Composition for supplemental oral hygiene

Abstract

An orally administrable composition for the maintenance of oral health comprising, as active ingredients an antibiotic agent, an anti-inflammatory agent and, optionally, a remineralizing agent. Also provided are methods of use of the composition for use in maintaining or improving oral health and for use in treatment of oral diseases or disorders, either by self¬ administration or by administration by a health care professional.

Description

COMPOSITION FOR SUPPLEMENTAL ORAL HYGIENECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 578,912 filed August 25, 2023, the entire disclosure of which is incorporated herein by reference.FIELD OF INVENTION

[0002] The invention relates to a medicinal composition for maintenance of oral health, particularly for the prevention or treatment of oral diseases or disorders, such as dental caries and periodontal disease.BACKGROUND

[0003] Oral diseases affect an estimated 3.5 billion people worldwide and are most prevalent in children, racialized communities, and developing nations (1). Dental caries and periodontal disease are responsible for most of these instances, with untreated caries in permanent teeth and severe periodontitis ranked as the first and sixth most prevalent health conditions in 2015, respectively (2). Both conditions are caused by the accumulation of plaque on the surfaces of the teeth and gums. Furthermore, the impact of oral diseases does not stop at the mouth and teeth. A growing body of evidence has linked oral health, particularly periodontal (gum) disease, to several chronic diseases including diabetes, heart disease, and stroke.

[0004] The most effective method to reduce one’s risk of developing oral diseases is to maintain an effective oral hygiene regimen; however, many people do not have the time or resources needed to upkeep such a program, which generally consists of brushing and flossing twice daily. Modem solutions to improve oral hygiene are often inaccessible by populations needing them the most - for example, while electric toothbrushes remove significantly more plaque than manual brushes, they are also 3-25 times more expensive (3). Further, traditional brushing requires clean water, which is infeasible for many in developing nations, as well as those ‘on the go’ in an increasingly mobile population. There is clearly an unmet need for accessible oral healthcare solutions.

[0005] Dental Caries

[0006] Dental caries, commonly known as tooth decay, is the localized destruction of enamel and dentin (4). This destruction is facilitated by thousands of bacterial species which form a bacterial biofdm (dental plaque) on the teeth. As the bacteria process monosaccharides and disaccharides introduced by the consumption of foods and beverages, they create acidic by-products which dissolve the dentin and enamel under the biofdm in a process known as demineralization (4,5). Dental caries is a chronic condition with a slow progression; however, the significant destruction of dental tissues can create irreversible cavitation (caries lesions) and eventually lead to tooth loss. Caries lesions are diagnosed via visual and radiographic examinations. Analysis of biofdm samples can confirm the presence of bacterial species highly associated with the production of acid by-products, including Lactobacilli and Streptococcus mutans (5). Removal of the bacterial biofdm is the first step in treating dental caries, after which dental practitioners commonly administer a fluoride solution to remineralize the enamel and dentin layers (6). Advanced decay requires more intensive treatments, including fillings and tooth extraction. Novel therapeutics include administering synthetic targeted antimicrobial peptides to facilitate the dissolution of the biofdm (7).

[0007] Periodontal Disease

[0008] Periodontal disease is an umbrella term for several chronic inflammatory conditions affecting the gums, bone, and other tissue supporting the teeth (the periodontium) (8). The disease first presents as gingivitis, an inflammation of the gums arising from dysbiosis within the biofdm. The condition manifests as gingival bleeding and swelling, which is normally reversible through professional dental cleaning and by practicing good oral hygiene (9). If left untreated, however, anaerobic bacteria will colonize deeper periodontal pockets, triggering an immune response characteristic of periodontitis. Periodontitis is the progressive destruction of the gingival tissue surrounding the teeth, which compromises tooth attachment, damages the periodontal ligament, and can ultimately degrade the alveolar bone (10). Patients with periodontitis are commonly given adjunctive local and systemic antibiotics. Invasive treatments such as access flap periodontal surgery, respective periodontal surgery, regenerative periodontal surgery, and tooth extraction may be required in advanced cases (11).

[0009] Medicinal Chewing Gums

[0010] The use of chewing gum as a drug delivery system offers a highly convenient method of administering both local and systemic medications via the oral cavity (12). It also provides a particularly effective method of increasing treatment compliance in children and the elderly. Medicated chewing gums often comprise typical ingredients found in nonmedicated gums and a small amount of active ingredient(s).

[0011] Chewing gum generally consists of a water insoluble gum base and a water- soluble outer layer (13). The water-soluble portion and flavors dissipate through the saliva during chewing and the gum base is retained in the mouth throughout the chew. The insoluble gum base typically comprises elastomers, resins, fats and oils, softeners, stabilizers, thickeners, surface active agents, and inorganic fillers. The water-soluble portion can include bulk sweeteners, high intensity sweeteners, flavoring agents, stabilizers, softeners, surface active agents, emulsifiers, colors, acidulants, fillers, antioxidants, and other components.

