 0.4 M (pH 8.9) did not lead to a significant reduction of bacterial amount, compared to lower concentrations of glycine e.g. 0.05 M-0.2 M.

[0214] Fig. 2 graphically illustrates the results of the absorbance for the situation of low PHMB concentrations, a higher absorbance indicating a lower effect on the biofilm.

[0215] As one can see from the results as illustrated in Fig. 3, in the early biofilm model, no pronounced synergistic effect can be observed, if 0.05 % PHMB was added to alkaline buffers.

[0216] To verify, if the early in vitro biofilm model set up with low concentrated bacterial start inoculum and short incubation time, can prohibit a possible synergistic effect of higher PHMB concentration e.g. 0.05 % in alkaline buffers, the experiment was repeated using a denser and older biofilm model (start inoculum 106CFU / ml, incubation time 72 hours). By using the adapted experiment design, a synergistic effect of 0.05 % PHMB in 0.05 M NaOH / 0.1 M glycine buffer was obtained, see the results in Fig. 4a. To assess the effect of pH and antiseptic substance on bacteria behaviour, a bacterial suspension of S. sanguinis was measured over 24 hours at an optical density of 600 nm and at 37°C. The incubation in neutral PBS, showed a significant growth of S. sanguinis over the time, whereas S. sanguinis grown in T. buffer with a pH of 9.7 showed a significant inhibitory effect. The addition of 0.015 % PHMB to the alkaline T. buffer with a pH of 9.7 resulted in a killing of bacteria over time, see the results in Fig. 4b.

[0217] Biocompatibility of testing reagents:

[0218] In order to test the biocompatibility of the different alkaline buffers, L929 murine fibroblasts were used.

[0219] Cells were seeded in a 96 well plate at a density of 1x106cells / ml and cultured for 24 hours, before they were treated with the different alkaline buffers for 30 minutes.

[0220] As a control, cells were cultured in fresh medium.

[0221] After the incubation time, the metabolic activity, used as an indirect marker for cytotoxicity, was measured with an AlamarBlue assay. Vital cells were able to transform the dye by redox reaction to a fluorescent product. Hence, the highest metabolic activity was observed for the control. A decreased metabolic activity goes along with possible toxic effects.

[0222] The incubation with pure sodium hydroxide (0.025 M, 0.05 M and 0.1 M) lead to a significant reduction in metabolic activity.

[0223] Also, alkaline buffers containing 0.05 M NaOH 10.05 M glycine (pH 11.06) and 0.1 M NaOH 10.05 M glycine showed clear toxic effects.

[0224] In comparison with the buffers mentioned before, alkaline bufffers containing 0.025 M NaOH / 0.05 M glycine or 0.05 M NaOH / 0.1 M glycine resulted in metabolic activities comparable to the control.

[0225] Moreover, it was observed, that the addition of 0.03 % CaCh to the alkaline buffers can have additional beneficial effects on the metabolic activity.

[0226] Fig. 5 graphically illustrates the results of the biocompatibility tests of the different alkaline buffers. The pH values of the samples in this figure are given in Table 4.

[0227] Table 4: measured pH values of the samples illustrated in Fig. 5

[0228] In order to evaluate the biocompatibility of PHMB compared with the one of CHX, L929 murine fibroblasts were treated for 60 minutes with different concentrations of PHMB and CHX, respectively, supplemented within the medium.

[0229] After the incubation with the antiseptic agents, the metabolic activity was measured using an AlamarBlue assay. The data were normalized to the control (cells in fresh medium) and thus set to 100 % metabolic activity. To compare the two antiseptic agents, the IC50 value, representing the concentration that allow 50% cell survival (bold horizontal line), was calculated for each one. The calculation revealed a IC50 value < 0.1 % for PHMB and < 0.01 % for CHX., see Fig. 6.

