Formulations and devices comprising lantibiotic-producing bacteria

Abstract

The invention relates to a composition for teeth cleaning comprising lantibiotic-producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous. The invention further relates to a dental device comprising a conserved lantibiotic-producing bacterial strain. of the. Further encompassed by the invention are the corresponding medical and non-medical uses and methods.

Description

[0001] Formulations and devices comprising lantibiotic-producing bacteria

[0002] The invention relates to a composition for teeth cleaning comprising lantibiotic- producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous. The invention further relates to a dental device comprising a conserved lantibiotic-producing bacterial strain. Further encompassed by the invention are the corresponding medical and non-medical methods and uses of the composition and device.

[0003] Related Art

[0004] The oral cavity is inhabited by complex microbial communities that can form biofilms which may subsequently lead to caries and periodontitis. Caries remains a major public health problem and is characterized by a multifactorial etiology.

[0005] In favorable conditions, cariogenic microbiota metabolize dietary carbohydrates into acids resulting in prolonged periods of the biofilm surrounding the teeth. Cariogenic microbiota can lead to demineralization of the enamel (white spot lesions, WSLs) or cavitated caries of the dentin. One representative model defined caries as a dynamic process of the microbial profile consisting of three reversible stages: dynamic stability, acidogenic, and aciduric stage (Haffajee AD, Socransky SS. Periodontal 2000. 1994;5:78-111 ; Okada H, Murakami S. Crit Rev Oral Biol Med. 1998;9(3):248-66.5,6). The shift from the dynamic stability with early colonizers to the acidogenic stage enhance the development of multispecies cariogenic biofilm, dominated by mutans streptococci, Lactobacillus species, bifidobactenal and opportunistic Actinomyces species. Additionally, the components and metabolic products of the microorganisms in the supra- and subgingival biofilm result in inflammation of the periodontium. Furthermore, there are bacteria which are strongly associated with periodontal disease. Their cellular components and metabolic products released into the supra- and subgingival biofilm result in inflammation of the periodontium by triggering the production of pro-inflammatory cytokines (Okada H, Murakami S. Cytokine expression in periodontal health and disease. Crit Rev Oral Biol Med. 1998; 9(3):248-66).

[0006] Although dental treatment should save oral health, there are some therapy options which enhance the caries risk of patients by increasing biofilm on the tooth surface. Orthodontic therapy for example can promote gingivitis, accumulation of the plaque and changes in the oral microbiome including proliferation of S. mutans as early as one week after insertion of the fixed orthodontic appliances (Reichardt E, Geraci J, Sachse S, Rddel J, Pfister W, Loffler B, Wagner Y, Eigenthaler M, Wolf M. Qualitative and quantitative changes in the oral bacterial flora occur shortly after implementation of fixed orthodontic appliances. Am J Orthod Dentofacial Orthop. 2019; 156: 735-44). S. mutans may be a special key in the development of caries associated lesions during orthodontic therapy. Therefore, adverse effects resulting in white spot lesions are common in orthodontic therapy with fixed appliance treatment.

[0007] According to the World Health Organization (WHO), probiotics are defined as viable microorganisms that confer a health benefit when administered in sufficient doses. Therefore, the use of probiotics might be also a promising tool to prevent the frequently occurring carious processes and persistent gingival inflammation in the oral cavity.

[0008] Further, dental biofilm can be reduced and controlled through daily oral care. However, toothpastes with live probiotics suffer from a variety of technical difficulties, such as keeping probiotics alive in the toothpaste or assuring sustained release of the probiotics. Moreover, common toothpastes include ingredients that may serve as excellent media for growth of the probiotics which finally results in a reduction in cell viability.

[0009] Thus, there is a need for improved means and methods to protect and restore oral hygiene and health.

[0010] The above technical problem is solved by the embodiments disclosed herein and as defined in the claims.

[0011] Summary of the invention

[0012] In the present invention, natural antimicrobial compounds produced by oral probiotic streptococci are be utilized as a highly promising treatment option, preferably to eliminate S. mutans pathogens.

[0013] The inventors found that in the anhydrous composition of the invention the active ingredients are highly stable and especially the lantibiotic-producing bacteria can be reconstituted and maintained viable in the anhydrous composition of the invention. Surprisingly, the viability of these bacteria is sufficiently long to survive a cleaning procedure and adhere to and colonize the oral cavity.

[0014] The advantage of the composition of the invention, especially the dental tab of the invention compared to other application forms comprising lantibiotic-producing bacteria is that it does not require a dedicated administration but can be applied with daily routines, such as toothbrushing and / or mouth rinsing. This improves ease of use and facilitates compliance to an application routine. Furthermore, these procedures can also facilitate the adherence and colonization of the bacterium. For example, during toothbrushing, other bacteria are mechanically removed, whereby adherence space is created for colonization of beneficial lantibiotic-producing bacteria.

[0015] Therefore, the composition of the invention provides an effective vehicle to enable or facilitate the administration of a lantibiotic-producing bacteria to the oral cavity, whereby the bacteria contribute to restoring or maintaining the oral microbiome without compromising it. Furthermore, the inventors showed that the lantibiotic-producing bacteria tolerate the presence of ingredients of the composition of the invention surprisingly well and long. Thus, the composition of the invention can improve dental health and reduce pathologies, such as inflammation in the oral cavity. Furthermore, lantibiotics typically do not induce resistance formation to antibiotics used in other pathologies. The lantibiotics described herein are well tolerated and emit low interaction risk with other therapies such as pharmacological therapies or orthodontic therapy. The growth of the administered bacteria themselves contributes synergistically with the regulatory lantibiotic effect to a healthy oral microbiome and prevents relapse after treatment.

[0016] Accordingly, the invention relates to, inter alia, the following embodiments:

[0017] 1. A composition for teeth cleaning comprising lantibiotic-producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous.

[0018] 2. The composition of embodiment 1 , wherein the composition is in the form of a single dosage unit.

[0019] 3. The composition of any one of the preceding embodiments, wherein the composition is formulated as solid dosage form, preferably the solid dosage form is selected from the group consisting of a tablet, capsule, and sachet; more preferably the solid dosage form is a tablet. 4. The composition of embodiment 3, wherein the composition is in the form of a solid chewable dosage form.

[0020] 5. The composition of any one of the preceding embodiments, wherein the lantibiotic-producing bacteria are conserved, preferably the lantibiotic-producing bacteria are lyophilized.

[0021] 6. The composition of any one of the preceding embodiments, wherein the lantibiotic-producing bacteria are salivaricin-producing bacteria.

[0022] 7. The composition of any one of the preceding embodiments, wherein the salivaricin-producing bacteria are of the species S. salivarius.

[0023] 8. The composition of any one of the preceding embodiments, wherein the species S. salivarius comprises or preferably is the strain S. salivarius K12 and / or M18.

[0024] 9. The composition of any one of the preceding embodiments, wherein the composition further comprises hyaluronic acid.

[0025] 10. The composition of any one of the preceding embodiments, wherein the composition does not comprise a synthetic surfactant, wherein preferably said synthetic surfactant is a sulfate, more preferably said sulfate is selected from the group comprising sodium lauryl sulfate, sodium laureth sulfate, and ammonium lauryl sulfat.

[0026] 11. The composition of any one of the preceding embodiments, wherein the composition comprises a flavonoid, preferably wherein the formulation comprises a propolis flavonoid.

[0027] 12. The composition of any one of the preceding embodiments, wherein the composition further comprises a buffer system.

[0028] 13. The composition of any one of the preceding embodiments, wherein the composition further comprises at least one selected from the group consisting of fluoride, vitamin D3, sweetener, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, flavoring agent, tea tree oil or powder, eugenol, xanthan gum, and magnesium stearate, wherein preferably the sweetener is not aspartame; and / or wherein preferably the sweetener is selected from the group consisting of xylitol, erythritol, sorbitol, maltitol, steviol glycosides, saccharose, saccharin, sucralose, honey, syrups, coconut sugar and isomalt.

[0029] 14. The composition of any one of the preceding embodiments, wherein the at least one cleaning agent is selected from the group consisting of bicarbonate, carbonate, micro- and macrocrystalline cellulose fibers, silica, and a combination of two or more thereof.

[0030] 15. A dental device comprising a conserved lantibiotic-producing bacterial strain, wherein the dental device is selected from the group consisting of aligner, applicator for the oral cavity, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece, dental stripe, wherein preferably the applicator for the oral cavity is selected from the group consisting of oral spray, dental spray and injector.

[0031] 16. Use of the composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for oral hygiene in a subject with a healthy oral cavity, preferably for cleaning the teeth and mucous membranes of an oral cavity.

[0032] 17. Use the composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin in a subject with a healthy oral cavity.

[0033] 18. The composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for use as a medicament.

[0034] 19. The composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for use according to embodiment 18 in the treatment or prevention of an oral bacterial infection.

[0035] 20. The composition of any one of the preceding embodiments 1-14 or the dental device of embodiment 15 for use according to embodiment 18 or 19, wherein the bacterial infection is an S. mutans infection. 21. The composition of any one of embodiments 1 -14 or the dental device of embodiment 15, for use in orthodontic therapy.

[0036] 22. The composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for use according to any one or embodiments 18-21 in the treatment or prevention of plaque, caries, white spot lesions, demineralized enamel, demineralized dentin, reduced salivary pH, inflammatory disease of the oral cavity and / or alveolar bone degradation in a subject; preferably the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

[0037] 23. The composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for use according to any one of embodiments 18-22 in treatment or prevention of S. mutans induced decrease of pH of the saliva in the oral cavity.

[0038] 24. A method of treatment of a disease in an oral cavity, said method comprises the steps of applying the composition of any one of embodiments 1 -14 or the dental device of embodiment 15 to the oral cavity of a subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0039] 25. A method of cleaning teeth and mucous membranes of an oral cavity comprising the steps of applying the composition of any one of embodiments 1 -14 or the dental device of embodiment 15 to the oral cavity of a subject, preferably a healthy oral cavity or a healthy subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0040] 26. A method of selectively promoting, in an oral cavity of a subject:

[0041] (a) growth, metabolic activity or colonization of bacteria that have beneficial effects on oral health, relative to growth, metabolic activity or colonization of pathogenic oral bacteria; or

[0042] (b) biofilm formation by bacteria that have beneficial effects on oral health, relative to biofilm formation by pathogenic oral bacteria; the method comprising contacting an oral cavity of the subject with the composition of any one of embodiments 1 -14 or the dental device of embodiment 15. 27. A method for plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in an oral cavity, decreasing periodontal-pathogen microbiota in an oral cavity, decreasing pathogenic microbiota in an oral cavity, decreasing biofilm in an oral cavity, remineralization of enamel and / or remineralization of dentin, the method comprises the steps of the steps of applying the composition of any one of embodiments 1 -14 or the dental device of embodiment 15 to the oral cavity of a subject, preferably a healthy oral cavity of a healthy subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0043] 28. The method of embodiments 27, wherein applying the composition comprises the use of a tool selected from the group consisting of toothbrush, dental floss, interdental brush, tongue scraper, aligner, dental applicator, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral spray, dental spray, oral cotton, dental cotton, injector, dental sud, mesh, fiber mat, fleece, stripe and polymer aligner.

[0044] 29. A method of reducing bacterial growth on a medical or dental device, the method comprising the steps of:

[0045] 1 ) reconstituting a conserved lantibiotic-producing bacterial strain; and

[0046] 2) combining the lantibiotic-producing bacterial strain in reconstituted form with the medical or dental device, preferably wherein the dental device is selected from the group consisting of dental brace, night guard, occlusal appliance, toothbrush aligner, dental thread, dental tip, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece and dental stripe.

[0047] Detailed Description of the Invention

[0048] Accordingly, in a first aspect, the invention relates to a composition for teeth cleaning comprising lantibiotic-producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous.

[0049] The composition of the invention is a dentifrice and suitable for and has the purpose of providing oral care and hygiene in the oral cavity. Especially, the composition of the invention is suitable for and has the purpose of cleaning the teeth and improving the microbiome in the oral cavity. Thus, the composition of the invention is prepared for cleaning the oral cavity, preferably for cleaning teeth.