[0012] Medicinal chewing gums for the maintenance of oral health first arose in the 1960s with the introduction of commercial fluoride gums to promote enamel remineralization (14). Fluoride gums offer an effective treatment for children suffering from caries and enamel erosion; however, the dosage must be carefully monitored to prevent users from suffering fluorosis or fluoride toxicity. Chewing gums have also been adapted as stain removal and teeth whitening agents, as described in 1998 U.S. Patent No. 5, 824, 291 A, which incorporates alkali metal percarbonate as the active ingredient. The inclusion of carbamide into chewing gums has been found to increase biofilm pH and provide anti-caries properties through an increase of ureolytic products, although its beneficial effect is limited to severe cases (15,16). Overall, medicated chewing gums provide a convenient method of drug delivery, and there is ample opportunity to introduce new formulations of active ingredients for the treatment and prevention of oral diseases.

[0013] Magnolia Bark Extract

[0014] Magnolia bark extract (MBE) is derived from Magnolia officinalis, a species of magnolia tree native to East and Southeast Asia. MBE can be extracted using a variety of techniques, including steam and hot water decoction, organic solvent extraction, and carbon dioxide supercritical fluid extraction (17). The extract’s two major constituents are the polyphenolic isomers magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl) and honokiol (5,3'-diallyl-2,4'-dihydroxybiphenyl) which typically comprise 87.2% and 10.8% of the extract, respectively (18).

[0015] MBE has extensive use in traditional Chinese medicine to treat fevers, anxiety, gastrointestinal disorders, and to provide pain relief, among many other uses. Recent studies have also demonstrated MBE’s effectiveness in the maintenance of oral health by inhibiting the growth of gram-positive and gram-negative bacteria associated with dental caries and periodontal disease (19,20). Both magnolol and honokiol are thought to contribute to MBE’s antibacterial properties, although the relevant mechanisms of action are still unclear (21).

[0016] Resveratrol

[0017] Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic compound found in many high-antioxidant foods, though it is particularly abundant in the skin of red grapes. It can be extracted using organic solvent extraction, carbon dioxide supercritical fluid extraction, and ultrasonic-assisted extraction (22). Both its cis- and trans- isomers are naturally occurring, with trans-resveratrol being more abundant due to its greater stability (23). Czs-resveratrol converts to trans-resveratrol upon exposure to light, heat, or low pH.

[0018] Resveratrol acts as an antioxidant and a free radical scavenger and has been studied as a potential solution to the oxidative stress induced by many prolific conditions, including cancer, neurodegenerative diseases, and inflammatory diseases like periodontitis (24,25). Early results indicate that resveratrol also reduces inflammation in periodontaltissues in vitro (25). Clinical use has been limited, however, due to resveratrol’s hydrophobic nature and low oral bioavailability (26).

[0019] Lipopolysaccharides (LPS) plays a major role in protecting biofilm in the mouth, resulting in LPS induced pathogenic effects such as tooth decay and gingivitis (27). One main pathway upregulated by LPS involves TLR4, which leads to an increase in inflammatory cytokine production. Resveratrol and its derivatives can, in part, block / suppress the phosphorylation of TLR4, ultimately decreasing the production of inflammatory cytokines. More directly, resveratrol and its derivatives inhibit the NF-kB activation, decreasing inflammatory cytokine production, in addition to downregulating cell adhesion molecules (ICAM-1 and VCAM-1) and iNOS expression (27).

[0020] Hydroxyapatite

[0021] Hydroxyapatite (HA; C as (P 64)3 (OH)) is a crystalline calcium phosphate mineral powder that forms the mineral phase of tooth enamel and dentin. As enamel cannot regenerate, oral healthcare professionals rely on synthetic remineralizing agents, most commonly fluorides, to supplement the enamel and protect the teeth from further erosion (28). Biomimetic HA is considered a safe alternative to fluoride, since HA can remineralize early caries lesions and reduce dental hypersensitivity without the risk of fluorosis (29,30).

[0022] Relevant Bacteria

[0023] There are various bacteria present in the oral cavity that are associated with teeth and gum issues. These bacteria may also be able to convert nitrate in the mouth into nitrite; nitrite is shown to have antimicrobial properties and stop the growth of certain diseasecausing bacteria.

[0024] Some of these bacteria present in the mouth include:• Peptostreptococcus stomatis - contributes to gum inflammation and bad breath• Porphyromonas endodontalis - related to endodontic infections (e.g. can lead to root canal infections)• Atopobium pcirvulum - normally found in the mouth, gastrointestinal tract and the urogenital system, and is generally harmless. However, it has been associated with oral diseases such as periodontitis• Haemophilus parainfluenzae - found in the mouth and upper respiratory tract. It is generally harmless. However, it has been associated with oral diseases such as periodontitis. These bacteria are nitrate reducers in the oral cavity.• Neisseria flavescens - found in the mouth, respiratory tract and genitourinary system. It is generally harmless, but has been shown to be associated with respiratory and genital infections. These bacteria have the ability to reduce nitrate into nitrite.• Rothia mucilaginosa - found in the mouth and respiratory tract. It is generally harmless, but has been associated with infections such as endocarditis. These bacteria have the ability to reduce nitrate into nitrite.• Veillonella atypica - found in the mouth and gastrointestinal tract. It is generally harmless, but has been associated with dental and respiratory infections. This bacteria species has a major contribution in converting nitrate into nitrite - nitrite is known to reduce the growth of certain pathogenic bacteria in the mouth.• Veillonella dispar - Found in the mouth, gastrointestinal tract and in the urogentical area. These bacteria are generally harmless, but have been associated with dental and respiratory infections. This bacterial species has a major contribution in converting nitrate into nitrite - nitrite is known to reduce the growth of certain pathogenic bacteria in the mouth.SUMMARY OF THE INVENTION