[0230] In order to evaluate the cell viability of the antiseptic agents PHMB and CHX, human primary cells (HPDLF) were treated for 1 minutes with different concentrations of PHMB and CHX, supplemented within T. buffer. After the incubation with the antiseptic agents, the metabolic activity was measured using an AlamarBlue assay (after 4 h). Low cell viability was observed for cells treated with CHX at the tested concentration of 0.06 and 0.12 % in T. buffer. For PHMB, low cell viability was obtained for cells treated with PHMB at a concentration of 0.15%, whereas PHMB at 0.05% only led to a reduced cell viability. PHMB at 0.025% and 0.015% revealed cell viabilities in the range of the T. buffer control. Cells treated with the negative control (5% DMSO) showed a low cell viability. See Fig. 7.

[0231] It is to be noted that this is valid for antiseptic applications. If the application is rather antiinflammatory (e.g. in the form to be used against mucositis), also higher concentrations of PHMB up to 0.2% can be used. The additional advantage relative to the use of CHX is then that contrary to using CHX based formulations, there is no staining effect on the teeth with the application of the PHMB formulation, and PHMB shows higher biocompatibility than CHX. Finally, the influence of ethanol on cell vitality was investigated. HPDLF cells were grown in FM cell culture medium as control. The effect of the addition of ethanol was studied by either spiking the cell culture medium with 10, 20 and 50% ethanol or the developed T. buffer and corresponding amounts of ethanol. After 5 minutes incubation with the different test substances, cell vitality was measured by the AlamarBlue assay, performed as described before. Ethanol at a concentration of 20 and 50% spiked to cell culture medium showed a significant decrease in cell vitality. Ethanol spiked to the T. buffer also caused a negative effect on cell vitality, see Fig. 8.

[0232] Regeneration of the oral mucosa:

[0233] The (oral) mucosa is composed of two main layers: the superficial epithelium and the underlying connective tissue, called the lamina propria. The epithelium is composed of stratified epithelial cells, while the lamina propria contains fibroblasts. To study the effect of buffer additives on the regenerative potential on the (oral) mucosa, HuGF cells were selected as in vitro test model.

[0234] Cell viability of HuGF cells was measured with an AlamarBlue assay, after the addition of glycine (1 mM, 10 mM, 100 mM), polyhexanide (0.0001 %) and a mixture of 10 mM glycine and polyhexanide (0.0001%), (designated as G10 / P) to HuGF cell culture medium and incubation for 1 (Fig. 9) or 7 days (Fig.10).

[0235] The addition of glycine at concentrations of 10 mM and 100 mM, to cell culture medium, revealed significantly lower cell viability after 1 and 7 days of incubation compared to the control (see Fig. 9, Fig.10). Cells treated with 1 mM glycine, or polyhexanide alone (0.0001 %) showed similar cell viability data in the comparison to the control at day 1. A strong increase in cell viability has been observed for HuGF treated with polyhexanide (0.0001 %) for 7 days (Fig.10).

[0236] Surprisingly, the mixture of polyhexanide (0.0001 %) and glycine (10 mM) (designated as G10 / P in these figures, in this case without dexpanthenol) revealed a significantly higher cell viability compared to glycine (10 mM) alone at day 1 and at day 7 (Fig. 9 and Fig. 10). Moreover, the mixture of polyhexanide and glycine (1 OmM) reached higher cell viability after 7 days of culture compared to the control (Fig. 10).

[0237] Scientific evidence indicates that, among other cell types, gingival epithelial cells possess a glycine-gated chloride channel, which, upon binding of glycine, leads to increased chloride influx into the cell. In general, changes in cellular Cl" concentration result in differential regulation of cellular functions such as transcription and translation, post-translation modifications, cell cycle and proliferation, cell volume, and pH levels. Without being bound to an explanation, we assume that the beneficial effect of polyhexanide on the cell viability of glycine (10 mM) treated cells, is based on an electrostatic interaction. Glycine is an amino acid with the chemical formula NH2-CH2-COOH. The charge of its ion is dependent on the pH of the solution that it is in. In acidic environments, a greater percentage of glycine molecules become positively charged. At a neutral pH of around 7, the ion is uncharged (a zwitterion), having both a positive charge and a negative charge. At higher pHs, glycine becomes more negatively charged (glycinate anion). Due to the fact, that polyhexanide is an polycation (positively charged) it may interact with glycine, so that the concentration of glycine that can bind to the glycine gated chlorine channel is reduced and thus also the chloride concentration intracellular will be reduced to a more beneficial level. reaction of HuGF cells treated with lnterleukin-6 (IL-6) is an important molecule during the wound healing process and is known to have a pro- and anti-inflammatory role. IL-6 may initially act as a pro-inflammatory cytokine during the early stages of an immune response, but later switch to an antiinflammatory role as the response progresses.