[0050] Lantibiotics

[0051] The term “lantibiotic-producing bacterial strain”, as used herein, refers to bacterial strain that synthesizes and secretes lantibiotics.

[0052] Lantibiotics are ribosomally synthesized, post-translationally modified antimicrobial peptides. The term “lantibiotics” as used herein refers to lanthionine-containing antibiotics. Preferably, lantibiotics are peptides and proteins defined by posttranslational modifications that introduce thioether amino acids lanthionine and / or methyllanthionine (Willey JM et al., Annu. Rev. Microbiol. 2007, 61 :477-501 ). The term “lantibiotics” comprises Class I, II, or III lantibiotics.

[0053] In certain embodiments, the lantibiotic described herein is a type Al and All lantibiotic.

[0054] In certain embodiments, the lantibiotic-producing bacterial strain is a salivaricinproducing bacterial strain. The term “salivaricin” as used herein refers to lantibiotics produced by Streptococcus salivarius (S. salivarius). In certain embodiments, the salivaricin described herein is selected from the group consisting of salivaricin A, salivaricin B, salivaricin G32 and salivaricin 9, preferably salivaricin A and salivaricin B.

[0055] The inventors found that salivaricins have an antimicrobial profile that prevents or reduces growth of pathogenic bacteria without disturbing the growth of healthy bacteria microbiome of the oral cavity, even when applied in a composition suitable for cleaning the teeth.

[0056] Accordingly, the invention is at least in part based on the finding that the composition of the invention suitable for teeth cleaning enables a particular beneficial antimicrobial profile.

[0057] Lantibiotic-producing bacterial strain

[0058] The composition of the invention can comprise one or more species or strains of lantibiotic-producing bacteria. Many lantibiotics have a bactericidal effect against a variety of gram-positive bacteria at nanomolar levels and some are active against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, and oxacillin-resistant gram-positives. The antimicrobial activity of the lantibiotics described herein preferably comprises or consists of an inhibitory effect against S. mutans. The antibacterial activity of a lantibiotic-producing bacteria against S. mutans can be evaluated by a minimum inhibitory concentration assay, using a microdilution method according to methods recommended by Clinical and Laboratory Standards Institute (CLSI) (Hecht D.W., Citron D.M., Cox M., et al. Clinical and Laboratory Standards Institute; Wayne, PA: 2007. Methods for antimicrobial susceptibility testing of anaerobic bacteria; Approved standard 7th edition (M11 -A7)). A milliliter of the lantibiotic-producing bacterial strain (1 x 107bacteria / ml) is inoculated into 10 ml M17 broth (BD bioscience, Sparks, MD, USA), and the bacterial suspension is incubated for 24 h in an aerobic condition. The lantibiotic-producing bacterial strain suspension is then centrifuged at 5000xg for 10 min, and the supernatant is transferred into a new 15 ml conical tube (SPL Life Sciences, Gyeonggi, Korea). The supernatant is filtered with a polyvinylidene fluoride filter (Millipore, Billerica, MA, USA). The filtered supernatant as a spent culture medium (SCM) is then used for the susceptibility assay. 180 pl of M17 broth is dispensed into 96-well plate (SPL Life Sciences). The SCM is added into a 1 st well containing the fresh medium and performed 2-fold serial dilution to the 11th column. S. mutans (ATCC 25175) cultivated with tryptic soy broth (BHI; BD bioscience) is counted with a bacterial counting chamber (Hausser Scientific, Horsham, PA, USA) and adjusted to 2 x 106bacteria / ml with fresh M17 broth. The prepared S. mutans suspension (20 pl) is inoculated into the well containing the mixed media. The plate was incubated at 37°C in an aerobic incubator. The bacterial growth was measured using optical density at 660 nm of wavelength by a microplate reader (BioTek, Winooski, VT, USA). The growth of S. mutans is measured using optical density at 660 nm of wavelength. Preferably, antibacterial activity of a lantibiotic- producing bacterial strain is present in case growth of S. mutans was significantly inhibited using undiluted SCM compared to control. In the alternative, S. mutans (1 x 106bacteria / ml) and S. salivarius K12 (1 x 107bacteria / ml or 1 x 108bacteria / ml) are co-cultivated using Transwell™ (pore size 0.4 pm; Coming Co., Coming, NY, USA) in 12-well plate. The bacterial suspension of S. mutans and S. salivarius were inoculated into inside and outside of Transwell™, respectively, and the plate was incubated at 37 °C for 24 h. The growth of S. mutans was measured optical density at 660 nm of wavelength. Preferably, antibacterial activity of a lantibiotic-producing bacterial strain is present in case growth of S. mutans was significantly inhibited compared to control. In certain embodiments, the lantibiotic-producing bacteria described herein is a Grampositive bacterium. In certain embodiments, the lantibiotic-producing bacteria described herein is a bacterium from the order of Lactobacillales. In certain embodiments, the lantibiotic-producing bacterial strain described herein is a bacterium from the family of Streptococcaceae.

[0059] In certain embodiments, the invention relates to the composition of the invention, wherein the lantibiotic-producing bacterial strain is of the species S. salivarius.

[0060] The inventors found that bacteria of the species S. salivarius are compatible and remain viable and reconstitutable in the composition of the invention. Especially, the inventors found that bacteria of the species S. salivarius are compatible and remain viable and reconstitutable in the presence of the at least one teeth cleaning agent included in the composition of the invention.

[0061] Accordingly, the invention is at least in part based on the finding that S. salivarius enables the composition of the invention to be particularly efficient in protecting and / or restoring oral hygiene and health.

[0062] The inventors found that S. salivarius strain M18 and K12 remain surprisingly long viable in anhydrous oral compositions, such as dent tabs. In certain embodiments, the invention relates to the composition of the invention, wherein the lantibiotic-producing bacterial strain comprises or is S. salivarius K12 or S. salivarius strain Mia (M18).

[0063] In certain embodiments, lantibiotic-producing bacterial strain comprises or consists of S. salivarius K12 and Streptococcus salivarius strain Mia (M18). The inventors showed that co-cultivation of S. mutans and S. salivarius K12 and M18 led to a synergistic effect in inhibition of S. mutans viability.

[0064] In certain embodiments, the lantibiotic-producing bacterial strain S. salivarius is S. salivarius Mia (M18). In certain embodiments, the invention relates to the composition of the invention, wherein S. salivarius is S. salivarius K12.

[0065] M18 is preferably Streptococcus salivarius subsp. salivarius Andrewes and Horder of ATCC reference No. BAA-2593. K12 is preferably Streptococcus salivarius subsp. salivarius Andrewes and Horder of ATCC reference No. BAA-1024 or BAA-1024d-5.

[0066] In some embodiments, the composition further comprises an additional probiotic. Suitable probiotics include, but are not limited to, Lactobacillus spp. (e.g., L. acidophilus, L. reuteri, L. rhamnosus, or L. salivarius), Bifidobacterium spp. (e.g. B. bifidum, B. longum, or B. lactis BB12), Streptococcus spp. (e.g. S. oralis, S. uberis, or Streptococcus salivarius K12), and Saccharomyces spp. (e.g. S. boulardii or S. cerevisiae), Limosilactobacillus spp. (e.g. L. reuteri), Lacticaseibacillus spp. (e.g. L. rhamnosus), or Ligilactobacillus spp. (e.g. L. salivarius).

[0067] In preferred embodiments, the lantibiotic-producing bacterial strain described herein is alive. The bacterial strain can be a naturally occurring strain or a genetically modified strain.

[0068] Anhydrous composition

[0069] Due to their aqueous nature and ingredients, aqueous toothpastes and gels require the addition of preservatives to prevent growth of pathogens and to avoid loss of viability an efficiency of added probiotics.

[0070] Thus, the composition of the invention is anhydrous. As used herein, the term “anhydrous” means that the composition has a water content of less than 20%, preferably less than 10%, more preferably less than 8%, again more preferably less than 6%, more preferably less than 3%, less than 2%, less than 1 %, less than 0.5%, less than 0.1 %, or less than 0.01 %. Percentages are % w / w based upon the total weight of the compositions of the present invention, unless otherwise indicated. In the present composition, water includes absorbed moisture from the environment. In some embodiments, the oral composition is non-aqueous.

[0071] Water content can be determined using methods known to those skilled in the art, preferably by a TGA Thermal Gravimetric Analyser from TA Instruments and associated software. The analyzer method is set to equilibrate at room temperature (25°C) followed by a linear ramp increase in temperature at 20°C per minute to a final temperature of 105°C, followed by a 20-minute hold at 105° C.

[0072] Preferably, the composition of the invention does not comprise an aqueous ingredient or aqueous solution. In certain embodiments, the aqueous ingredients of the composition are dehydrated. Preferably, the ingredients of the composition are comprised in the composition as dry powders.

[0073] The composition of the present invention or its ingredient may be dehydrated for example by drying, such as air drying, vacuum drying, fluidized bed drying, spray drying, and lyophilization (freeze drying). The terms “lyophilization” and “freeze drying” are used herein interchangeably and refer to the preparation of a composition in dry form by rapid freezing and dehydration in the frozen state (sometimes referred to as sublimation). Lyophilization takes place at a temperature that results in the crystallization of ingredients in the composition.

[0074] Preferably, the composition of the invention is not oil-based or lipid-based. Preferably, oil comprised in the composition of the invention is limited to oils used as flavoring agent or as antibacterial, antifungal, antioxidant or anti-inflammatory agent, such as peppermint or tea tree oil. Preferably, in case the composition of the invention comprises oils, said oils are comprised as dry powder.

[0075] Teeth cleaning agent

[0076] The composition of the inventions comprises at least one cleaning agent.

[0077] In preferred embodiments, the cleaning agent is an abrasive. Preferably, the composition comprises 8-20% w / w of an abrasive. An abrasive cleans the teeth, i.e. , it removes plaque, debris, and surface stains from the teeth.

[0078] The cleaning agent is preferably selected from the group consisting of bicarbonate, carbonate, preferably micro- and macrocrystalline cellulose fibers, titanium dioxide, aluminum oxide, aluminum hydroxide (AI(OH)3), calcium hydrogen phosphates, hydrated aluminum oxides, clay (e.g. bentonite and kaolin), activated charcoal, tetrasodium pyrophosphate, disodium pyrophosphate, sodium chloride, sodium salts, phosphate salts, silica, polyethylene (PE), polypropylene (PP) and tenside (surfactant) zeolites, and hydroxyapatite (Cas(PO4)3OH and a combination of two or more thereof. More preferably, the cleaning agent does not comprise a surfactant. Carbonate is preferably calcium, magnesium or sodium carbonate, more preferably sodium carbonate. Bicarbonate is preferably sodium bicarbonate. Silica is preferably silicon dioxide. Silica can be hydrated or hydrophobic silica.

[0079] More preferably, the cleaning agent is selected from the group consisting of bicarbonate, carbonate, micro- and macrocrystalline cellulose fibers, silica, and a combination of two or more thereof. In other preferred embodiments, the cleaning agent is selected from the group consisting of bicarbonate, carbonate, micro- and macrocrystalline cellulose fibers, silica, a gum, preferably xanthan gum, and a combination of two or more thereof. In preferred embodiments, the cleaning agent is carbonate, preferably sodium carbonate. In preferred embodiments, the cleaning agent is silica. In preferred embodiments, the cleaning agent is micro- or macrocrystalline cellulose fibers. In preferred embodiments, the cleaning agent is carbonate, preferably sodium carbonate, micro- or macrocrystalline cellulose fibers, silica and optionally a gum, preferably xanthan gum.

[0080] In certain embodiments, the composition comprises an abrasive in an amount of about 1 to about 40%, about 1 to about 30%, about 1 to about 25%, about 1 to about 20%, about 5 to about 40%, about 5 to about 30%, about 5 to about 25%, about 5 to about 15%, about 10 to about 35%, about 15 to about 30%, about 6 to about 14%, about 7 to about 13%, about 8 to about 12%, about 9 to about 11 %, or about 10% w / w based on the total weight of the composition. In some embodiments, the composition comprises an abrasive in an amount of about 1 %, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11 %, about 12%, about 13%, about 14%, or about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21 %, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% w / w based on the total weight of the composition.