[0025] An object of the present application is to provide a composition

[0026] According to one aspect of the present invention is provided a orally administrable composition comprising: a) at least one antibiotic agent; b) at least one antiinflammatory agent; c) optionally, a remineralizing agent; and d) one or more additive or excipient, wherein the composition is formulated for topical delivery of active ingredients to mucous membranes and surfaces in the oral cavity of a subject.

[0027] In certain embodiments, the at least one antibiotic agent comprises an antibiotic that has activity against Peptostreptococcus stomatis, Porphyromonas endodontalis , Atopobium parvulum, Haemophilus parainfluenzae, Neisseria flavescens, Rothia mucilaginosa, Veillonella atypica, Veillonella dispar or a combination of two or more thereof.. In some examples, the antibiotic is MBE, or active ingredients thereof.

[0028] In certain embodiments, the at least one anti-inflammatory agent is a nonsteroidal anti-inflammatory agent, such as one that disrupts or downregulates TLR4 related pathways in the subject. In some examples, the at least one anti-inflammatory agent comprises resveratrol, either as a compound or as part of a natural extract.

[0029] In certain embodiments, the composition comprises a remineralizing agent, which can be a fluoride or non-fluoride remineralizing agent, or a combination thereof. For example, the non-fluoride remineralizing agent can be hydroxyapatite (HA) (for example, nano-HAs), a-tricalcium phosphate (TCP), -TCP ( -TCP), functionalized tricalcium phosphates, amorphous calcium phosphate, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), bioglass (bioactive glass (45 S5)), xylitol, di calcium phosphate dehydrate (DCPD) or a combination thereof. Preferably the non-fluoride remineralizing agent is HA.

[0030] In certain embodiments, the composition additionally comprises one or more further active agents, for example, an antioxidant (e.g., ascorbic acid), antiseptic (e.g., chlorhexidine), antifungal agent (e.g., hydrogen peroxide, clotrimazole, nystatin, miconazole, or a combination thereof), analgesic / anesthetic (e.g., lidocaine), antihistamine / anti cholinergic, antacid (e.g., magnesium hydroxide / aluminum hydroxide to coat the mouth), or a combination of two or more thereof.

[0031] In some embodiments, the composition is in the form of a chewable composition (e.g., a chewable tablet or a chewing gum), a liquid solution (e.g., a mouthwash or a rinse), a paste, a powder, a gel, a friable tablet, an edible film, a lozenge, a spray.

[0032] According to a further aspect of the present invention is provided the use of the present orally administrable composition to prevent caries and periodontal disease, strengthen enamel, and maintain a subject’s general oral health and hygiene.

[0033] According to a further aspect of the present invention is provided a chewable composition (e.g., chewable table or chewing gum) for the maintenance of oral health comprising a core gum base and an outer coating, wherein the active ingredients are only present in the outer coating, or in both the outer coating and the gum base. In certain embodiments, the composition contains the antibiotic, the anti-inflammatory agent and the remineralizing agent, with each comprising 0.1-17% of the tablet in a ratio of approximately 1:2:2 by weight.

[0034] According to a further aspect of the present invention is provided a liquid solution for the maintenance of oral health comprising the active ingredients and a surfactant in a solution. In certain embodiments, the formulation contains a surfactant, antibiotic, an anti-inflammatory, and a remineralizing agent, with each comprising 0.1-40% of the weight total percent of the solution.

[0035] According to a further aspect of the present invention is provided the use of the chewable tablet to prevent caries and periodontal disease, strengthen enamel, and maintain one’s general oral health and hygiene.

[0036] According to a further aspect of the present invention is provided the use of the solution to prevent caries and periodontal disease, strengthen enamel, and maintain one’s general oral health and hygiene.

[0037] In certain embodiments the tablet includes Gum base, Sorbitol, Xylitol, Maltitol, Natural and artificial flavors, Magnesium stearate, hydroxyapatite, Resveratrol, Magnolia bark extract, Sucralose, Vegetable glycerin, Artificial Colors (FD&C Blue # 1 lake OR Gum Arabic, Blue # 1), and Silicon dioxide.

[0038] In certain embodiments of the solution includes hydroxyapatite, Resveratrol, Magnolia bark extract, soy lecithin, and natural and artificial flavors.BRIEF DESCRIPTION OF FIGURES

[0039] The present invention will be further understood from the following description with reference to the Figures, in which:

[0040] Figures 1 A and IB show an illustration of the chewable composition according to one embodiment of the present application, in a circular pill shape.

