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WO2025132965A1 - Formulations et dispositifs comprenant des bactéries productrices de lantibiotiques - Google Patents

Formulations et dispositifs comprenant des bactéries productrices de lantibiotiques Download PDF

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Publication number
WO2025132965A1
WO2025132965A1 PCT/EP2024/087670 EP2024087670W WO2025132965A1 WO 2025132965 A1 WO2025132965 A1 WO 2025132965A1 EP 2024087670 W EP2024087670 W EP 2024087670W WO 2025132965 A1 WO2025132965 A1 WO 2025132965A1
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composition
dental
oral cavity
salivarius
certain embodiments
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Elisabeth REICHARDT
Claudia REICHARDT
Klaus Neuhaus
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/99—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from microorganisms other than algae or fungi, e.g. protozoa or bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/87—Application Devices; Containers; Packaging

Definitions

  • 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.
  • 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.
  • 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.
  • common toothpastes include ingredients that may serve as excellent media for growth of the probiotics which finally results in a reduction in cell viability.
  • natural antimicrobial compounds produced by oral probiotic streptococci are be utilized as a highly promising treatment option, preferably to eliminate S. mutans pathogens.
  • 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.
  • 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.
  • 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.
  • the lantibiotic-producing bacteria tolerate the presence of ingredients of the composition of the invention surprisingly well and long.
  • the composition of the invention can improve dental health and reduce pathologies, such as inflammation in the oral cavity.
  • 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.
  • the invention relates to, inter alia, the following embodiments:
  • a composition for teeth cleaning comprising lantibiotic-producing bacteria and at least one teeth cleaning agent, wherein the composition is anhydrous.
  • composition of any one of the preceding embodiments, wherein the salivaricin-producing bacteria are of the species S. salivarius.
  • 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.
  • composition of any one of the preceding embodiments, wherein the composition further comprises hyaluronic acid.
  • 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.
  • 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.
  • composition of any one of the preceding embodiments, wherein the composition comprises a flavonoid, preferably wherein the formulation comprises a propolis flavonoid.
  • composition of any one of the preceding embodiments, wherein the composition further comprises a buffer system.
  • 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.
  • 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
  • the sweetener is not aspart
  • 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.
  • composition of any one of embodiments 1 -14 or the dental device of embodiment 15 for use as a medicament are provided.
  • 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.
  • 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.
  • lantibiotic-producing bacterial strain refers to bacterial strain that synthesizes and secretes lantibiotics.
  • Lantibiotics are ribosomally synthesized, post-translationally modified antimicrobial peptides.
  • lantibiotics refers to lanthionine-containing antibiotics.
  • 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.
  • the lantibiotic described herein is a type Al and All lantibiotic.
  • the lantibiotic-producing bacterial strain is a salivaricinproducing bacterial strain.
  • salivaricin refers to lantibiotics produced by Streptococcus salivarius (S. salivarius).
  • 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.
  • 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.
  • 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.
  • the composition of the invention can comprise one or more species or strains of lantibiotic-producing bacteria.
  • 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.
  • MRSA methicillin-resistant Staphylococcus aureus
  • the antimicrobial activity of the lantibiotics described herein preferably comprises or consists of an inhibitory effect against S. mutans.
  • 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)).
  • CLSI Clinical and Laboratory Standards Institute
  • M11 -A7 Clinical and Laboratory Standards Institute
  • a milliliter of the lantibiotic-producing bacterial strain (1 x 10 7 bacteria/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 10 6 bacteria/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.
  • 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.
  • S. mutans (1 x 10 6 bacteria/ml) and S. salivarius K12 (1 x 10 7 bacteria/ml or 1 x 10 8 bacteria/ml) are co-cultivated using TranswellTM (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 TranswellTM, 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.
  • antibacterial activity of a lantibiotic-producing bacterial strain is present in case growth of S. mutans was significantly inhibited compared to control.
  • the lantibiotic-producing bacteria described herein is a Grampositive bacterium.
  • the lantibiotic-producing bacteria described herein is a bacterium from the order of Lactobacillales.
  • the lantibiotic-producing bacterial strain described herein is a bacterium from the family of Streptococcaceae.
  • the invention relates to the composition of the invention, wherein the lantibiotic-producing bacterial strain is of the species S. salivarius.
  • 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.
  • 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.
  • 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).