[0081] Single dosage unit

[0082] In a preferred embodiment, the teeth cleaning composition of the invention in the form of a single dosage unit.

[0083] The composition of the invention can be formulated in separate single dosage units. The terms “dose unit” and “dosage unit” are used herein interchangeably and refer to a portion of a pharmaceutical composition that contains a fixed amount of a therapeutic agent, herein preferably the number of lantibiotic-producing bacteria, for a single administration to provide a therapeutic or prophylactic effect. The term “single dose / dosage unit” refers to the smallest unit of packaging containing a certain quantity of pharmaceutical product. For example, in a box of seven capsules, each capsule is a single-dose; or a vial of injection is a single-dose. Such dosage unit may be administered as many times as needed to elicit a therapeutic or prophylactic response, i.e. , one to a plurality (e.g., 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, preferably 1 to 4, more preferably 1 to 3 or 1 to 2 times or once per day. The term “fixed amount of a therapeutic agent ... to provide a therapeutic or prophylactic effect” refers to an amount of the compound, herein preferably the number of lantibiotic-producing bacteria, for (i) treating a specific disease, condition or disorder, or (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease, condition or disorder. The amount of the compound of the present application composing the therapeutically or prophylactically effective amount varies dependently on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be determined routinely by those skilled in the art in accordance with their knowledge and the present disclosure.

[0084] In certain embodiments, the single dosage unit has a dose of at least about 105, at least about 106, at least about 107, at least about 108, at least about 109, at least about 1010, at least about 1011, at least about 1012, at least about 1013, at least about 1014, or at least about 1015colony forming units (cfu) of the lantibiotic-producing bacterial strain. In certain embodiments, the single dosage unit has a dose of between about 105and about 1015, between about 106and about 1014, between about 107and about 1013, or between about 109and about 1012colony forming units of the lantibiotic-producing bacterial strain. Most preferably, the single dosage unit has a dose of 1x1012colony forming units of the lantibiotic-producing bacterial strain, wherein the lantibiotic- producing bacterial strain is preferably S. salivarius, more preferably S. salivarius strain M18 and / or K12.

[0085] Preferably, the composition of the invention is a ready-to-use formulation. “Ready-to- use,” as used herein, refers to a formulation that does not require constitution or dilution with a prescribed amount of diluent, e.g., water for injection or other suitable diluent, before use by the designated route. For example, a formulation in a vial, of the desired concentration, that only needs to be drawn up into a syringe.

[0086] In preferred embodiments, the teeth cleaning composition of the invention is formulated as a solid dosage form. Non-limiting examples of suitable solid dosage forms include tablets (e.g., suspension tablets, bite suspension tablets, rapid dispersion tablets, chewable tablets, melt tablets, effervescent tablets, bilayer tablets, etc.), caplets, capsules (e.g., a soft or a hard gelatin capsule filled with solid and / or liquids), powder (e.g., a packaged powder, a dispensable powder or an effervescent powder), lozenges, sachets, cachets, troches, pellets, granules, gum, film. More preferably, the teeth cleaning composition of the invention is formulated as tablet, capsule, or sachet. In an again more preferred embodiment, the teeth cleaning composition of the invention is formulated as tablet.

[0087] Preferably, the teeth cleaning composition of the invention is formulated as solid chewable dosage form. Preferably the solid chewable dosage form is suitable and formulated for teeth brushing.

[0088] Dent tab

[0089] In a preferred embodiment, the composition of the invention is formulated as a dent tab. In a preferred embodiment, the single dosage unit is formulated as a dent tab. The terms dent tab and toothpaste tablets are used herein interchangeably.

[0090] The term “dent tab”, as used herein, refers to tooth cleaning composition in the form of a tablet. Preferably the dent tab is chewable. The dent tab of the invention is intended to be applied to an area in the oral cavity such as the teeth. Preferably, the dent tab is applied to the teeth for cleaning and preventive purposes. For cleaning, one tablet is chewed and mixed with saliva to form a paste in the mouth. Then the tooth surfaces and gums are cleaned and polished by means of a toothbrush.

[0091] In contrast to a solid dent tab, a toothpaste is not anhydrous, but formulated as ointment, paste, gel or creme, formulated on a water, oil in water or a water in oil basis. Typically, a toothpaste comprises a wetting and / or humectant agent and has a viscosity of 70,000-100,000 mPa, e.g., measured by a method viscometer at 25-40°C.

[0092] The dent tab of the invention provides a beneficial availability of probiotics and high colonization efficacy in vivo. A probiotic is released during the cleaning process, which provides enough time for the probiotic to be retained in the oral cavity to achieve colonization. Moreover, the dental tab of the invention provides a precisely controllable, fixed and ready-to-use dosage form.

[0093] In a preferred embodiment, the composition of the inventions is formulated as dent tab and the at least one cleaning agent is selected from the group consisting of bicarbonate, carbonate, micro- and macrocrystalline cellulose fibers, titanium dioxide, aluminum oxide, silica (silicon dioxide), polyethylene (PE), polypropylene (PP) and tenside (surfactant) and a combination of two or more thereof. More preferably, the cleaning agent does not comprise a surfactant. Preferably, the cleaning agent is selected from the group consisting of bicarbonate, carbonate, micro- and macrocrystalline cellulose fibers, silica, and a combination of two or more thereof.

[0094] Preferably, the dent tab further comprises a buffering agent or buffer system. Preferably, the dent tab further comprises a lubricant. Preferably, the dent tab further comprises a flavoring agent. Preferably, the dent tab further comprises an additive. The additive is preferably selected from the group consisting of fluoride, cholecalciferol, sweetener, tea tree powder, xanthan gum, hyaluronic acid, and propolis and a combination of two or more thereof. Preferably, the dent tab further comprises a buffering agent or buffer system, lubricant, flavoring agent, and additive selected from the group consisting of fluoride, cholecalciferol, sweetener, tea tree powder, xanthan gum, hyaluronic acid, and propolis and a combination of two or more thereof.

[0095] In a more preferred embodiment, the composition of the inventions is formulated as dent tab and the at least one cleaning agent is selected from the group consisting of carbonate, cellulose fibers, silica and a combination of two or more thereof; the composition further comprises a buffer system comprising an acid and a bicarbonate, preferably said acid is citric acid, and said bicarbonate is sodium bicarbonate; a flavoring agent, and optionally an additive selected from the group consisting of a hyaluronic acid, fluoride, cholecalciferol, sweetener, tea tree powder, xanthan gum, and propolis and a combination of two or more thereof, wherein preferably the lantibiotic-producing bacterial strain is S. salivarius, preferably K12 or / and Mia (M18). In a more preferred embodiment, the composition of the inventions is formulated as dent tab and the at least one cleaning agent is selected from the group consisting of carbonate, cellulose fibers, silica and a combination of two or more thereof; the composition further comprises a buffer system comprising an acid and a bicarbonate, preferably said acid is citric acid, and said bicarbonate is sodium bicarbonate; a flavoring agent, hyaluronic acid, fluoride, and optionally an additive selected from the group consisting of cholecalciferol, sweetener, tea tree powder, xanthan gum, and propolis and a combination of two or more thereof, wherein preferably the lantibiotic- producing bacterial strain is S. salivarius, preferably K12 or / and Mia (M18). In an again more preferred embodiment, the composition of the inventions is formulated as dent tab and the at least one cleaning agent comprises carbonate, cellulose fibers, and silica; the composition further comprises a buffer system comprising an acid and a bicarbonate, preferably said acid is citric acid, and said bicarbonate is sodium bicarbonate, a hyaluronic acid, flavoring agent, fluoride; and optionally an additive selected from the group consisting of cholecalciferol, sweetener, tea tree powder, xanthan gum, and propolis and a combination of two or more thereof, wherein preferably the lantibiotic-producing bacterial strain is S. salivarius, preferably K12 or / and Mia (M18).

[0096] Preferably, the dent tab of the invention comprises a flavoring agent. Said flavoring is preferably peppermint oil. More preferably, said peppermint oil is comprised in the dent tab as peppermint powder.

[0097] In a preferred embodiment, the dent tab is coated, e.g., with a flavoring agent or an enteric coating.

[0098] The tent tab can be coated, preferably by edible coatings. Edible coatings can be applied as layers on the surface of the dent tab to protect the product from the effect of the environment and to reduce the diffusion of oxygen into the tab. The used coating material typically and preferably comprises polysaccharides, peptides, proteins, and / or nanoparticles. Coating material(s) can comprise one or more compounds selected from the group consisting of pectin, alginate, chitosan, maltodextrin, starch, especially modified starch, cellulose, whey, sodium caseinate, gluten, and gelatin.

[0099] Conserved status

[0100] In a preferred embodiment, the lantibiotic-producing bacteria is present in the composition of the invention in a conserved status. The term “conserved” as used herein in the context of the lantibiotic-producing bacteria refers to a state in which the bacteria do not or not substantially proliferate and has a reduced or no metabolism compared to a bacterium in a non-conserved state. The conserved state is furthermore a state from which a bacterium can be reconstituted to a proliferative non-conserved state. In preferred embodiments, the conserved bacteria are lyophilized bacteria.

[0101] The inventors found that conserved lantibiotic-producing bacteria can be reconstituted and maintained viable in the composition of the invention, especially in the dent tab of the invention described herein. The inventors further found that conserved lantibiotic- producing bacteria can be reconstituted and activated shortly before and especially during administration of the product, e.g., during a teeth cleaning, and that the activated bacteria adhere and colonize the oral cavity. Saliva can be used to activate the lyophilized lantibiotic-producing bacterial strain. In certain embodiments, the composition provides an environment for reconstituting the conserved lantibiotic-producing bacterial with saliva upon administration to the human cavity. For example, the composition can be formulated as a dent tab, wherein the saliva activates the composition and its ingredients, especially the lyophilized lantibiotic-producing bacterial strain of the composition.

[0102] In certain embodiments, the invention relates to the composition of the invention, wherein the lantibiotic-producing bacteria are present in a reconstituted form. The term “reconstituted form”, as used herein, in the context of a bacterial strain refers to a bacterial strain that underwent at least partially reconstitution from a conserved state (e.g., lyophilized) to a non-conserved state. Reconstitution is never fully complete, and a certain percentage of conserved bacteria will remain. As such, a bacterial strain “present in a reconstituted form” can be distinguished from a bacterial strain in a nonconserved that has never undergone reconstitution by the co-presence of a conserved and non-conserved bacteria. In certain embodiments, the reconstituted form described herein is a conserved : non-conserved bacteria ratio of not more than 10:1 , not more than 9: 1 , not more than 8: 1 , not more than 7:1 , not more than 6: 1 , not more than 5: 1 , not more than 4: 1 , not more than 3: 1 , not more than 2:1 , not more than 1 :1 , not more than 1 :2, not more than 1 :3, not more than 1 :4, not more than 1 :5, not more than 1 :6, not more than 1 :7, not more than 1 :8, not more than 1 :9 and not more than 1 :10. In certain embodiments, the reconstituted form described herein is a conserved : nonconserved bacteria ratio of between 10:1 and 1 :10, between 9:1 and 1 :9 or between 8:1 and 1 :8.

[0103] Ingredients of the composition

[0104] In a very preferred embodiment, the composition further comprises hyaluronic acid. More preferably, the composition further comprises hyaluronic acid powder. The inventors found that a certain grade of humidity, e.g., as stored in hyaluronic acid can improve survival and adhesion of the bacteria in the composition of the invention and have a positive effect on bacterial viability and indirectly on the oral microbiome. As demonstrated, hyaluronic acid enhanced viability and growth of S. salivarius (Figure 2). The terms additives as used herein comprises hyaluronic acid Accordingly, the invention is at least in part based on the finding that hyaluronic acid in the composition of the invention synergistically increases the efficiency in protecting and / or restoring oral hygiene and health.