[0041] Figure 1C shows an illustration of the chewable composition according to one embodiment, in a circular pill shape and halved to illustrate dimensions.

[0042] Figure ID shows an illustration of the chewable composition according to one embodiment, in a circular pill shape and halved to illustrate alternative dimensions. It is blue with white specks.DETAILED DESCRIPTION

[0043] Unless otherwise explained, 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 disclosure belongs. Patent applications, patents, and publications referred to herein to assist in the understanding of the aspects described are herewith incorporated by reference in their entirety.

[0044] In understanding the scope of the present application, the articles “a”, “an”, “the”, and “said” are intended to mean that there are one or more of the elements. Additionally, the term “comprising” and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms “including”, “having” and their derivatives.

[0045] It will be understood that any aspects describing as “comprising” certain components may also “consist of’ or “consist essentially of’, wherein “consisting of’ has a closed-ended or restrictive meaning and “consisting essentially of’ means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention.

[0046] All ranges given herein include the end of the ranges and also any intermediate range points, whether explicitly stated or not.

[0047] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0048] Reference throughout this specification to “one embodiment,” “an embodiment,” “another embodiment,” “a particular embodiment,” “a related embodiment,” “a certain embodiment,” “an additional 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. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, or characteristics of each embodiment may be combined in any suitable manner in one or more embodiments.

[0049] The term “and / or” as used in a phrase such as “X and / or Y” herein is intended to include “X and Y”, “X or Y”, “X”, and “Y”.

[0050] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least + / - 5% of the modified term if the deviation would not negate the meaning of the word it modifies.

[0051] The term “stable”, as used herein, preferably refers to compounds which possess stability sufficient to allow manufacture and which maintain the integrity of the compound for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the purposes detailed herein.

[0052] The term “subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans.

[0053] The term “administration” as used herein refers to the delivery and / or administration of a provided composition to a subject. In particular, “oral administration” as used herein refers to the delivery and / or administration of a provided composition to a subject via their mouth. It should be understood that such delivery and / or administration is intended to encompass self-administration by the subject as well as administration by a medical professional.

[0054] The term “topical”, as used herein refers to a route of administration by application to mucous membranes and surfaces in the oral cavity.

[0055] The term “treating”, or “treatment”, as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable. Treatment methods comprise administering to a subject, or having a subject self-administer, a therapeutically effective amount of a composition as described in the application and optionally consists of a single administration, or alternatively comprises a series of applications.

[0056] The term “preventing”, or “prevention”, refers to the prevention of a disease or disorder in a subject who may be exposed to or susceptible to a disease or disorder, or to a disease-causing agent, prior to the occurrence of the disease or disorder. Prevention further refers to a reduction in the risk of acquiring or developing (i.e., causing at least one clinical symptom) a disease or disorder that should not occur. The term “prophylaxis” is related to and encompassed by the term “prevention” and refers to measures or procedures whose purpose is prevention rather than treatment or cure of a disease or disorder. Prevention methods comprise administering to a subject, or having a subject self-administer, a therapeutically effective amount of a composition as described in the application and optionally consists of a single administration, or alternatively comprises a series of applications.

[0057] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. The abbreviation “e.g.” is used herein to indicate a non-limiting example. The word “or” is intended to include “and” unless the context clearly indicates otherwise.

[0058] The present inventors have surprisingly found that a combination of an antibiotic, and an anti-inflammatory agent can be used successfully in an oral, topical, multifunctional composition for treatment or prevention of oral diseases or disorders. The composition is useful for the improvement and / or maintenance of oral health. The composition is formulated for topical delivery of the active ingredients for localized treatment or prevention of diseases or disorders in the mouth, or oral cavity of a subject.

[0059] In some embodiments, the composition additionally comprises a remineralizating agent to additionally provide the benefit of aiding in tooth remineralization.

[0060] When taken by a subject, the composition provides a variety of advantageous effects, including, but not limited to, one or more of: preventing the formation of caries, preventing or treating periodontal disease, preventing or reducing periodontitis, repairing and strengthening enamel, reducing breath malodour, and maintaining good oral health.

[0061] Antibiotic

[0062] The present composition comprises one or more antibiotics. As used herein and unless otherwise indicated, the term “antibiotic” refers to a compound that can destroy or inhibit the growth of other microorganisms (e.g., bacteria) in an animal, including a human. In some embodiments, the antibiotic or combination of antibiotics included in the present oral composition kills or inhibits the growth of one or more of Peptostreptococcus stomatis, Porphyromonas endodontalis , Atopobium parvulum, Haemophilus parainfluenzae, Neisseria flavescens, Rothia mucilaginosa, Veillonella atypica, and Veillonella dispar.

[0063] The present composition provides a local therapeutic effect within the mouth, including in the gums, inner lips, cheeks and / or tongue. With particular reference to the antibiotic, a “local therapeutic effect” is intended to reference an antibiotic effect on and in the surfaces and soft tissues in the oral cavity, including a submucosal effect. Accordingly, the antibiotic(s) employed in the present composition will also be capable of transport across the oral mucosa.