  • lantibiotic-producing bacterial strain comprises or consists of S. salivarius K12 and Streptococcus salivarius strain Mia (M18).
  • S. salivarius K12 and Streptococcus salivarius strain Mia 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.
  • the lantibiotic-producing bacterial strain S. salivarius is S. salivarius Mia (M18).
  • the invention relates to the composition of the invention, wherein S. salivarius is S. salivarius K12.
  • 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.
  • 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).
  • the lantibiotic-producing bacterial strain described herein is alive.
  • the bacterial strain can be a naturally occurring strain or a genetically modified strain.
  • 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.
  • the composition of the invention is anhydrous.
  • 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.
  • water includes absorbed moisture from the environment.
  • the oral composition is non-aqueous.
  • 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).
  • drying such as air drying, vacuum drying, fluidized bed drying, spray drying, and lyophilization (freeze drying).
  • 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.
  • the single dosage unit has a dose of 1x10 12 colony 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.
  • the composition of the invention is a ready-to-use formulation.
  • Ready-to- use 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.
  • a formulation in a vial, of the desired concentration that only needs to be drawn up into a syringe.
  • the teeth cleaning composition of the invention is formulated as a solid dosage form.
  • 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.
  • the teeth cleaning composition of the invention is formulated as tablet, capsule, or sachet.
  • the teeth cleaning composition of the invention is formulated as tablet.
  • the teeth cleaning composition of the invention is formulated as solid chewable dosage form.
  • the solid chewable dosage form is suitable and formulated for teeth brushing.
  • the composition of the invention is formulated as a dent tab.
  • the single dosage unit is formulated as a dent tab.
  • dent tab and toothpaste tablets are used herein interchangeably.
  • the dent tab further comprises a buffering agent or buffer system.
  • the dent tab further comprises a lubricant.
  • the dent tab further comprises a flavoring agent.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the dent tab is coated, e.g., with a flavoring agent or an enteric coating.
  • 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.
  • 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.
  • 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.
  • the composition provides an environment for reconstituting the conserved lantibiotic-producing bacterial with saliva upon administration to the human cavity.
  • 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.
  • the invention relates to the composition of the invention, wherein the lantibiotic-producing bacteria are present in a reconstituted form.
  • reconstituted form 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.
  • 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.
  • 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.
  • 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.
  • the composition further comprises hyaluronic acid. More preferably, the composition further comprises hyaluronic acid powder.
  • hyaluronic acid e.g., as stored in hyaluronic acid
  • 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.
  • 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.
  • 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).
  • 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), dimethyldioct
  • 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.
  • the composition does not comprise a surfactant is selected from the group comprising sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfat.
  • a surfactant is selected from the group comprising sodium lauryl sulfate, sodium laureth sulfate, ammonium lauryl sulfat.
  • the composition does not comprise sodium lauryl sulfate (SLS).
  • SLS sodium lauryl sulfate
  • 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.
  • sodium lauryl sulfate or “SLS”
  • compositions without tensides preferably without SLS, prolonged the viability of the comprised bacterial strain in the oral cavity making the probiotics more effective.
  • 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.
  • the composition of the invention comprises a surfactant.
  • 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.
  • 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.
  • the composition of the invention further comprises a flavonoid.
  • flavonoid refers to a class of polyphenolic secondary metabolites found in plants and propolis.
  • the chemical structure of the flavonoid described herein comprises a flavan structural element.
  • the composition of the invention further comprises a propolis flavonoid.
  • propolis flavonoid refers to a flavonoid present in propolis, preferably a flavonoid derived from propolis.
  • buffering system refers to a system that resists dilution and changes in pH when acids or bases are added.
  • buffer systems are made of either a weak acid and its salt or a weak base and its salt.
  • the buffer system comprises is bicarbonate.
  • 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.
  • 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.
  • 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.
  • the composition comprises cellulose fibers, citric acid, sodium bicarbonate, carbonate, silica, xanthan gum, and magnesium stearate and optionally hyaluronic acid.
  • 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.
  • 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.
  • 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.
  • the composition comprises silica and carbonate as cleaning agent and further citric acid, sodium bicarbonate, xanthan gum, and magnesium stearate and optionally hyaluronic acid.
  • 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.