[0105] In certain embodiments, the composition of the invention does not comprise a surfactant or tenside. More preferably, the composition of the invention does not comprise a synthetic surfactant or synthetic tenside.

[0106] As used herein, the term “synthetic surfactant” or “synthetic tenside” are non-natural surfactants / tensides, i.e. not of natural origin and not synthetized after the specification of a natural surfactant. Synthetic surfactants are preferably synthetically produced with a final structure that is different from the natural surfactants occurring naturally in cells. Synthetic surfactants are preferably selected from the group consisting of organosulfates like sodium lauryl sulfate (SLS), sodium dodecyl sulfate (SDS) related potassium and ammonium salts. Synthetic surfactants are preferably selected from the group consisting of organosulfates, such as SDS, SLS; protonated primary, secondary and tertiary amines as well as quaternary ammonium salts, such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride (DODMAC), and dioctadecyldimethylammonium bromide (DODAB).

[0107] In certain embodiments, the composition does not comprise cationic or anionic surfactants. In certain embodiments, the composition does not comprise a sulfate or a surfactant comprising a sulfate residues. In certain embodiments, the composition does not comprise lauryl or laureth sulfate. In certain embodiments, the tensides excluded in the composition of the invention are selected from the group consisting of sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfat, sodium lauroyl sarcosinate, , Polosamer 407 and lauryl glucoside. In certain embodiments, the composition does not comprise a surfactant is selected from the group comprising sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfat. Preferably the composition does not comprise sodium lauryl sulfate (SLS). The term ’’surfactant” is used interchangeably with the term tenside and refers to chemical compounds that decrease the surface tension or interfacial tension between two liquids, a liquid and a gas, or a liquid and a solid. Surfactants may function as emulsifiers, wetting agents, detergents, foaming agents, or dispersants. The term comprises anionic, cationic and zwitterionic (amphoteric) surfactants. The terms “sodium lauryl sulfate” or “SLS” are used herein interchangeably.

[0108] The inventors found that compositions without tensides, preferably without SLS, prolonged the viability of the comprised bacterial strain in the oral cavity making the probiotics more effective. As such, the absence of tensides, preferably SLS, improves stability, shelf life as well as survival and adhesion post administration. Accordingly, the invention is at least in part based on the finding that the absence of SLS, preferably the absence of tensides increases the efficiency in protecting and / or restoring oral hygiene and health.

[0109] In other embodiments, the composition of the invention comprises a surfactant. Preferably, the surfactant is zwitterionic or anionic, preferably zwitterionic. The surfactant can include a betaine, lauryl or lauroyl residue, more preferably betaine. But preferably, said surfactant is of plant origin (herbal surfactant) or is synthetized after the specification of a surfactant of plant origin. In other more preferred embodiments, the composition of the invention comprises a surfactant, wherein the surfactant is sodium lauroyl glutamate or cocamidopropyl betaine. More preferably, the surfactant is cocamidopropyl betaine. For cocamidopropyl betaine, the inventors could show that it has no or only a minor impact on viability of S. salivarius strains.

[0110] In certain embodiments, the composition of the invention further comprises a flavonoid. The term “flavonoid”, as used herein, refers to a class of polyphenolic secondary metabolites found in plants and propolis. In certain embodiments, the chemical structure of the flavonoid described herein comprises a flavan structural element.

[0111] In certain embodiments, the composition of the invention further comprises a propolis flavonoid. The term “propolis flavonoid”, as used herein, refers to a flavonoid present in propolis, preferably a flavonoid derived from propolis.

[0112] The inventors found that flavonoids such as propolis flavonoids can improve survival and adhesion of the bacteria when applied to the oral cavity and have a positive effect on the oral microbiome. Accordingly, the invention is at least in part based on the finding that flavonoids such as propolis flavonoids synergistically increases the efficiency in protecting and / or restoring oral hygiene and health. The terms additives as used herein comprises flavonoid and propolis flavonoid. Due to the anhydrous character of the composition of the invention, no preservatives are required to prevent growth of pathogens. Preservatives are typically non-selective and lead to probiotic cell death, and therefore loss in efficacy within a short time. Thus, preferably the composition of the invention does not comprise a preservative.

[0113] In another preferred embodiment, the composition of the invention does not comprise gelatine.

[0114] In certain embodiments, the composition of the invention is prepared such that it is not to be swallowed. This effect is preferably achieved by the cleaning agent of the composition, preferably, cellulose fibers and silica. Thus, in preferred embodiments, the cleaning agent of the composition of the invention comprises cellulose fibers and / or silica, preferably cellulose fibers and silica. The phrase “composition is prepared such that it is not to be swallowed”, as used herein, refers to a composition that is not swallowed in its intended use. In certain embodiments, the “composition is prepared such that it is not to be swallowed” refers to an administration selected from the group consisting of buccal administration, sublingual administration, intraoral topical administration, supragingival administration, subgingival administration and topical administration on the teeth. Alterations in the microbiome are usually triggered by swallowable compositions. However, the inventors found that the composition of the invention can emit its effect when not swallowed. As such the composition of the invention can comprise ingredients that are unsuitable for the digestive tract. In certain embodiments, the composition of the invention further comprises a viscosity modifier.

[0115] The term “viscosity modifier”, as used herein, refers to a thickening agent and a substance or composition used to alter the viscosity of the composition. In certain embodiments the viscosity modifier described herein is at least one selected from the group consisting of carboxymethyl cellulose, xanthan gum, gellan gum, hydroxyethyl cellulose, carrageenan, guar gum, sodium alginate, silica and bentonite clay. Preferably, silica is hydrophobic silica.

[0116] In certain embodiments, the composition of the invention does not comprise an emulsifier. Preferably the excluded emulsifier is selected from the group consisting of polysorbate 80, sorbitan oleate, egg lecithin, soybean lecithin, and polyoxyl 35 castor oil. In certain embodiments, the composition of the invention further comprises a buffering agent or a buffer system. Advantageously, the buffering agent or system may promote growth of the probiotic in the oral composition of the composition and / or act as an abrasive. The term “buffering agent” or “buffer”, as used herein, refers to a substance, combination of substances or composition used to alter and / or stabilize the pH of the composition, preferably the buffering agent has its main buffer function in the range of 6.2 to 7.6.

[0117] Suitable buffering agents include, but are not limited to, calcium carbonate, sodium bicarbonate, sodium chloride, sodium or potassium phosphate salts (such as sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate), magnesium carbonate, hydrated aluminum oxides, bentonite clays, kaolin clay, urea, or a combination of any two or more thereof.

[0118] A very preferred buffering agent is bicarbonate, preferably sodium bicarbonate. A further very preferred buffering agent is insoluble (non-precipitated) calcium carbonate which demonstrates good microbial long-term stability. In other very preferred embodiments, the calcium carbonate is insoluble calcium carbonate. A preferred combination of buffering agents is bicarbonate and carbonate, preferably sodium bicarbonate and sodium carbonate.

[0119] The term “buffering system”, as used herein, refers to a system that resists dilution and changes in pH when acids or bases are added. Preferably, buffer systems are made of either a weak acid and its salt or a weak base and its salt. In a preferred embodiment, the buffer system comprises is bicarbonate. In a preferred embodiment, the buffer agent comprises bicarbonate and an organic acid, preferably a weak organic acid. More preferably, the buffer system comprises bicarbonate and citric acid, again more preferably the buffer system comprises sodium bicarbonate and citric acid.

[0120] The composition can include an amino acid, preferably a basic amino acid, such as L- arginine or L-lysine.

[0121] In some embodiments, the oral composition comprises the buffering agent in an amount of about 1 to about 40% w / w based on the total weight of the composition. For example, the composition may comprise the buffering agent in an amount of about 5 to about 35%, or about 5 to about 25%, or about 10 to about 20% w / w based on the total weight of the composition. In some embodiments, the composition comprises the buffering agent in an amount of about 5%, about 10%, about 15%, about 20%, about 25%, or about 30% w / w based on the total weight of the composition.

[0122] The inventors found that compositions used for cleaning the teeth can be used as a vehicle to administer beneficial bacteria. This is unexpected, since teeth cleaning compositions typically remove bacteria to prevent pathologies such as dental caries. However, the inventors found that replacing pathological bacteria with beneficial bacteria during the cleaning process by the composition of the invention synergistically improves oral hygiene and health. Furthermore, the administration of the bacteria and the cleaning can be achieved in one step when using the composition of the invention.

[0123] Accordingly, the invention is at least in part based on the finding that simultaneous cleaning and administration of the bacteria described herein synergistically increases the efficiency in protecting and / or restoring oral hygiene and health.

[0124] In certain embodiments, the composition of the invention comprises a flavoring agent. Said flavoring is preferably peppermint oil. More preferably, said peppermint oil is comprised in the form of peppermint powder. In certain embodiments, the composition further comprises peppermint oil. In a preferred embodiment, the composition comprises 0.1 - 0.5% w / w peppermint powder.

[0125] In certain embodiments, the composition of the invention, wherein the composition further comprises tea tree oil or powder, preferably teat tree powder.

[0126] Tea tree powder and peppermint powder or the oil thereof show a synergistic antimicrobial effect with the lantibiotic(s) described herein.

[0127] In certain embodiments, the composition further comprise at least one additive selected from the group consisting of: fluoride, zinc, vitamin D3, sweetener, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, mint flavor, tea tree oil and / or powder, eugenol, xanthan gum, and magnesium stearate.

[0128] In certain embodiments, the composition comprises fluoride, zinc, vitamin D3, sweetener, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, mint flavor, tea tree oil or powder, eugenol, xanthan gum, propolis, hyaluronic acid and magnesium stearate. In certain embodiments, the composition further comprises fluoride, vitamin D3, flavoring agent, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, tea tree oil or powder, eugenol, xanthan gum, propolis, hyaluronic acid and magnesium stearate and optionally a sweetener. In certain embodiments, the composition comprises fluoride, flavoring agent, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, tea tree oil or powder, eugenol, xanthan gum, hyaluronic acid and magnesium stearate and optionally a sweetener. In certain embodiments, the composition further comprises a flavoring agent, cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, tea tree oil or powder, eugenol, xanthan gum, hyaluronic acid and magnesium stearate and optionally a sweetener and propolis.

[0129] In certain embodiments, the composition comprises cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, xanthan gum, and magnesium stearate and optionally hyaluronic acid. In certain embodiments, the composition comprises cellulose fibers, silica and carbonate as cleaning agent and further citric acid, sodium bicarbonate, xanthan gum, and magnesium stearate and optionally hyaluronic acid. In certain embodiments, the composition comprises cellulose fibers and silica as cleaning agent and further citric acid, sodium bicarbonate, xanthan gum, and magnesium stearate, and optionally hyaluronic acid. In certain embodiments, the composition comprises cellulose fibers and carbonate as cleaning agent and further citric acid, sodium bicarbonate, xanthan gum, and magnesium stearate, and optionally hyaluronic acid. In certain embodiments, the composition comprises silica and carbonate as cleaning agent and further citric acid, sodium bicarbonate, xanthan gum, and magnesium stearate and optionally hyaluronic acid. Optionally, the composition further comprises fluoride, vitamin D3, flavoring agent, tea tree oil or tea tree powder, eugenol, xanthan gum, propolis, hyaluronic acid and optionally a sweetener.

[0130] In preferred embodiments, the composition further comprises a fluoride source. The fluoride source may be a fluoride salt. Said fluoride is preferably selected from the group consisting of sodium fluoride, sodium monofluorophosphate and olaflur / aminfluorid, stannous fluoride, or a combination of two or more thereof. Preferably the composition further comprises between 500 and 1450 ppm, preferably between 950 ppm and 1450 ppm. In some embodiments, the composition comprises a fluoride source in an amount of about 0.3 to about 4%, or about 0.4 to about 3%, or about 0.5 to about 2%, or about 0.6 to about 1 %, or about 0.7% w / w based on the total weight of the composition. In some embodiments, the composition comprises a fluoride source in an amount of about 0.5 to about 1 .5%, or about 0.6 to about 1 .2% w / w based on the total weight of the composition.