[0064] Antibiotics that are suitable for use in the composition of the present application are those that are stable at about 37°C, are soluble or partially soluble in water, and are soluble or partially soluble in saliva. In some embodiments, the solubility of the antibiotic(s) is improved by incorporating one or more surfactant in the composition. The antibiotic or combination of antibiotics in the present composition must be active under conditions present in the oral cavity.

[0065] Preferably, but not necessarily, the antibiotic or combination of antibiotics is in the form of a powder to aid in manufacture of the composition.

[0066] Non-limiting examples of antibiotics that can be included in the composition are MBE, Magnolol or Honokiol, or a combination thereof.

[0067] As would be appreciated by the skilled person, the amount of antibiotic present in the composition will be dependent on the particular antibiotic. However, typically, the amount will be less than would be required for systemic application since only a local therapeutic effect is targeted.

[0068] Anti-inflammatory Agent

[0069] The present composition comprises one or more anti-inflammatory agents. As used herein and unless otherwise indicated, the term “anti-inflammatory agent” refers to acompound that reduces inflammation or inflammatory responses in an animal, including a human. In particular, the one or more anti-inflammatory agents provide an anti-inflammatory effect within the mouth, for example, in the gums, inner lips, cheeks and / or tongue.

[0070] In some embodiments, the one or more anti-inflammatory agents provide protection against or treatment of stomatitis, which is inflammation of the oral mucosa.

[0071] As noted above, the present composition provides a local therapeutic effect within the mouth, including in the gums, inner lips, cheeks and / or tongue. With particular reference to the anti-inflammatory, a “local therapeutic effect” is intended to reference an antiinflammation effect on and in the soft tissues and surfaces in the oral cavity, including a submucosal effect. Accordingly, the anti-inflammatory agent(s) employed in the present composition will also be capable of transport across the oral mucosa.

[0072] Anti-inflammatory agents that are suitable for use in the in the composition of the present composition are those that are stable at about 37°C, are soluble or partially soluble in water, and are soluble or partially soluble in saliva. In some embodiments, the solubility of the anti-inflammatory agent(s) is improved by incorporating one or more surfactant in the composition. The anti-inflammatory agent or combination of anti-inflammatory agents in the present composition must be active under conditions present in the oral cavity.

[0073] In some embodiments, the anti-inflammatory agent(s) is a non-steroidal antiinflammatory agent.

[0074] Non-limiting examples of anti-inflammatory agents that can be included in the present oral composition are resveratrol and derivatives thereof, 3,5,4'-trihydroxystilbene, red grape extract, and other compounds that disrupt or downregulate TLR4 related pathways, leading to a decrease in inflammatory cytokine production, and compounds that disrupted the LPS.

[0075] Relevant to its oral topical application, resveratrol has anti-inflammatory properties, as well as anti-oxidant, anti-microbial, osteoprotective, and immune-modulatory properties.

[0076] Remineralizing Agent

[0077] In some embodiments, the present composition further comprises one or more remineralizing agent. As used herein and unless otherwise indicated, the term “remineralizing agent” refers to a compound that promotes formation of hydroxyapatite on a tooth surface inan animal, including a human. A remineralizing agent provides a source of calcium and phosphate ions. In some embodiments, the remineralizing agent(s) in the composition aid in remineralization of the carious lesion by replenishing lost minerals, including calcium and phosphate ions, into the tooth structure. These remineralizing agents can also be useful in the treatment of white spot lesions, early childhood caries, dental erosion, root caries, and dentin hypersensitivity.

[0078] Remineralizing agents that are suitable for use in the in the composition of the present composition are those that provide a local source of calcium and / or phosphate ions and are stable at 37°C. Suitable remineralizing agents are able to deliver calcium and / or phosphate ions under conditions present in the mouth. In some embodiments, a remineralizating agent can provide a controlled delivery of calcium and / or phosphate ions and / or improve remineralization properties of saliva.

[0079] When a remineralizing agent is present in the composition, the composition is formulated to have a pH of about 7.0 or higher, or about 7.5 or higher, without being too basic for oral use or administration.

[0080] Preferably, but not necessarily, the remineralizing agent or combination of remineralizing agents is in the form of a powder to aid in manufacture of the composition.

[0081] The remineralizing agent can be a fluoride or non-fluoride remineralizing agent, or a combination thereof.

[0082] Non-limiting examples of non-fluoride remineralizing agents that can be included in the present composition are hydroxyapatite (HA) (for example, nano-HAs), a-tricalcium phosphate (TCP), -TCP ( -TCP), functionalized tricalcium phosphates, amorphous calcium phosphate, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), bioglass (bioactive glass (45 S 5)), xylitol, di calcium phosphate dehydrate (DCPD) or a combination thereof. Preferably the non-fluoride remineralizing agent is HA. In some embodiments, the remineralizing agent can be in nanoparticulate form. Nanoparticles for remineralizing can be, for example, calcium fluoride nanoparticles, calcium phosphate-based nanomaterials, nano- HA particles, ACP nanoparticles, or nanobioactive glass materials.