[0238] In an initial experiment, the effect of glycine, polyhexanide, and dexpanthenol on IL-6 release in unstimulated HuGF cells was investigated. For this purpose, the cells were cultured in a 48-well plate and treated with glycine (1 mM, 10 mM, and 100 mM), polyhexanide (0.0001%), and dexpanthenol (0.1%). After 1 and 7 days of incubation at 37°C, the supernatant was collected and IL-6 levels were determined using an ELISA kit. For all three substances, a reduced IL-6 level compared to the control was observed. Glycine showed a concentration-dependent effect after 1 day of incubation, with the strongest reduction in IL-6 levels observed following treatment with 100 mM glycine. After 7 days of incubation, IL-6 levels were most reduced following treatment with a cocktail consisting of 10 mM glycine, 0.0001% polyhexanide, and 0.1% dexpanthenol.

[0239] In summary, the study showed that all three substances exert an anti-inflammatory effect in unstimulated HuGF cells, see Fig. 11 (after 1 day) and Fig. 12 (after 7 days). The strong IL-6 reduction in dependence on the glycine concentration can be explained by the antiinflammatory effect of glycine after LPS stimulation. The process of how glycine reduce IL- 6 levels is not fully understood today, however there are assumptions that the influx of chloride ions leads to a decreased intracellular Ca2+concentrations and thus to reduced IL-

[0240] 6 levels. In regard to the cell viability results (Fig. 9 and 10) demonstrating that the mixture of polyhexanide and glycine (10 mM) increase cell viability, it was hypnotized that the addition of polyhexanide to glycine (10 mM) will increase IL-6 levels by the electric interaction. Surprisingly, the addition of polyhexanide to glycine (10mM), keep a reduced IL-6 level (anti-inflammatory activity) while have a beneficial effect on the cell viability (Fig. 12).

[0241] To further investigate the effect of glycine on IL-6 levels, HuGF cells were treated with 1 mM, 10 mM, and 100 mM glycine and this time stimulated with 100 pg / ml Poly l:C HMW. Treatment with 1 mM glycine resulted in a reduced IL-6 level, while 10 mM as well as 100 mM glycine led to an increased IL-6 level. Treatment with 100 mM glycine did not further increase IL-6 levels compared to 10 mM glycine, see Fig. 13. This effect has also been observed for the cocktail.

[0242] In summary, the results indicate that starting at a concentration of 10 mM glycine in the medium, stimulated HuGF cells respond with increased IL-6 release.

[0243] In the next step, the three substances glycine, polyhexanide, and dexpanthenol were tested in stimulated HuGF cells, using less Poly IC HMW. For this purpose, the cells were cultured in a 48-well plate and treated with different concentrations of glycine (20 mM), polyhexanide (0.0001 %), and dexpanthenol (0.1 %). To simulate a viral infection, the cells were stimulated with 10 pg / ml Poly l:C HMW, a TLR3 agonist. In contrast, increasing the concentration of glycine to 20 mM results in a strong increase in IL-6 levels, which is also reflected in the cocktail of substances, see Fig. 14.

[0244] It can be concluded, that in less stimulated cells, the oversaturation of glycine led to stronger IL-6 levels. In general, cell experiments investigating the glycine effect on inflammation are using physiological concentrations that are in the range of the EC50 value for glycine gated chloride channels (1mM). To our understanding, nobody until now, studied the effect of oversaturated glycine on inflammation. Based on our experiments and without being bound, it seems, that an oversaturated glycine concentration can convert the anti-inflammatory effect into a pro-inflammatory effect, starting at 10 mM.