[0131] Preferably, the composition further comprises a sweetener. Preferably, the sweetener is not aspartame. More preferably, the sweetener is selected from the group consisting of xylitol, erythritol, sorbitol, maltitol, steviol glycosides, saccharose, saccharin, sucralose, honey, syrups, coconut sugar and isomalt. In certain embodiments, the sweetener described herein is a non-caloric sweetener such as aspartame, acesulfame K or stevioglycosides. In certain embodiments, the sweetener described herein is a caloric sugar substitute such as xylitol, sorbitol, erythritol or mannitol.

[0132] The inventors found that non-sugar sweeteners prolong viability of the bacteria, while protecting teeth by not providing nutrients to tooth-adherent cariogenic bacteria. Accordingly, the invention is at least in part based on the finding that simultaneous cleaning and administration of the bacteria described herein synergistically increases the efficiency in protecting and / or restoring oral hygiene and health. In some embodiments, the composition comprises a sweetener in an amount of about 0.05 to about 5%, about 0.1 to about 4%, about 0.2 to about 3%, about 0.3 to about 2%, about 0.4 to about 1 %, or about 0.5% w / w based on the total weight of the composition.

[0133] In certain embodiments, the composition of the invention further comprises a wetting and / or humectant agent, thickening agent, foaming agent, flavoring agent, preservative and colorant. In certain embodiments, the composition of the invention further comprises a thickening agent, foaming agent, flavoring agent, and colorant. In certain embodiments, the composition of the invention further comprises a thickening agent, flavoring agent, and colorant.

[0134] In preferred embodiments, the composition of the invention further comprises an additive selected from the group consisting of an enzyme, antibacterial agent, antiinflammatory agent, antioxidant (e.g. vitamin D, C or E), and analgesic agent and a combination of one or more thereof. In certain preferred embodiments, the composition of the invention further comprises an additive selected from the group consisting of colourant, a foaming agent (e.g. polysorbate 80), a whitening agent (e.g. carbamide peroxide or hydrogen peroxide), a tooth sensitivity agent (e.g. potassium nitrate, arginine or stannous fluoride), anti-cariogenic agents (e.g. xylitol, fluoride, Manuka honey or tannins), a remineralisation agent (e.g. hydroxyapatite or calcium phosphate), prebiotics (e.g. galactose or raffinose), and / or natural extracts (e.g. amla (Phyllanthus emblica), neem (Azadirachta indica), clove (Syzygium aromaticum), tulst (Ocimum tenuiflorum), or turmeric (Curcuma longa). A variety of pharmaceutically acceptable additives suitable for oral administration of viable or lyophilized bacteria are well known in the art (see, for example, Remington'sPharmaceuticalSciences, 18th ed., Gennaro, ed., 1990, Mack Publishing Co., Easton, Pa., or Remington's Pharmaceutical Sciences, 23rd ed., Adejare, ed., 2021 , Academic Press Inc., incorporated herein by reference).

[0135] Preferably, the composition of the invention does not comprise a foaming agent, especially that kill or decreases viability of lantibiotic-producing bacteria or S. salivarius, such as glycerol, foaming agents, and / or water.

[0136] Examples of antibacterial agents include, but are not limited to, xylitol, erythritol, antibacterial honey (such as Manuka and Kamahi honey), propolis, and tea tree oil. Preferably, the antibacterial agent is xylitol. Antibacterial agents that decrease viability of probiotics should be avoided or used in amounts that are low enough to avoid substantially reducing viability of the probiotic in the composition.

[0137] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form. Preferably said solid dosage form is a tablet, wherein more preferably said tablet is a chewable tablet.

[0138] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, preferably a tablet, wherein the composition further comprises hyaluronic acid. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or a synthetic surfactant. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition does not comprise a preservative and / or a synthetic surfactant. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, preferably a tablet, wherein the composition further comprises hyaluronic acid, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or a synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition does not comprise a preservative and / or a synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers.

[0139] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, preferably a tablet, wherein the composition further comprises hyaluronic acid, and the cleaning agent is a combination of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or a synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a solid dosage form, wherein the composition does not comprise a preservative and / or a synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers.

[0140] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or synthetic surfactant.

[0141] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition does not comprise a preservative and / or synthetic surfactant. In certain embodiments, the lantibiotic- producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers.

[0142] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M 18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid, and the cleaning agent is a combination of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M 18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers.

[0143] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers.

[0144] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and propolis and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and propolis and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers.

[0145] In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and eugenol and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is a combination of silica, carbonate and cellulose fibers. In certain embodiments, the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S. salivarius K12 and / or M18, the composition is in the form of a tablet, preferably a chewable tablet, wherein the composition further comprises hyaluronic acid and eugenol and does not comprise a preservative and / or synthetic surfactant, and the cleaning agent is selected from the group consisting of silica, carbonate and cellulose fibers.

[0146] Dental devices

[0147] In certain embodiments, the invention relates to a dental device comprising a conserved lantibiotic-producing bacteria, wherein the dental device is selected from the group consisting of an aligner, applicator for the oral cavity, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece, dental stripe. The dental device can for example be coated with a powder of a conserved lantibiotic- producing bacteria, preferably a lyophilized S. salivarius, preferably S. salivarius of strain K12 or M18. As such, the dental device is prevented from undesired bacterial growth. Further, the dental device can be cleaned by the composition described herein.

[0148] Alternatively, the dental device can be a device for the application of a reconstituted lantibiotic-producing bacteria, preferably for the application of the composition described herein comprising the reconstituted lantibiotic-producing bacteria.

[0149] In certain embodiments, the invention relates to a dental device comprising a conserved lantibiotic-producing bacteria, wherein the dental device is an applicator for the oral cavity selected from the group consisting of oral spray, dental spray and injector.

[0150] In certain embodiments, the invention relates to the dental device described herein, wherein the lantibiotic-producing bacteria are one or more salivaricin-producing bacteria.

[0151] In certain embodiments, the invention relates to the dental device described herein, wherein the salivaricin-producing bacteria are of the species S. salivarius.

[0152] In certain embodiments, the invention relates to the dental device described herein, wherein S. salivarius comprises or consists of S. salivarius K12 and / or S. salivarius M18.

[0153] Teeth cleaning and other uses

[0154] In certain embodiments, the invention relates to a use of a composition comprising lantibiotic-producing bacteria for cleaning teeth. Preferably said composition is anhydrous and the bacteria are conserved. In certain embodiments, the invention relates to the use of a conserved lantibiotic-producing bacterial strain and ingredients of a composition for oral hygiene in a subject with a healthy oral cavity.

[0155] In preferred embodiments, a healthy subject comprises a healthy oral cavity.

[0156] In certain embodiments, the invention relates to the use of the composition of the invention or the dental device of the invention for oral hygiene in a subject with a healthy oral cavity. In certain embodiments, the invention relates to use of the composition, preferably formulated as dent tab, or use of the dental device of the invention, for cleaning the teeth and mucous membranes of an oral cavity in a subject with a healthy oral cavity. Preferably, the dent tab of the invention is employed as a dentifrice by introducing it into the mouth, crushing it between the teeth, and then brushing the teeth, with saliva acting as a fluid vehicle, for the crushed tablet particles.

[0157] The term “healthy” oral cavity, as used herein, refers to an oral cavity with an intact gingiva, oral mucosa and teeth or substantially intact gingiva, oral mucosa and teeth, wherein no inflammatory symptoms measured by periodontal screening index (PSI) or caries symptoms measured by DMF-T / S index are perceived.

[0158] In certain embodiments, the oral cavity includes the teeth, the lips, the lining inside the cheeks and lips, the front two thirds of the tongue, the upper and lower gums, the palatinal zone, the floor of the mouth under the tongue, the bony roof of the mouth, the area behind the wisdom teeth, Oropharynx, Nasopharynx and the entrance to the auditory tube, preferably the teeth, the upper and lower gums.

[0159] In certain embodiments, the administration of the composition of the invention to the oral cavity described herein is selected from the group consisting of buccal administration, sublingual administration, intraoral topical administration, supragingival administration, subgingival administration and topical administration on the teeth.

[0160] Oral hygiene includes actions in the oral cavity such as brushing (teeth and / or tongue), flossing and rinsing. In certain embodiments, the oral hygiene further includes cleaning and / or preventing contamination of devices for the oral cavity such as dental splints, braces, aligner, applicator for the oral cavity, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece, dental stripe

[0161] In certain embodiments, the composition of the invention or the dental device of the invention are provided with instructions on how to prepare the composition of the invention. In certain embodiments the use described herein is practiced by a private person. In other embodiments, the use described herein is practiced in a commercial context, e.g., in a nursing home, in a dentist practice or in a hospital. The person skilled in the art is aware of how to write or read the instructions accordingly.

[0162] In certain embodiments, the invention relates to the use of the composition of the invention or the dental device of the invention for plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin in a subject with a healthy oral cavity.

[0163] In certain embodiments, the invention relates to the use of an anhydrous composition comprising conserved lantibiotic-producing bacterial strain for plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin in a subject with a healthy oral cavity.

[0164] Preferably, in the uses of the composition of the invention or the dental device of the invention, wherein the composition or device comprises two or more different bacterial strains. Preferably, the two different bacterial strains are S. salivarius K12 and S. salivarius M18.

[0165] Treatment, prevention and oral care

[0166] The composition of the invention is useful for improving the oral health of a subject. For example, by preventing or treating any of the conditions identified in W02001027143, W02002070719, and W02005007178, all incorporated herein by reference in their entireties and Burton, J.P, et al., 2013 J. Med. Microbiol. 62, 875- 884; Burton, J.P, et al., 2013, PLoS ONE 8; Di Pierro, et al. 2015, Clin Cosmet InvestigDent. 7:107-13; L Scariya, D.V, N., M Varghese, 2015. Int. J., PharmaBio Sci. 6, 242-250 mentioning S. salivarius in reduction of dental plaque, support of oral health and oral flora, reduction of dental caries, dental cares, treating and preventing gingivitis, and periodontitis.

[0167] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use as a medicament.

[0168] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in oral care. In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in oral hygiene. In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin in a subject with a healthy oral cavity.

[0169] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of an oral bacterial infection.

[0170] In certain embodiments, the invention relates to a method of treatment and / or prevention of a disease of the oral cavity, said method comprises the steps of applying the composition or the dental device of the invention to an oral cavity of a subject. Preferably said method is for treatment and / or prevention of plaque, caries, white spot lesions, demineralized enamel, demineralized dentin, reduced salivary pH, oral bacterial infection, inflammatory disease of the oral cavity and / or alveolar bone degradation, and for in orthodontic therapy. Preferably the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

[0171] In certain embodiments, the invention relates to a method for oral care, said method comprises the steps of applying the composition or the dental device of the invention to an oral cavity of a subject, preferably to the healthy oral cavity of a subject.

[0172] The term "patient" or "subject" refers to a mammal, such as a human and mammal of veterinary and research interest including, but not limited to a dog or cat. Preferably, the patient or subject is a human.

[0173] In certain embodiments, the invention relates to use of composition of the invention for the manufacture of a medicament for the treatment of a disease in the oral cavity.

[0174] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment and / or prevention of caries, periodontitis, gingivitis, inflammation of the oral cavity, inflammation of the nasopharynx, otitis, bone degradation, reducing pH, halitosis, plaque, mucositis, white spot lesions, remineralization of the enamel, remineralization of dentin, and salivary gland diseases.

[0175] In certain embodiments, the invention relates to a method of treatment and / or prevention of periodontitis, gingivitis, inflammation of the oral cavity, inflammation of the nasopharynx, otitis, bone degradation, reducing pH, halitosis, plaque, mucositis, white spot lesions, remineralization of the enamel, remineralization of dentin, and salivary gland diseases.

[0176] The term "treatment" (and grammatical variations thereof such as “treat” or “treating”) generally refers to obtaining desired pharmacological and / or physiological effects, including partially or completely stabilizing or curing a disease and / or an effect the disease has. As used herein, "treatment" encompasses any treatment of a disease in a patient, including (a) inhibiting a symptom of the disease, i.e., blocking the progression of the disease; or (b) alleviating a symptom of the disease, i.e., causing remission of the disease or the symptom. The term "treatment", as used herein, refers preferably to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.