[0083] Additional Active Agents

[0084] In some embodiments, the present oral composition additionally comprises one or more additional active ingredient. For example, the composition can additionally comprise an antioxidant (e.g., ascorbic acid), antiseptic (e.g., chlorhexidine), antifungal agent (e.g.,hydrogen peroxide, clotrimazole, nystatin, miconazole, or a combination thereof), analgesic / anesthetic (e.g., lidocaine), antihistamine / anti cholinergic, antacid (e.g., magnesium hydroxide / aluminum hydroxide to coat the mouth), or a combination of two or more thereof.

[0085] In some embodiments, the present oral composition comprises: an antibiotic, for example, MBE, Magnolol or Honokiol (used together or separately); an anti-inflammatory agent, for example, resveratrol, 3,5,4’-trihydroxystilbene, or red grape extract; and (optionally) a remineralizing agent, for example, hydroxyapatite or hydroxyapatite.

[0086] In certain embodiments, the antibiotic is MBE, the anti-inflammatory agent is resveratrol, and the remineralizing agent is hydroxyapatite.

[0087] In certain embodiments, the antibiotic, anti-inflammatory agent, and remineralizing agent in the formulation have a ratio of about 1 :2:2 by weight (for example, 15 mg MBE, 30 mg resveratrol, 30 mg HA).

[0088] Oral Composition

[0089] The oral composition of the present application can be in the form of a chewable composition (for example, a chewable tablet or a chewing gum), a liquid solution (for example, a mouthwash or a rinse), a paste, a powder, a gel, a friable tablet, an edible film, a lozenge, a spray or the like. The excipients included in the composition can vary depending on the form of the composition. However, selection of the specific excipients and amounts thereof would be well within the abilities of the person skilled in the art.

[0090] In some embodiments, the composition comprises an additive, as surface active agent, that increases the solubility of the active ingredients. Such an additive can be selected from surfactants, soaps, wetting agents, and emulsifiers. In accordance with certain embodiments, the composition of the present application comprises one or more surfactant, such as magnesium stearate or soy lecithin, which can be useful to assist in dissolution of the active ingredients.

[0091] By way of example, Magnolia Bark Extract is a hydrophobic compound extract, however, there are several oral cavity delivery agents that may be used to enhance the release of the MBE from the oral composition. In a chewing gum product, the gum base is hydrophobic, which also inhibits the release of the MBE. In the various embodiments of the present oral composition, the MBE is combined with a surface active agent and may beencapsulated, spray dried, or formulated into a coating, or combinations thereof in order to facilitate release of the MBE into the oral cavity

[0092] Irrespective of the form of the composition, the composition can additionally comprise one or more inactive ingredient. For example, the composition can comprise one or more inactive ingredient selected from preservatives, sweetening agents, astringents, humectants, fragrances, thickeners, emulsifiers, softening agents, stabilizers, plasticizers fillers, binding agents, waxes, pigments, buffering agents, chelating agents, natural oils (or “essential” oils), colourants, and natural and artificial flavouring agents, as are known in the art.

[0093] Non-limiting examples of suitable flavouring agents are natural oils, including, for example, peppermint oil, spearmint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, parsley seed oil, sweet oil of birch, cinnamon oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, methylsalicylate, menthol, peppermint menthol, other polyols, cinnamon, natural citrus complex, and combinations thereof.

[0094] Non-limiting examples of sweetening agents, including sucrose, dextrose, xylitol, sorbitol, monk fruit, erythritol, stevia, steviol glycosides, aspartame, acesulfame potassium, sucralose, saccharin, neotame, advantame, dipeptides, cyclamates, and combinations thereof.

[0095] Non-limiting, illustrative, embodiments of particular composition forms are described below.

[0096] Chewable composition

[0097] In some embodiments, the oral composition is a chewable composition that comprises a core surrounded by a coating.

[0098] Optionally, the active ingredients in the chewing composition are entirely or primarily present in the outer coating, while the core of the composition optionally comprises a gum base. As used in this context, the term “primarily” means that at least 70%, 75%, at least 80%, at least 85%, at least 90% or at least 95%, by weight, of the active ingredients are in the coating of the chewable composition (e.g., chewing gum), with the remainder of the active ingredients being in the core.

[0099] The present inventors have found that including active ingredients in the outer coating improves oral bioavailability and enhances the effectiveness of the product. This can also be an advantageous design for incorporation of other active ingredients, especially foringredients where oral bioavailability is otherwise poor. In some embodiments, both the coating and the core of the chewable composition contains one or more active ingredient.

[0100] In some embodiments, the chewable composition is a chewing gum. Chewing gum generally consists of a water-insoluble gum base and a water-soluble coating along with flavouring or sweetening agents. The water-soluble portion and flavours dissipate through the saliva during chewing, while the gum base is retained in the mouth.

[0101] In some embodiments, the insoluble gum base comprises synthetic elastomers, including polyisobutylene, isobutylene-isoprene copolymers, styrene-butadiene copolymers, polyvinyl acetate, polyisoprene, polyethylene, vinyl acetate, vinyl laurate copolymers, comfree menthol, comsoft menthol, or combinations thereof.