[0245] However, IL-6 is a pro-inflammatory cytokine and it has also been shown to play a role in immune regulation by stimulating the production of IL-10, an anti-inflammatory cytokine, as reported before. IL-6 can induce IL-10 production in various cell types. For example, it has been demonstrated that IL-6 can promote IL-10 production in CD4+ T cells. These IL-10- producing T cells exhibit characteristics of Tr1 cells and can suppress inflammatory responses triggered for example by LPS (lipopolysaccharides).

[0246] Based on these findings and the elevated IL-6 levels observed with glycine, an additional experiment was conducted in which HuGF cells were treated with 20 mM glycine, 0.0001% polyhexanide, and 0.1 % dexpanthenol and stimulated with 10 pg / ml Poly l:C HMW. Since IL-10 production occurs at a later time point, supernatants were collected after 1 and 7 days and analyzed using an ELISA kit. Compared to the control, a strong increase in IL-10 levels was detected on day 7 following incubation with 20 mM glycine, see Fig. 14. That a short overexpression of pro-inflammatory mediators such as TNF-alpha and IL-6 can have a positive effect on the overall infection rate.

[0247] The clinical case with virus-induced aphthae also shows positive effects on healing. Aphthae are usually caused by viruses, which is why IL-6 levels are temporarily elevated even in acute wounds. This is consistent with the study findings. In addition, the antiviral effect is evident.

[0248] Herpetic gingivostomatitis is a specific form of inflammation of the oral mucosa (stomatitis) caused by a primary infection with herpes viruses. It is also referred to as gingivostomatitis herpetica. The condition presents with infectious aphthae that appear acutely and are extremely painful. Early antiviral therapy appears to reduce the severity and duration of the disease, as well as the risk of neurological complications, with immune-compromised individuals benefiting especially from early treatment. Therefore, the current composition was tested not only for its wound-healing properties but also for its antiviral activity.

[0249] For this purpose, HSV type 1 viruses were incubated for one minute with a composition containing 0.045 M NaOH, 0.03 M glycine, 0.5% dexpanthenol, with or without 0.0225% polyhexanide. The mixture was then diluted with cell culture medium and applied to Vero cells. Subsequently, a plaque reduction assay was performed as described above. Compared to the control, both the buffer without polyhexanide and the buffer with polyhexanide showed antiviral effects, as almost no plaques could be counted (see Fig. 17 and Fig. 18). The addition of polyhexanide further reduced the number of plaques to zero.

[0250] In summary: IL-6 is released early in response to injury and plays a central role in initiating the inflammatory response, which is essential for wound healing. By activating immune cells and promoting inflammation, IL-6 contributes to the removal of necrotic tissue and bacteria from the wound, thereby supporting wound cleansing. At the same time, IL-6 promotes healing by stimulating the release of anti-inflammatory cytokines such as IL-10 and supporting the formation of new blood vessels. So, short-term elevated IL-6 levels have a positive effect on wound healing.

[0251] Based on clinical observations, see Fig. 19, showing a surprisingly shortened healing time of aphthous stomatitis following administration of the currently described composition, and in conjunction with the experimental data, it can be assumed that the clearance / inflammation phase of the wound healing process proceeds more rapidly and transitions more quickly into the proliferative phase. Several clinical cases were recorded with patients having an aphthous ulcer (aphthous ulcer, recurrent aphthous ulcer, aphtous from traumata, aphthous herpetica). For the clinical cases a formulation as given in Table 3a was used, where the values for Glycerol and Xylitol was in the lower ranges and there was no Ca donor, no preservative and no colorant. Patients reported a free from pain feeling after 2 days of rinsing with the investigated composition. After one week, aphthous lesions have been completely removed and oral mucosa has been regenerated. Patients and dentist reported a faster healing period of the aphthous ulcer after using the investigated composition. In vitro data and previous publications indicate an accelerated clearance phase, by elevated lnterleukin-6 levels and thus to a faster transition from the inflammatory phase to the proliferative phase of the wound healing process.

[0252] Similar effects were clinically observed using the same formulation with several patients showing aphthous lesions based on non-viral infections as well as aphthous lesions induced by herpes simplex in the inner and out lip area.