[0177] The term "prevention", as used herein, relates preferably to the capacity to prevent, minimize or hinder the onset or development of a disorder, disease or condition before its onset. Prevention done in a subject with a risk of developing a disorder, disease or condition. In certain embodiments, the subject with a risk of developing an oral infection is a subject with damaged gingiva, oral mucosa and / or teeth. In certain embodiments, the subject with a risk of developing an oral infection is a subject with at least one selected from the group of tissue damage in gingiva, tissue damage in oral mucosa, increased inflammation in at least one part of the oral cavity, history or ongoing orthodontic therapy, recent history, planned or ongoing dentist procedure, recent history, planned or ongoing surgical procedure in the oral cavity and history of an oral infection. The term “recent history”, as used herein refers to not more than 6 months ago, not more than 5 months ago, not more than 5 months ago, not more than 4 months ago, not more than 3 months ago, not more than 2 months ago, not more than 1 month ago, not more than 3 weeks ago, not more than 2 weeks ago or not more than 1 week ago.

[0178] The terms "administer", "administration" and "administering" refer to physically introducing the composition comprising a therapeutic agent to an individual using any of a variety of methods and delivery systems known to those skilled in the art. Preferably, the administration is oral administration, more preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0179] The term “oral bacterial infection”, as used herein, refers to bacterial growth in the oral cavity with cariogenic, periodontal-pathogen and / or pathogenic bacteria characterized by increased inflammation compared to a healthy subject and / or with disease symptoms.

[0180] In certain embodiments, the oral bacterial infection is a bacterial infection with 100000 or more colony forming units of a cariogenic, periodontal-pathogen and / or pathogenic bacteria per ml saliva, preferably with 500000 or more colony forming units of a cariogenic, periodontal-pathogen and / or pathogenic bacteria per ml saliva, more preferably infection with 1000000 or more colony forming units of a cariogenic, periodontal-pathogen and / or pathogenic bacteria per ml saliva.

[0181] In certain embodiments, the bacterial infection is an S. mutans infection.

[0182] The term “S. Mutans infection”, as used herein, refers to S. mutans growth in the oral cavity characterized by increased inflammation compared to a healthy subject and / or with disease symptoms. Symptoms of a S. mutans infection are reduced pH value of the saliva.

[0183] In certain embodiments, the S. mutans infection is a S. mutans infection 100000 or more colony forming units S. mutans per ml saliva, preferably 1000000 or more colony forming units S. mutans per ml saliva.

[0184] In certain embodiments, the composition of the invention or the dental device of the invention is used in the treatment or prevention of plaque, caries, white spot lesions, demineralized enamel, demineralized dentin, reduced salivary pH, inflammatory disease of the oral cavity and / or alveolar bone degradation in a subject. Optionally said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity.

[0185] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of S. mutans- induced decrease of pH of the saliva in the oral cavity.

[0186] In certain embodiments, the “S. mutans-induced decrease of pH of the saliva” described herein is a saliva pH of below 6.2, below 6, below 5.8, below 5.6, below 5.4 or below 5.2.

[0187] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of plaque in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity. The term “plaque”, as used herein refers to dental plaque. Dental plaque is a sticky film of bacteria that constantly forms on the teeth, in particular in infected oral cavities.

[0188] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of caries. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity.

[0189] The term “caries”, as used herein, refers to an infectious disease resulting from toothadherent cariogenic bacteria that metabolize sugars to produce acid. In certain embodiments, the caries described herein is the dental damage resulting from toothadherent cariogenic bacteria that metabolize sugars to produce acid. Various factors such as genetic predisposition and nutrition can deregulate the oral microbiome and / or favor the growth of cariogenic bacteria, which can progress into caries. The composition described herein can dampen or inhibit the growth of these tooth-adherent cariogenic bacteria by the competitive growth of the lantibiotic producing bacteria and the antimicrobics they emit. Accordingly, the invention is at least in part based on the caries effect of the composition of the invention.

[0190] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of white spot lesions in a subject. Preferably, said subject has at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity. The term “white spot lesions”, as used herein refers to opacities that occur under the surface, particularly in the presence of an oral infection and upon demineralization of the enamel.

[0191] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention demineralized enamel in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity. The term “demineralized enamel”, as used herein refers to the DMF-T / S Index. Enamel begins to demineralize when the oral pH drops below 5.5.

[0192] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of reduced salivary pH in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity. The term “reduced salivary pH”, as used herein refers to a salivary pH lower than a reference subject with a healthy oral cavity, preferably a pH 6.2, below 6, below 5.8, below 5.6, below 5.4 or below 5.2.

[0193] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of inflammatory disease of the oral cavity in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity.

[0194] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment and / or prevention of an inflammatory disease. In preferred embodiments, the composition of the invention or the dental device of the invention is used in the treatment or prevention of an inflammatory disease of the oral cavity and / or alveolar bone degradation in a subject. In certain embodiments, the inflammatory disease described herein is at least one inflammatory disease selected from the group consisting of periodontitis, glossitis, stomatitis, inflammation of the nasopharynx, otitis and mucositis. More preferably the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

[0195] The term “inflammatory disease”, as used herein, refers to a disease, a disorder and / or a condition that is characterized by increased inflammation. Inflammation is characterized by a dysregulation of inflammation markers and / or increased immune cell infiltration, activation, proliferation, and / or differentiation in the blood, in a tissue, in an organ and / or in a certain cell-type. In certain embodiments, the inflammatory disease described herein is an inflammatory disease characterized by increased inflammation in the oral cavity.

[0196] An inflammation marker is a marker that is indicative for inflammation in a subject. Inflammatory markers include, without limitation, CRP, erythrocyte sedimentation rate (ESR), and procalcitonin (PCT), Interleukin (e.g., IL-1 R1 , IL-1 , IL-2, IL-3, IL-4, IL-5, IL- 6, IL-7, IL-8, IL-9, IL-10, IL-11 , IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL- 20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31 , IL-33, IL-32, IL-33, IL-35 or IL-36), Tumor necrosis factor (e.g., TNF alpha, TNF beta), NF-KB, Interferon (e.g., interferon alpha, interferon beta, interferon gamma) MIP-I, MCP-I, RANTES, Cyclooxygenase (C0X)-2, other chemokines and / or other cytokines. An inflammatory marker may also be detectable indirectly, e.g., by detection of an inhibitory factor of an inflammatory marker (e.g., binding factor and / or antagonist). In some embodiments, the inflammatory marker is measured in cells involved in inflammation, in cells affected by cells involved in inflammation, in a tissue, and / or in a body liquid, e.g., the gingival crevicular fluid or the blood. In some embodiments, the inflammation marker is indicative for immune cell infiltration, activation, proliferation and / or differentiation. Detection of the inflammation marker or the ratio of two or more inflammation markers is detected outside the normal range. The normal range of inflammation markers and whether a marker (ratio) has to be below or above a threshold to be indicative for inflammation is known to the person skilled in the art. In some embodiments, the gene expression level, the RNA transcript level, the protein expression level, the protein activity level and / or the enzymatic activity level of at least one inflammation marker is detected. In some embodiments at least one inflammation marker is detected quantitatively and / or qualitatively.

[0197] A deregulated microbiome and / or the growth of pathological bacteria induce(s) an immune response that can result in inflammation and progress into an inflammatory disease. The composition or the dental device of the invention can dampen or inhibit the growth of these tooth-adherent cariogenic bacteria by the competitive growth of the bacteria in the composition or the dental device of the invention and the antimicrobics they emit. Accordingly, the invention is at least in part based on the anti-inflammatory effect of the composition of the invention or the dental device of the invention.

[0198] In certain embodiments, the invention relates to composition of the invention or the dental device of the invention for use in the treatment or prevention of alveolar bone degradation in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity.

[0199] The term “alveolar bone degradation”, as used herein refers to degradation of the alveolar bone typically induced by a periodontal disease such as periodontitis.

[0200] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity in the treatment or prevention of any combination of plaque, caries, white spot lesions, demineralized enamel, demineralized dentin, reduced salivary pH, inflammatory disease of the oral cavity and alveolar bone degradation.

[0201] In certain embodiments, the invention relates to the composition of the invention or the dental device of the invention for use in the treatment or prevention of an inflammatory disease of the oral cavity in a subject. Preferably, said subject has an at least partially inflamed cavity or an at least partially inflamed and infected oral cavity, wherein the inflammatory disease of the oral cavity selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

[0202] The term “otitis media”, as used herein, refers to an inflammatory disease of the middle ear. The means and methods described herein can enable the antimicrobial effect and the improvement of the local microbiome by providing lantibiotics and / or lantibiotic- producing bacteria that can pass through the tuba auditiva.

[0203] The term “halitosis”, as used herein, in the context of an inflammatory disease refers to a foul or offensive odor originating from the oral cavity characterized by an infection in the oral cavity. In certain embodiments, the halitosis in the context of an inflammatory disease is further characterized by at least one selected from the group consisting of periodontal infection, odontogenic infection, xerostomia and mucosal lesion. The means and methods described herein can enable the antimicrobial effect and the improvement of the local microbiome and prevent or treat the cause of the halitosis. The term “mucositis”, as used herein, refers to an inflammatory disease of the mucosis preferably the mucosis of the oral cavity. The means and methods described herein can enable the antimicrobial effect and the improvement of the local microbiome and prevent or treat the cause of the mucositis and / or secondary infections.

[0204] The term “sialadenitis”, as used herein, refers to an inflammatory salivary gland disease. During sialadenitis, the salivary glands are infected by bacteria or prone to be infected by bacteria. In certain embodiments the sialadenitis is induced by bacteria. Typical bacteria inducing sialadenitis are A-Streptococcus such as Streptococcus pyogenes. Lantibiotics such as salivaricin (e.g. derived from K12) is able to inhibit S. pyogenes.

[0205] The term “Gingivitis”, as used herein, refers to an inflammatory disease or disorder of the gingiva, preferably bacteria-induced gingiva. Symptoms of gingivitis include swollen gums, bright red gums, gums that are tender or painful to the touch, bleeding gums. The means and methods described herein can enable the antimicrobial effect and the improvement of the local microbiome and prevent or treat the cause and / or symptoms of the gingivitis, prevent progression to periodontitis and / or secondary infections.

[0206] The term “periodontitis”, as used herein, refers to an inflammatory disease or disorder of the tissues surrounding the teeth that is more severe than gingivitis. Symptoms of periodontitis include Gum swelling that recurs, Gingival recession, bone degradation, and loosening tooth or falling out tooth. Diagnosis of periodontitis can be achieved by inspecting the gum tissue around the teeth, e.g., visually and / or with a probe and X- rays. The means and methods described herein can enable the antimicrobial effect and the improvement of the local microbiome and prevent or treat the cause and / or symptoms of the gingivitis, prevent progression to periodontitis and / or secondary infections.

[0207] In certain embodiments, the invention relates to a method of treatment or prevention comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject.

[0208] In certain embodiments, the invention relates to a method of preventing one or more of gingivitis, periodontitis, peri-im plantitis, peri-implant mucositis, necrotizing gingivitis, necrotizing periodontitis and caries in a subject, the method comprising contacting an oral cavity of the subject with the composition or the dental device of the invention.

[0209] In certain embodiments the step of “applying the composition or the dental device of the invention to the oral cavity”, as described herein is a form of administration selected from the group consisting of buccal administration, sublingual administration, intraoral topical administration, supragingival administration, subgingival administration and topical administration on the teeth.

[0210] In certain embodiments, the invention relates to a method of treatment comprising the steps of applying the composition or the dental device of the invention supra- and / or subgingivally to the oral cavity of a subject.

[0211] In certain embodiments, the invention relates to a method of treatment comprising the steps of applying the composition or the dental device of the invention to the nasopharynx, the tongue and / or teeth of a subject.

[0212] In certain embodiments, the invention relates to a method of cleaning teeth and mucous membranes of an oral cavity comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject, preferably a healthy subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0213] In certain embodiments, the invention relates to a method of cleaning teeth and mucous membranes of an oral cavity comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject, preferably a healthy subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally.