[0102] In other embodiments, the insoluble gum base comprises natural elastomers, including chicle, spruce gum, wax crown gum, jelutung, guttakay rubber, nispero, leche caspi, rosidinha, jelutong, pendare, perillo, niger gutta, tunu, paraffin wax, candelilla wax, beeswax, or combinations thereof.

[0103] In other embodiments, the insoluble gum base comprises a combination of natural and synthetic elastomers.

[0104] In some embodiments, the chewing gum contains acesulfame potassium and other no-calorie sweeteners that are commonly used to help with masking the taste of active ingredients.

[0105] The insoluble gum base can also incorporate softeners and emulsifiers. Softeners are commonly added to chewing gum in order to optimize the chewability and ‘mouth feel’ of the gum, while emulsifiers provide lubrication and aid in the production of saliva.

[0106] In some embodiments, the insoluble gum base contains softeners and / or emulsifiers, including tallow, hydrogenated tallow, hydrogenated and partially-hydrogenated vegetable oils, cocoa butter, glycerol monostearate, magnesium stearate, glycerol triacetate, glycerin, lecithin, or combinations thereof.

[0107] The gum base can further include flavouring and sweetening agents, as is typical of most chewing gums. Usually, the flavouring agents are oils, as described above, which are mixed into the gum base during preparation. Sweetening agents, as described above, are incorporated similarly and include both natural and artificial sugars.

[0108] In some embodiments, the insoluble gum base contains further ingredients, such as colorants, fillers (e.g. calcium carbonate, talc), solubilizers (e.g. polyethylene glycol), and stabilizers (e.g. poloxamer 334).

[0109] In some embodiments, the insoluble gum base comprises about 0.1-10% by weight resveratrol.

[0110] In some embodiments, the insoluble gum base comprises about 0.1-10% by weight MBE.

[0111] In some embodiments, the gum base comprises about 50% to about 99%, or about 60 to about 90%, by weight of the entire weight of the chewable composition.

[0112] In some embodiments the outer coating of the composition comprises both active and non-active ingredients. The coating can be a powder affixed to the gum base, or it could be resiliently attached to the gum base.

[0113] In some embodiments, the outer coating’s active ingredient formulation comprises an antibiotic, an anti-inflammatory, and (optionally) a remineralizing agent in a ratio of about 1:2:2 by weight (for example, 15 mg MBE, 30 mg resveratrol, 30 mg HA). In certain embodiments, the active ingredients are MBE, resveratrol, and hydroxyapatite.

[0114] In some embodiments, the active ingredients comprise about 1% to about 95% by weight of the chewable composition, or about 1% to about 95% by weight of the coating of the chewable composition.

[0115] In some embodiments, the chewable composition comprises Gum base, Sorbitol, Xylitol, Maltitol, Natural and artificial flavors, Magnesium stearate, hydroxyapatite, Resveratrol, Magnolia bark extract, Sucralose, Vegetable glycerin, Artificial Colors (FD&C Blue # 1 lake OR Gum Arabic, Blue # 1), and Silicon dioxide.

[0116] In some embodiments, the outer coating further comprises flavouring agents, including peppermint oil, spearmint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, parsley seed oil, sweet oil of birch, cinnamon oil, oil of nutmeg, oil of sage, oil of bitter almonds, cassia oil, methylsalicylate, menthol, peppermint menthol, other polyols, cinnamon, natural citrus complex, or combinations thereof.

[0117] In some embodiments, the outer coating further comprises sweetening agents, including sucrose, dextrose, xylitol, sorbitol, monk fruit, erythritol, stevia, steviol glycosides,aspartame, acesulfame potassium, sucralose, saccharin, neotame, advantame, dipeptides, cyclamates, or combinations thereof.

[0118] In certain embodiments, the outer coating further comprises xylitol, sorbitol, or combinations thereof. In some embodiments the xylitol and / or sorbitol comprise from about 60% to about 95%, or about 66.6% to about 93.7% of the outer coating, but in certain embodiments they comprise at least about 80%, at least about 90%, or about 93.7% by weight of the outer coating.

[0119] In some embodiments, the outer coating further comprises magnesium stearate.

[0120] In some embodiments, the exterior coating comprises about 10% to about 40%, about 10% to about 38%, or about 11.8% to about 35.3% by weight of the entire weight of the gum.

[0121] Chewing gums are commonly found in several shapes, including dragee, cylindrical, spherical, and circular pill shapes. In some embodiments, the chewing has a circular pill shape with a diameter of approximately 8.69 mm (as shown in Figure 1C) and as shown it is white with blue specks. In some embodiments, the tablet has a circular pill shape with a diameter of approximately 8.49mm (as shown in Figure ID) and as shown it is blue with white specks.

[0122] In some embodiments, the tablet has a total mass of from about 1900 mg to about 2200 mg, or from about 1963 to about 2048 mg, or about 2 g.

[0123] Liquid composition

[0124] In an alternative embodiment, the oral composition is liquid solution, such as mouth wash or mouth rinse.