[0253] Key findings:

[0254] Some of the key findings of the experimental evidence can be summarised as follows:

[0255] • A particularly pronounced synergistic effect of PHMB and alkaline buffers was obtained for PHMB concentrations in the range of 0.002 % - 0.04 %, in an early biofilm formation model (start inoculum 103CFU / ml, incubation time 24 hours) with Streptococcus sanguinis. In experiments using an early biofilm formation set up, little synergistic effect of PHMB and alkaline buffers was observed with PHMB concentrations > 0.05 %.

[0256] • Alkaline buffers containing 0.05 M NaOH and < 0.05 M glycine tend to lead to too high pH and to pH > pKa, resulting in a reduced antimicrobial activity. Buffers containing 0.05 M NaOH and glycine > 0.4 M resulted also in less antimicrobial activity. Best performance in terms of synergistic effect (antimicrobial activity) was achieved with buffers containing 0.05 M NaOH and 0.05 M- 0.2 M glycine (pH range 11.06 to 9.8).

[0257] • A synergistic effect with PHMB (0.05 %) and an alkaline buffer (0.05 M NaOH / 0.1 M glycine) was proven in an in vitro biofilm model with higher bacterial load (106 CFU / ml) and longer incubation time (72 hours).

[0258] • Biocompatibility tests with L929 murine fibroblasts showed a good tolerance of alkaline buffers containing 0.025 M NaOH / 0.05 M glycine or 0.05 M NaOH / 0.1 M glycine + 0.03 % CaCh (pH 9.78). This indicates that alkaline buffers composed of NaOH / glycine with a pH < 10 can be viewed as biocompatible. Biocompatibility tests with L929 murine fibroblasts and PHMB and CHX revealed the following IC50 values: PHMB < 0.1 %, CHX < 0.01 %. These data indicate a higher biocompatibility for PHMB than for CHX.

[0259] Cell vitality after exposure to the proposed formulations is very good compared with other products; the presence of ethanol negatively affects the cell vitality, so alcoholic components are rather to be avoided the proposed composition provides an optimum balance between high activity and biocompatibility for oral tissue cells the proposed composition shows a significant and lasting therapeutic and / or preventive effect for the above-mentioned infections or lesions of the oral mucosa, i.e. of corresponding oral mucosa infections or lesions which are based on the above-mentioned origins.

[0260] Buffer additives such as glycine, polyhexanide and dexpanthenol in proper concentrations and proportions increase epithelial and fibroblast growth and thus can have a beneficial effect on the regeneration of injured oral mucosa

[0261] Buffer additives such as glycine, polyhexanide and dexpanthenol in proper concentrations and proportions significantly lower lnterleukin-6 release in unstimulated human gingival fibroblasts compared to control, demonstrating an antiinflammatory effect of the testing agents.

[0262] Suprisingly, in stimulated fibroblasts, glycine has been observed in a concentration dependent manner to further increase shortly an lnterleukin-6 release in fibroblasts. At a concentration between 10 mM and 100 mM of glycine an increased level of lnterleukin-6 has been detected in stimulated fibroblast. Concentrations at 2 mM did not lead to an increased level of lnterleukin-6 release.

[0263] Suprisingly, for the first time a selective effect of the amino acid glycine has been detected. In unstimulated gingivial fibroblasts, glycine possesses an antiinflammatory property, whereas in stimulated gingival fibroblasts (imitating a viral infection), glycine can act for a short time as pro-inflammatory agent and can thus increase clearance rate.

[0264] Alkaline buffer with dexpanthenol and glycine possess an antiviral effect against HSV-1. Moreover, the addition of polyhexanide to the alkaline buffer composition can further increase the antiviral efficacy.

Claims

CLAIMS1. Composition for use for the treatment and / or prevention of infections or lesions of the animal or human mucosa, wherein the composition comprises or consists of the following components:(a) polyhexanide (PHMB) or a salt thereof in a concentration in the range of 0.001- 0.2% w / v, preferably in the range of 0.005-0.1 % w / v;(b) an organic or inorganic buffer different from a) with at least one pKs value in the range of 8.5-11 .5 in a concentration in the range of 0.01-1 M, preferably in the range of 0.05-0.2 M;(c) further additives in a concentration in the range of 0-40% w / v;(d) optionally water; wherein preferably the pH value of the composition is in the range of 8 - 11.5, in particular in the range of 8.5 - 11.5.