[0214] @ln certain embodiments, the invention relates to a method for plaque reduction or prevention, white spot lesion reduction or prevention, odor reduction or prevention, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing or preventing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin in a subject with a healthy oral cavity; the treatment or prevention of an oral bacterial infection; for use in orthodontic therapy; reduction or prevention of: caries, demineralized enamel, demineralized dentin, reduced salivary pH, inflammatory disease of the oral cavity and / or alveolar bone degradation in a subject; the method comprises the steps of applying the composition or the dental device to the oral cavity of a subject, wherein preferably the composition is applied to the teeth, supra- and / or subgingivally. Preferably the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

[0215] In certain embodiments, the invention relates to a method of selectively promoting, in an oral cavity of a subject: (a) growth, metabolic activity or colonization of bacteria that have beneficial effects on oral health, relative to growth, metabolic activity or colonization of pathogenic oral bacteria; or (b) biofilm formation by bacteria that have beneficial effects on oral health, relative to biofilm formation by pathogenic oral bacteria; the method comprises contacting an oral cavity of the subject with the composition or the dental device of the invention. In certain embodiments, the invention relates to a method for plaque reduction the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In certain embodiments, the invention relates to a method for white spot lesion reduction the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In certain embodiments, the invention relates to a method for odor reduction, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In certain embodiments, the invention relates to a method for increasing salivary pH, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In certain embodiments, the invention relates to a method for decreasing cariogenic microbiota in the oral cavity, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In certain embodiments, the cariogenic microbiota described herein comprises or consists of strains selected from the group consisting of: S. mutans, streptococcaceae, lactobacillaceae, bifidobacterium dentium, acidophil or acidogene bacterial strains, Candida albicans. In certain embodiments, the invention relates to a method for decreasing periodontal-pathogen microbiota in the oral cavity, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity, wherein the application is applied supra- and / or subgingivally.

[0216] In certain embodiments, the invention relates to a use of the composition of the invention for decreasing of periodontal-pathogens and / or decreasing periodontal- pathogen microbiota biofilm in the oral cavity, wherein the periodontal-pathogen microbiota comprises or consists of strains selected from the group consisting of: aggregatibacter actinomycetemcomitans, fusobacterium nucleatum, porphyromonas gingivalis, prevotella intermedia, and fastidious anaerobes including Tannerella forsythia and Treponema denticola.

[0217] In certain embodiments, the invention relates to a method for decreasing pathogenic microbiota in the oral cavity, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity.

[0218] In certain embodiments, the invention relates to a method for decreasing biofilm in the oral cavity, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity.

[0219] In certain embodiments, the invention relates to a method for remineralization of the enamel, the method comprising the steps applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity.

[0220] In certain embodiments, the invention relates to a method for remineralization of dentin, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity.

[0221] In certain embodiments, the invention relates to a method for and combination of the group selected from plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and remineralization of dentin, the method comprising the steps of applying the composition or the dental device of the invention to the oral cavity of a subject with a healthy oral cavity. In preferred embodiments, the phrase “applying the composition to the oral cavity of a subject with a healthy oral cavity” is “applying the composition supra- and / or subgingivally to the oral cavity of a subject with a healthy oral cavity”.

[0222] In certain embodiments, the invention relates to method of the invention, wherein applying the composition comprises the use of a tool selected from the group consisting of: toothbrush, dental floss, interdental brush, tongue scraper, aligner, dental applicator, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral spray, dental spray, oral cotton, dental cotton, injector, dental sud, mesh, fiber mat, fleece, stripe and polymer aligner.

[0223] These tools may be used in the medical or non-medical methods.

[0224] The combining step may be used in the medical or non-medical methods.

[0225] In certain embodiments, the invention relates to a method of reducing bacterial growth on a dental or medical device, the method comprising the steps of 1 ) reconstituting conserved lantibiotic-producing bacteria; and 2) combining the lantibiotic-producing bacteria in reconstituted form with the dental or medical device.

[0226] In certain embodiments, the invention relates to a method of reducing bacterial growth on a dental or medical device, the method comprising the steps of: 1 ) reconstituting conserved lantibiotic-producing bacteria; and 2) combining the lantibiotic-producing bacteria in reconstituted form with the dental or medical device, wherein the dental device is selected from the group consisting of aligner, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece and dental stripe.

[0227] In certain embodiments, the invention relates to the method of reducing bacterial growth on a dental or medical device described herein, wherein the lantibiotic- producing bacteria are one or more salivaricin-producing bacterial strains.

[0228] In certain embodiments, the invention relates to the method of reducing bacterial growth on a dental or medical device described herein, wherein the salivaricinproducing bacteria are of the species S. salivarius.

[0229] In certain embodiments, the invention relates to the method of reducing bacterial growth on a dental or medical device described herein, wherein S. salivarius comprises or consists of S. salivarius K12 and / or S. salivarius M18. In certain embodiments, the invention relates to the packaged product of the invention for use in orthodontic therapy.

[0230] In certain embodiments, the invention relates to method of maintaining and / or reestablishing a healthy oral microbiota in a subject, the method comprising contacting an oral cavity of the subject with the composition of the invention.

[0231] In certain embodiments, the invention relates to the composition of the invention for use in orthodontic therapy.

[0232] In certain embodiments, the invention relates to the dental or medical device of the invention, for use in orthodontic therapy.

[0233] The term “orthodontic therapy”, as used herein, refers to any dental appliance configured to be adhered to the teeth for a prolonged period of time. This prolonged period of time can be at least an hour, at least a day, at least a week, at least a month or at least a year. In certain embodiments, the orthodontic therapy described herein is intended to change the position of a patient’s teeth (e.g. teeth aligners, retainers, braces), preferably in accordance with a plan, such as an orthodontic treatment plan. In certain embodiments, the orthodontic therapy described herein is intended to maintain the position and / or integrity of the teeth (e.g., retainers against teeth grinding) or to regulate the position of the upper respiratory tract (e.g., snoring treatment).

[0234] As such the composition can be applied directly locally on the oral cavity or on the dental appliance and indirectly do the oral cavity.

[0235] Dental treatment should support oral health, certain therapy options enhance the caries risk of patients, e.g., by increasing biofilm on the tooth surface. Orthodontic therapy for example can promote gingivitis, accumulation of the plaque and changes in the oral microbiome including proliferation of S. mutans. S. mutans may be a special key in the development of caries associated lesions during orthodontic therapy. The inventors found that the composition if the invention can dampen or inhibit the growth of S. mutans and / or other pathological bacteria by the competitive growth of the bacteria in the composition and the antimicrobics they emit.

[0236] Accordingly, the invention is at least in part based on the teeth preserving properties of the composition of the invention, “a,” “an,” and “the” are used herein to refer to one or to more than one (i.e. , to at least one, or to one or more) of the grammatical object of the article, “or” should be understood to mean either one, both, or any combination thereof of the alternatives, “and / or” should be understood to mean either one, or both of the alternatives.

[0237] Throughout this specification, unless the context requires otherwise, the words “comprise”, “comprises” and “comprising” and variations thereof will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. The terms “include” and “comprise” are used synonymously, “preferably” means one option out of a series of options not excluding other options, “e.g.” means one example without restriction to the mentioned example. By “consisting of” is meant including, and limited to, whatever follows the phrase “consisting of”.

[0238] The term “essentially”, “about” or “approximately” and the like when used in connection with an attribute or numerical value particularly defines exactly the attribute or value and additionally encompass, unless the context indicates otherwise, numerical values within a range having a lower limit that is 0-10% smaller than the indicated numerical value and having an upper limit that is 0-10% larger than the indicated numerical value. The term “about” or “approximately” means preferably ±10%, more preferably ±5%, again more preferably ±3% or most preferably ±0% (referring to the given numeric value, respectively). In each of the invention embodiments, „about” can be deleted. All ranges of values disclosed herein, should refer and include to any and all values falling within said range including the values defining the range.

[0239] Reference throughout this specification to “one embodiment”, “an embodiment”, “a particular embodiment”, “a related embodiment”, “a certain embodiment”, “an additional embodiment”, “some embodiments”, “a specific embodiment” or “a further embodiment” or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. It is also understood that the positive recitation of a feature in one embodiment, serves as a basis for excluding the feature in a particular embodiment. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0240] The general methods and techniques described herein may be performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated.

[0241] While embodiments of the invention are illustrated and described in detail in the figures and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. It will be understood that changes and modifications may be made by those of ordinary skill within the scope and spirit of the following claims. In particular, the present invention covers further embodiments with any combination of features from different embodiments described above and below. The invention also covers all further features shown in the figures individually, although they may not have been described in the previous or following description. Also, single alternatives of the embodiments described in the figures and the description and single alternatives of features thereof can be disclaimed from the subject matter of the other aspect of the invention.

[0242] Brief description of Figures

[0243] Figure 1 : Co-Cultivation S. Salivarius K12 / S. mutans and S. Salivarius M18 / S. mutans (Example 2)

[0244] Figure 2: Hyaluronic acid Test (24h Co-Cultivation, Example 3). Viability of S. Salivarius with hyaluronic acid (Example 2)

[0245] Well plate 1 : S. salivarius K12 (A) resp. M18 (B), THB (black)

[0246] Well plate 2: S. salivarius K12 (A) resp. M18 (B), Hydrogel with 0.1 % Hyaluronic acid, THB (gray)

[0247] Figure 3: Viability of S. Salivarius in peppermint oil (Example 4) A) Well plate 1 : S. Salivarius K12, THB (black)

[0248] Well plate 2: S. Salivarius K12 and peppermint oil (gray)

[0249] B) Well plate 1 : S. Salivarius M18, THB (black)

[0250] Well plate 2: S. Salivarius M18 and peppermint oil (gray)

[0251] Figure 4: Viability of S. Salivarius in 0.01 % SLS (Example 5)

[0252] A) Well plate 1 : S. Salivarius K12, THB (black)

[0253] Well plate 2: S. salivarius K12 and SLS, THB (gray)

[0254] B) Well plate 1 : S. Salivarius M18, THB (black)

[0255] Well plate 2: S. salivarius M18 and SLS, THB (gray)

[0256] Figure 5: Viability of S. Salivarius in toothpaste without SLS (Example 6)

[0257] A) Well plate 1 : S. Salivarius K12, THB, (black)

[0258] Well plate 2: S. salivarius K12 in toothpaste without SLS, THB (gray)

[0259] B) Well plate 1 : S. Salivarius M18, THB (black)

[0260] Well plate 2: S. salivarius M18 in toothpaste without SLS, THB (gray)

[0261] Figure 6: pH measurement of S. salivarius K12 for 144 hours (Example 7)

[0262] Well plate 1 : S. mutans, THB

[0263] Well plate 2: S. sobrinus, THB

[0264] Well plate 3: S. salivarius K12, THB

[0265] Well plate 4: S. salivarius K12-S. mutans-S. sobr / nus-Co-Cultivation, THB

[0266] Well plate 5: S. mutans-S. sobr / nus-Co-Cultivation, THB

[0267] Figure 7: Viability of S. Salivarius in rinse resp. serum (Example 8)

[0268] A) Well plate 1 : S. Salivarius K12, THB, (black)

[0269] Well plate 2: S. salivarius K12 in rinse, THB (gray, pattern)

[0270] Well plate 3: S. salivarius K12 in serum, THB (dark gray)

[0271] B) Well plate 1 : S. Salivarius M18, THB (black) Well plate 2: S. salivarius M18 in rinse, THB (gray, pattern)

[0272] Well plate 3: S. salivarius M18 in serum, THB (dark gray)

[0273] EXAMPLES

[0274] Aspects of the present invention are additionally described by way of the following illustrative non-limiting examples that provide a better understanding of embodiments of the present invention and of its many advantages. The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques used in the present invention to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should appreciate, in light of the present disclosure that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

[0275] Exemplarily ingredients of a dent tab: 1 Tablet: > 0,35 g

[0276] - S. salivarius K12 and / or M18 (freeze-dried, 1x1012colony forming units)