  • 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.
  • the composition further comprises between 500 and 1450 ppm, preferably between 950 ppm and 1450 ppm.
  • 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.
  • 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.
  • the composition further comprises a sweetener.
  • 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.
  • the sweetener described herein is a non-caloric sweetener such as aspartame, acesulfame K or stevioglycosides.
  • the sweetener described herein is a caloric sugar substitute such as xylitol, sorbitol, erythritol or mannitol.
  • xylitol fluoride, Manuka honey or tannins
  • a remineralisation agent e.g. hydroxyapatite or calcium phosphate
  • prebiotics e.g. galactose or raffinose
  • 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).
  • 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.
  • a foaming agent especially that kill or decreases viability of lantibiotic-producing bacteria or S. salivarius, such as glycerol, foaming agents, and/or water.
  • antibacterial agents examples include, but are not limited to, xylitol, erythritol, antibacterial honey (such as Manuka and Kamahi honey), propolis, and tea tree oil.
  • 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.
  • 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.
  • said solid dosage form is a tablet, wherein more preferably said tablet is a chewable tablet.
  • the composition is in the form of a solid dosage form, wherein the composition does not comprise a preservative and/or a synthetic surfactant.
  • 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.
  • the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S.
  • 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.
  • the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S.
  • 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.
  • 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.
  • the lantibiotic-producing bacterial strain is S. salivarius, preferably of the strain S.
  • 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.
  • 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.
  • the invention relates to the dental device described herein, wherein the lantibiotic-producing bacteria are one or more salivaricin-producing bacteria.
  • the invention relates to the dental device described herein, wherein the salivaricin-producing bacteria are of the species S. salivarius.
  • the invention relates to the dental device described herein, wherein S. salivarius comprises or consists of S. salivarius K12 and/or S. salivarius M18.
  • the invention relates to a use of a composition comprising lantibiotic-producing bacteria for cleaning teeth.
  • a composition comprising lantibiotic-producing bacteria for cleaning teeth.
  • said composition is anhydrous and the bacteria are conserved.
  • 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.
  • a healthy subject comprises a healthy oral cavity.
  • 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.
  • 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.
  • 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.
  • healthy oral cavity 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.
  • PSI periodontal screening index
  • DMF-T/S index DMF-T/S index
  • 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.
  • 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.
  • 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.
  • the use described herein is practiced by a private person.
  • 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.
  • 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.
  • the invention relates to the use of an anhydrous composition
  • 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.
  • the composition or device comprises two or more different bacterial strains.
  • the two different bacterial strains are S. salivarius K12 and S. salivarius M18.
  • composition of the invention is useful for improving the oral health of a subject.
  • 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.
  • the invention relates to the composition of the invention or the dental device of the invention for use as a medicament.
  • 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.
  • 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.
  • 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.
  • 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.
  • the inflammatory disease of the oral cavity is selected from the group consisting of otitis media, halitosis, mucositis, sialadenitis, gingivitis and periodontitis.
  • 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.
  • patient refers to a mammal, such as a human and mammal of veterinary and research interest including, but not limited to a dog or cat.
  • patient or subject is a human.
  • 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.
  • 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.
  • 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.
  • treatment 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.
  • 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.
  • treatment 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.
  • prevention 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.
  • the subject with a risk of developing an oral infection is a subject with damaged gingiva, oral mucosa and/or teeth.
  • 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.
  • cent history 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.
  • administer refers 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.
  • the administration is oral administration, more preferably the composition is applied to the teeth, supra- and/or subgingivally.
  • oral bacterial infection 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.
  • 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.
  • the bacterial infection is an S. mutans infection.
  • 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.
  • said subject has an at least partially inflamed cavity or an at least partially inflamed and at least partially infected oral cavity.