2. Composition according to claim 1 , wherein it is for use for the treatment and / or prevention of odontogenic or non-odontogenic infections or lesions of the oral mucosa, in particular originating from at least one selected the group consisting of: perleche; scarlet fever; pharyngitis; acute necrotising ulcerative mucositis; impetigo contagiosa; stomatitis gangraenose (noma); chelitis glandularis apostem atosa; gingivostomatitis herpetica; herpes stabistis recidivans; herpes zoster; herpes simplex; hand-foot-mouth; human papilloma virus; HIV; oral candidiasis; oral lichen planus; lichen ruber planus; leukoplakia, erythroplakia; methicillin-resistant staphylococcus aureus; gingivitis / periodontitis; mucositis / peri-implantitis; alveolar osteomyelitis or osteolytis.

3. Composition according to claim 1 or 2, wherein the polyhexanide (PHMB) of component (a) has a weight average molecular weight Mw in the range of 1000-4000 g / mol, or 1500-4000 g / mol, preferably in the range of 2000-2800 g / mol, or in the range of 2400- 3000 g / mol; and / or wherein the polyhexanide (PHMB) of component (a) has a polydispersity (PDI) in the range of 1.4-2.2, preferably in the range of 1.7-2.8; and / or wherein the polyhexanide (PHMB) of component (a) takes the form of polyhexamethylene biguanide hydrochloride, and / or wherein the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.002 - 0.15 % w / v or 0.002-0.1% w / v, preferably in therange of 0.005-0.07% w / v or 0.005-0.05% w / v, in particular in the range of 0.007 - 0.03% w / v or 0.007-0.02% w / v or 0.007-0.015% w / v.

4. Composition according to any of the preceding claims, wherein the organic or inorganic buffer of component (b) is selected from the group consisting of: amino acid, in particular selected from the group consisting of alanine, glycine, asparagine, isoleucine, leucine, serine, threonine, valine, or a combination thereof, in particular glycine; bicarbonate buffer, in particular selected from the group consisting of: carbonate bicarbonate buffer, triethyl ammonium bicarbonate buffer; borate buffer, in particular sodium borate buffer;(acetic acid) ethanolamine buffer; or a combination or mixture thereof, wherein preferably the organic or inorganic buffer of component (b) is selected from the group consisting of: glycine, alanine, valine, leucine, isoleucine, or a combination or mixture thereof, and wherein in particular the organic or inorganic buffer of component (b) is only glycine in a concentration in the range of 0.05 - 0.2 M, and / or wherein 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, and / or wherein the concentration of the organic or inorganic buffer of component (b), preferably selected as glycine only, in the composition is in the range of 0.05-0.8 M, preferably in the range of 0.08-0.5 M, in particular in the range of 0.1-0.2 M.

5. Composition according to any of the preceding claims, wherein it is antimicrobial and antiviral, and / or wherein it is for the treatment of tissue, which is exposed due to burnings, in particular due to 2ndor 3rddegree burnings.

6. Composition according to any of the preceding claims, wherein it takes the form of a solid, semi-solid or liquid formulation, in particular an aqueous suspension or solution, a gel, a foam, a tincture, a tablet, in particular coated tablet, a paste, a chewing gum, a stripe or plaster.