[0277] - Aroma (e.g., Natural mint): 5-40% w / w

[0278] - Magnesium Stearate: 5-40% w / w

[0279] - Fluoride: 1450 ppm, or 950 ppm

[0280] - optionally Cholecalciferol (Vitamin D3): 5-40% w / w

[0281] - Citric acid: 5-40% w / w

[0282] - Sodium Bicarbonate: 5-40% w / w

[0283] - Sodium Carbonate: 5-40% w / w

[0284] - Silica: 5-40% w / w

[0285] - Sweetener: 5-40% w / w

[0286] - Cellulose fibers: 5-40% w / w

[0287] - optionally Tea tree powder: 5-40% w / w - optionally Eugenol: 5-40% w / w

[0288] - Xanthan gum: 5-40% w / w

[0289] - Hyaluronic acid: 5-40% w / w

[0290] - optionally Propolis: 5-40% w / w

[0291] - optionally Cocam idopropyl Betaine: 5-40% w / w

[0292] - optionally Arginine: 5-40% w / w

[0293] Manufacturing of tablets

[0294] In a first step, the active pharmaceutical ingredient (API) and excipients, e.g., as listed above, were accurately weighed. These components were then mixed thoroughly to achieve a homogenous powder blend. Next, the powder blend was passed through a roller compactor. This compactor consists of two counter-rotating rollers that exert pressure on the powder, forming large, dense compacts or ribbons. Then, the compacts or ribbons were reduced in size through milling or screening. This step breaks down the large compacts into smaller granules with the desired particle size distribution. The milled granules may undergo additional sizing to achieve the desired particle size. This step helps ensure uniformity in the final tablet. After sizing, the granules may be blended again to ensure a consistent mixture and prevent segregation of particle sizes. Next, lubricants were added to the granules to improve flowability during compression. This step is especially important to prevent sticking to the tablet press. The granules were then compressed into tablets using a tablet press.

[0295] This process produced stable and high-quality dent tabs.

[0296] Example 1: Agar-Hemmhof-Test (AHT)

[0297] Three different indicator strains (streptococci: S. sanguinis, S. sobrinus, S. mutans', were incubated as overnight cultures on Columbia blood agar (Fa. Oxoid) at 37°C in 5% CO2. Under aseptic conditions, a 10 mm diameter reservoir was punched out after agar solidification and then incubated with 0.3 ml of K12 (FLORASSIST® Throat Health, Fa. Life Extension, Netherlands) and M18 (FLORASSIST® Oral Hygiene, Fa. Life Extension, Netherlands) solution (BHI, Difco Laboratories) for 48 hours at 37°C in 5% CO2. Sterile physiological saline was used as a negative control and 3% chlorhexidine as a positive control. Table 1 : comparison of Agar-Hem mhof-Test (AHT) Results

[0298] Example 2: Biofilm assay - Co-Cultivation S. Salivarius K12 / S. mutans and S. Salivarius M18 / S. mutans

[0299] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after co-cultivation), 5 minutes, 1 hour, 2 hours, 24 hours after cocultivation.

[0300] Well plate 1 : S. salivarius K12 versus S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0301] Well plate 2: S. salivarius M18 versus S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0302] Results: S. salivarius K12 and M18 showed antimicrobial activity against S. mutans, plated on Mitis-Salivarius Selective Agar (Mitis Salivarius Agar, Sigma-Aldrich), 24h, aerobic atmosphere of 5% CO2. (Figure 1 )

[0303] Example 3: Biofilm assay - Hyaluronic acid

[0304] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after co-cultivation), 5 minutes, 1 hour, 2 hours, 24 hours after cocultivation.

[0305] A) Well plate 1 : S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0306] Well plate 2: S. salivarius K12 and Hydrogel with 0.1 % Hyaluronic acid (Fa. TRB Chemedica AG), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose. B) Well plate 1 : S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0307] Well plate 2: S. salivarius M18 and Hydrogel with 0.1 % Hyaluronic acid (Fa. TRB Chemedica AG), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0308] Results: Hydrogel with 0.1 % Hyaluronic acid enhanced viability and growth of S. salivarius K12 resp. M18 in vitro (Figure 2)

[0309] Example 4: Biofilm assay - Peppermint oil

[0310] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after Co-cultivation), 5 minutes, 1 hour, 2 hours, 24 hours after cocultivation.

[0311] A) Well plate 1 : S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose (black)

[0312] Well plate 2: S. salivarius K12 and 0.1 % of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0313] Well plate 3: S. salivarius K12 and 0.2% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0314] Well plate 4: S. salivarius K12 and 0.3% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0315] Well plate 5: S. salivarius K12 and 0.4% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0316] Well plate 6: S. salivarius K12 and 0.5% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0317] Results: Co-cultivation of S. salivarius K12 and peppermint oil (0.1 - 0.5%) decreased S. salivarius K12 viability only after 2 hours according to different peppermint oil concentrations (Figure 3).

[0318] B): Well plate 1 : S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0319] Well plate 2: S. salivarius M18 and 0.1 % of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose. Well plate 3: S. salivarius M18 and 0.2% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0320] Well plate 4: S. salivarius M18 and 0.3% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0321] Well plate 5: S. salivarius M18 and 0.4% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0322] Well plate 6: S. salivarius M18 and 0.5% of peppermint oil (Fa. Puressentiel), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0323] Results: The co-cultivation of S. salivarius M18 and peppermint oil (0.1 - 0.5%) decreased S. salivarius M18 viability after 24 hours according to different peppermint oil concentrations. S. salivarius M18 showed better viability compared to S. salivarius K12 among co-cultivation with peppermint oil (0.1 - 0.5%) (Figure 3).

[0324] Example 5: Biofilm assay - SLS

[0325] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after Co-cultivation), 5 minutes, 1 hour, 2 hours, 24 hours after cocultivation.

[0326] A): Well plate 1 : S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0327] Well plate 2: S. salivarius K12 and 0.01 % SLS (Fa. Merck), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0328] B): Well plate 1 : S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0329] Well plate 2: S. salivarius M18 and 0.01 % SLS (Fa. Merck), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0330] Results: Toothpaste with 0.01 % SLS decreased the viability of S. salivarius K12 resp. M18 significantly. There was no viability of S. salivarius K12 immediately after cocultivation (baseline) in vitro (Figure 4). Example 6: Biofilm assay - SLS free

[0331] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after co-cultivation), 5 minutes, 1 hour, 2 hours, 24 hours after cocultivation.

[0332] A): Well plate 1 : S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0333] Well plate 2: S. salivarius K12 with toothpaste (SLS-free) (Fa. Curaden), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0334] B): Well plate 1 : S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0335] Well plate 2: S. salivarius M18 with toothpaste (SLS-free) (Fa. Curaden), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0336] Results: Toothpaste without SLS does not compromise the viability of S. salivarius K12 resp. M18 after 5 minutes in vitro (Figure 5). S. salivarius M18 showed better viability compared to S. salivarius K12 among co-cultivation with toothpaste (SLS-free).

[0337] Example 7: Biofilm assay - pH improvement

[0338] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) (Figure 6): pH measurement of S. salivarius K12 for 144 hours

[0339] Well plate 1 : S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0340] Well plate 2: S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0341] Well plate 3: S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0342] Well plate 4: S. salivarius K12-S. mutans-S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0343] Well plate 5: S. mutans-S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose. Results: S. salivarius K12 improved pH into physiological range during co-cultivation with cariogen-associated bacteria for 144 hours (Figure 6).

[0344] Example 8: Biofilm assay - Rinse and serum

[0345] Biofilm assay in 96 well plates (24h, aerobic atmosphere of 5% CO2, 37°C) at baseline (immediately after co-cultivation), 5 minutes, 1 hour, 24 hours after co-cultivation.

[0346] A): Well plate 1 : S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0347] Well plate 2: S. salivarius K12 with rinse (elmex sensitive) resp. serum (elmex on the go) (Fa. Elmex; Colgate-Palmolive), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0348] B): Well plate 1 : S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0349] Well plate 2: S. salivarius M18 with rinse (elmex sensitive) resp. serum (elmex on the go) (Fa. Elmex; Colgate-Palmolive), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.

[0350] Results: Rinse as well as serum (with alcohol) do not compromise the viability of S. salivarius K12 resp. M18 after 5 minutes in vitro (Figure 7).

[0351] Example 9: Co-cultivation of S. mutans and S. salivarius K12 and / or M18

[0352] Co-cultivation of S. mutans and S. salivarius K12 and / or M18 led to the inhibition of S. mutans viability, thereby, preventing its biofilm formation. The co-cultivation of S. mutans ATCC 25175 with S. salivarius K12 and / or S. salivarius M18 led to a complete inhibition of S. mutans viability in suspensions. Antimicrobial activity of S. salivarius K12 and S. salivarius M18 was determined via methods known in the art, especially as described in Future Microbiol. 2009;4:819-35.

Claims

Claims1. A composition for teeth cleaning comprising lantibiotic-producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous.

2. The composition of claim 1 , wherein the composition is in the form of a single dosage unit.

3. The composition of claim 1 or 2, wherein the composition is formulated as solid dosage form, preferably the solid dosage form is selected from the group consisting of tablet, caplet, capsule, powder, lozenge, sachet, cachet, troche, pellet, granules, gum, film; more preferably the solid dosage form is a tablet.

4. The composition of claim 3, wherein the composition is in the form of a solid chewable dosage form.

5. The composition of any one of the preceding claims, wherein the lantibiotic- producing bacteria are conserved, preferably the lantibiotic-producing bacteria are lyophilized.

6. The composition of any one of the preceding claims, wherein the lantibiotic- producing bacteria are salivaricin-producing bacteria.

7. The composition of any one of the preceding claims, wherein the salivaricinproducing bacteria are of the species S. salivarius.

8. The composition of any one of the preceding claims, wherein the species S. salivarius comprises or preferably is the strain S. salivarius K12 and / or M18.

9. The composition of any one of the preceding claims, wherein the composition further comprises hyaluronic acid.

10. The composition of any one of the preceding claims, wherein the composition does not comprise a synthetic surfactant, wherein preferably said synthetic surfactant is a sulfate, more preferably said sulfate is selected from the group comprising sodium lauryl sulfate, sodium laureth sulfate, and ammonium lauryl sulfat.11 . The composition of any one of the preceding claims, wherein the composition comprises a flavonoid, preferably wherein the formulation comprises a propolis flavonoid.

12. A dental device comprising a conserved lantibiotic-producing bacterial strain, wherein the dental device is selected from the group consisting of aligner, applicator for the oral cavity, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece, dental stripe, wherein preferably the applicator for the oral cavity is selected from the group consisting of oral spray, dental spray and injector or the dental device is selected from the group consisting of aligner, dental thread, dental tip, toothbrush, tongue brush, dental stick, oral cotton, dental cotton, dental sud, dental mesh, dental fiber mat, dental fleece, dental stripe, and injector.

13. Use of the composition of any one of claims 1 -1 1 or the dental device of claim 12 for non-therapeutic oral hygiene in a subject with a healthy oral cavity, preferably for non-therapeutic cleaning the teeth and mucous membranes of a healthy oral cavity, more preferably for non-therapeutic: plaque reduction, white spot lesion reduction, odor reduction, increasing salivary pH, decreasing cariogenic microbiota in the oral cavity, decreasing periodontal-pathogen microbiota in the oral cavity, decreasing pathogenic microbiota in the oral cavity, decreasing biofilm in the oral cavity, remineralization of the enamel and / or remineralization of dentin, in a subject with a healthy oral cavity.

14. The composition of any one of claims 1-11 or the dental device of claim 12 for use as a medicament, preferably for treatment or prevention of an oral bacterial infection and for use in orthodontic therapy.

15. The composition of any one of claims 1-11 or the dental device of claim 12 for use according to claim 14 in the treatment or prevention of plaque, caries, white spot lesions, demineralized enamel, demineralized dentin, reduced salivary pH, inflammatory disease of the oral cavity and / or alveolar bone degradation in a subject; preferably the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.

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