  • demineralized enamel refers to the DMF-T/S Index. Enamel begins to demineralize when the oral pH drops below 5.5.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the invention relates to the dental or medical device of the invention, for use in orthodontic therapy.
  • orthodontic therapy 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.
  • 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.
  • 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).
  • 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.
  • FIG. 1 Co-Cultivation S. Salivarius K12/S. mutans and S. Salivarius M18/S. mutans (Example 2)
  • Well plate 1 S. salivarius K12 (A) resp. M18 (B), THB (black)
  • Well plate 2 S. salivarius K12 (A) resp. M18 (B), Hydrogel with 0.1 % Hyaluronic acid, THB (gray)
  • FIG. 3 Viability of S. Salivarius in peppermint oil (Example 4)
  • A) Well plate 1 S. Salivarius K12, THB (black)
  • Well plate 2 S. Salivarius M18 and peppermint oil (gray)
  • Well plate 1 S. Salivarius K12, THB (black)
  • Well plate 2 S. salivarius K12 and SLS, THB (gray)
  • Well plate 2 S. salivarius M18 and SLS, THB (gray)
  • Well plate 1 S. Salivarius K12, THB, (black)
  • Well plate 2 S. salivarius K12 in toothpaste without SLS, THB (gray)
  • Well plate 1 S. mutans, THB
  • Well plate 4 S. salivarius K12-S. mutans-S. sobr/nus-Co-Cultivation, THB
  • Well plate 5 S. mutans-S. sobr/nus-Co-Cultivation, THB
  • Well plate 1 S. Salivarius K12, THB, (black)
  • Well plate 2 S. salivarius K12 in rinse, THB (gray, pattern)
  • Well plate 3 S. salivarius K12 in serum, THB (dark gray)
  • Well plate 1 S. Salivarius M18, THB (black)
  • Well plate 2 S. salivarius M18 in rinse, THB (gray, pattern)
  • Well plate 3 S. salivarius M18 in serum, THB (dark gray)
  • Aroma e.g., Natural mint: 5-40% w/w
  • the active pharmaceutical ingredient (API) and excipients were accurately weighed. These components were then mixed thoroughly to achieve a homogenous powder blend.
  • 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.
  • the granules may be blended again to ensure a consistent mixture and prevent segregation of particle sizes.
  • 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.
  • Example 1 Agar-Hemmhof-Test (AHT)
  • 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.
  • Well plate 1 S. salivarius K12 versus S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius M18 versus S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Well plate 1 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • 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.
  • 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.
  • Well plate 1 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose (black)
  • Well plate 2 S. salivarius K12 and 0.1 % of peppermint oil (Fa. Purdict), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 3 S. salivarius K12 and 0.2% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 4 S. salivarius K12 and 0.3% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 5 S. salivarius K12 and 0.4% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 6 S. salivarius K12 and 0.5% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 1 S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius M18 and 0.1 % of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 3 S. salivarius M18 and 0.2% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 4 S. salivarius M18 and 0.3% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 5 S. salivarius M18 and 0.4% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 6 S. salivarius M18 and 0.5% of peppermint oil (Fa. Purnegative), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Well plate 1 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius K12 and 0.01 % SLS (Fa. Merck), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 1 S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius M18 and 0.01 % SLS (Fa. Merck), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Well plate 1 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius K12 with toothpaste (SLS-free) (Fa. Curaden), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 1 S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. salivarius M18 with toothpaste (SLS-free) (Fa. Curaden), Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 1 S. mutans, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 2 S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 3 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 4 S. salivarius K12-S. mutans-S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • Well plate 5 S. mutans-S. sobrinus, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Well plate 1 S. salivarius K12, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Well plate 1 S. salivarius M18, Todd Hewitt Broth (THB; Difco Laboratories) with 0.5% sucrose.
  • 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.
  • Example 9 Co-cultivation of S. mutans and S. salivarius K12 and/or M18
  • 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.

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  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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Abstract

L'invention concerne une composition pour le nettoyage des dents comprenant des bactéries productrices de lantibiotiques et au moins un agent de nettoyage des dents, la composition étant anhydre. L'invention concerne en outre un dispositif dentaire comprenant une souche bactérienne productrice de lantibiotiques conservée. L'invention concerne en outre les utilisations et les méthodes médicales et non médicales correspondantes.
PCT/EP2024/087670 2023-12-21 2024-12-19 Formulations et dispositifs comprenant des bactéries productrices de lantibiotiques Pending WO2025132965A1 (fr)

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WO2001027143A1 (fr) 1999-10-12 2001-04-19 Blis Technologies Limited Lantibiotique
WO2002070719A2 (fr) 2001-01-19 2002-09-12 Trustees Of The University Of Pennsylvania Systeme d'expression genique regulable
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