7. Composition according to any of the preceding claims, wherein the additives of component (c) are selected from the group consisting of: surfactants, including ionic and non-ionic surfactants, thickeners, compatibilizers, phytopharmaca, vitamins, includingprovitamins, in particular anionic surfactants, in particular selected from alkyl sulfates, alkyl ether sulfates, alkyl sulphonates, alkylbenzyl sulfonates, a-olefin-sulphonates, alkylamide sulphonates, alkarylpolyether sulphates, alkylamidoether sulfates, alkyl monoglyceryl ether sulfates, alkyl monoglyceride sulfates, alkyl monoglyceride sulfonates, alkyl succinates, alkyl sulfosuccinates, alkyl ether sulfosuccinates, alkyl sulfosuccinamates, alkyl amidosulfosuccinates; alkyl sulfoacetates, alkyl phosphates, alkyl ether phosphates, alkyl ether carboxylates, alkyl amidoethercarboxylates, acyl lactylates, alkyl isethionates, acyl isethionates, carboxylate salts 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 alkyl betaines; alkylamido betaines; alkylamido sultaines; alkyl mono- and di-amphocarboxylates; amine oxides; and mixtures thereof, nonionic surfactants or thickeners or compatibilizers, in particular selected from ethoxylated fatty alcohols, ethoxylated alkylphenols, ethoxylated Guerbet alcohols, ethoxylated vegetal oils, polypropylene glycol, polyethylene glycol, block copolymers of propylene glycol and / or ethylene glycol, ethoxylated sorbitan esters, sorbitan esters, alkyl polyglucosides, alkyl glucamides, PVA, cellulose including HPMC, CMC, starch, gum Arabic, gellan gum, and mixtures thereof; film-formers, emulgators, foaming agents, resins, tannic acid, anti-corrosion agents, perfumes, dyes, stabilisers, complexing agents, organic solvents, in particular alcohols, disinfectants, preservatives, vitamins, in particular vitamin A, vitamin B, vitamin C, provitamins, in particular panthenol, in particular panthenol in a concentration in the range of 0.1-5 %w / v, or mixtures or combinations thereof.

8. Composition according to any of the preceding claims, wherein the concentration of the additives of component (c) is in the range of up to 30% w / v or up to 20% w / v, or less than 20% w / v or less than 15% w / v or less than 10 % w / v or less than 5% w / v, wherein dyes as part of component (c) are preferably present in a concentration in the range less than 0.2% w / v, preferably less than 0.1% w / v, particularly preferably in the range of 0.001-0.05% w / v or 0.0 w / v.

9. Composition according to any of the preceding claims, wherein the composition contains water and has a pH value in the range of 8.5 - 10.5 or in the range of 8-11 , preferably in the range of 8.5-10.5, in particular in the range of 9.5-10.

10. Composition according to any of the preceding claims, wherein the polyhexanide (PHMB) of component (a) has a weight average molecular weight Mw in the range of 2400-3000 g / mol, wherein the polyhexanide (PHMB) of component (a) takes the form of polyhexamethylene biguanide hydrochloride, and wherein the concentration of the polyhexanide (PHMB) of component (a) in the composition is in the range of 0.007-0.015% w / v, wherein the organic or inorganic buffer of component (b) is selected as glycine in a concentration of the organic or inorganic buffer of component (b) in the composition in the range of 0.05 - 0.2 M or 0.1-0.2 M, and wherein the concentration of the further additives of component(c) is less than 15% w / v or less than 10 % w / v or less than 0.01% w / v, preferably in the range of 0.001- 0.01% w / v.11 . Composition according to any of the preceding claims for the treatment or prevention of at least one of viral, fungal or autoimmune infection or at least one of viral, fungal or colonisation or both.

12. Composition according to claim 11 for the treatment and / or prevention of herpes simplex, aphtoid lesions or at least one of oral lichen planus and lichen ruber planus.

13. Composition according to any of the preceding claims, wherein, next to components (a) - (d) the composition further comprises the following component:(e) at least one sugar alcohol having at least three carbon atoms, preferably in a concentration of up to 75% w / v, preferably in a concentration of up to 70% w / v or in the range of 0.5-5% or 5-50% w / v or in the range of 10-40% w / v or 20-30%, wherein preferably said 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, maltotetraitol, or a combination thereof, preferably a combination of glycerol and xylitol.

14. Composition according to any of the preceding claims, wherein it is free from ethanol or comprises less than 10 % w / v or less than 5 % w / v or less than 2% w / v of ethanol.

15. Composition according to any of the preceding claims, wherein it is free from linear or branched alkyl or arylalkyl monohydric alcohols with 1 - 9 or 1 - 6 carbon atoms,in particular free from methanol, ethanol, propanol, 1-phenyl-1 -propanol or a combination thereof, or 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 linear or branched alkyl or arylalkyl monohydric alcohols.

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