[0125] In addition to the active ingredients, such a liquid composition will additionally comprise a solvent. The solvent can comprise, for example, water, an alcohol (e.g., ethanol, 2- propanol, 1,3-propanediol), a glycol (e.g., butylene glycol), or a combination thereof.

[0126] In certain embodiments, the liquid composition comprises a surfactant, a remineralizing agent, an antibiotic, and an anti-inflammatory agent.

[0127] In certain embodiments the solution comprises a surfactant, a remineralizing agent, an antibiotic, and an anti-inflammatory agent which cumulatively equate to a total weight pervolume of about 0.05% to about 20%, about 0.1% to about 15%, or about 0.1% to about 10% of the solution.

[0128] In certain embodiments, the formulation contains natural and artificial flavors in addition to the surfactant, remineralizing agent, antibiotic, and anti-inflammatory agent.

[0129] In certain embodiments, the solution is water-based. In certain embodiments, the surfactant is soy lecithin.

[0130] Film composition

[0131] In an alternative embodiment, the oral composition is a film, similar in form to LISTERINE® POCKETPAKS® Fresh Breath Strips.

[0132] In addition to the active ingredients, the present film composition additionally comprises a film-forming agent.

[0133] The film-forming agent used in the films according to the present application can be selected from pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragacanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl polymer, amylose, high amylose starch, hydroxypropylated high amylose starch, dextrin, pectin, chitin, chitosan, levan, elsinan, collagen, gelatin, zein, gluten, soy protein isolate, whey protein isolate, casein and mixtures thereof. Alternatively, a mixture of at least three types of film forming agents, such as maltodextrins, fillers (for example, microcrystalline cellulose (MCC)) and hydrocolloids (for example, sodium aliginate), can be effectively utilized to prepare stand alone edible films.

[0134] The oral compositions of the present application can be manufactured using standard methods and techniques. As would be well understood by the skilled person, during manufacture care is taken to avoid temperatures that would result in degradation or inactivation of the active ingredients in the formulation.

[0135] Method of Use

[0136] The present application further comprises a method of improving oral health, or of preventing or treating oral diseases or disorders. The method comprises use of an oral composition comprising an antibiotic, an anti-inflammatory agent and, optionally, a remineralizing agent, as described herein.

[0137] In some embodiments, the subject uses the composition at least once a day, or once a day, twice a day or three times a day. For example, the composition can be taken or chewed, or administered after each meal.

[0138] The nature of the use of the composition will depend on its form. For example, when the composition is a chewing gum, the gum is chewed by the subject for at least 10 seconds, at least 20 seconds, at least 30 seconds or at least 1 minute before being spit out by the subject. Alternatively, if the composition is a liquid mouth wash or rinse, the subject will swish an amount of the mouth wash or rinse around the entire mouth for at least 10 seconds, at least 20 seconds, at least 30 seconds or at least 1 minute before spitting out the mouth wash or rinse. In another alternative, in which the oral composition is ingestible (e.g., a friable table, an edible film or a lozenge) the subject takes the composition and allows it to stay in the mouth until the composition has dissolved entirely. As the composition dissolves, the subject can swallow the dissolving composition. However, to improve efficacy, the subject should retain all or a portion of the composition in the mouth for at least 10 seconds, at least 20 seconds, at least 30 seconds or at least 1 minute.

[0139] To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in any way.EXAMPLES

[0140] EXAMPLE 1: Sample formulations of the chewable tablet

[0141] Formulations 1 and 2 were prepared utilizing the ingredient ratios shown in Table 1.Table 1. Sample formulations of the invention.

[0142] To prepare the gum in formulations 1 and 2 of Table 1, Natural gum base (Chicle tree sap, candelilla wax, and natural citrus complex; AB natural base SA SV, Mexico, catalog #: NB-PW-060), Xylitol (Now foods Guelph, CA, catalog #: 86983), and Sorbitol (Royal command, China, catalog #: 152538) were melted at ~100°C and continuously stirred until homogonous. Vegetable glycerin (Glycerin supplier, Houston, US), calcium carbonate (Now foods, Bloomindale, USA, catalog #: NOW81245), and soy lecithin (Molecular ingredients,imported by Qualifirst foods, China, catalog #: 152128) were added to the homogeneous mixture and stirred until the solution was once again homogeneous. The mixture was removed from the heat and as it was cooling to room temperature, a stir stick was used to remove and aliquot 1.87 ± 0.04 g of gum which was then manually shaped into a dragee shape. Once cooled to room temperature the gum pieces were placed in a tube containing a blend of resveratrol (Liftmode, Chicago, USA, catalog #: RE-SVEL-0005), MBE (Liftmode, Chicago, US, catalog #: AG-OBAX-7XJV), and HA (for example 2 only, Fluidinova, Portugal, nanoXIM.CarePowder) and subsequently gently shaken. Once removed from the tube, the gum pieces presented a coated outer layer of the blended powders. Once the powder has been added the average mass was 2.02 ± 0.07g.

[0143] The formulations provided a suitable and agreeable, chewable product, that lasts more than 5 minutes while chewing. The formulations are manufactured into tablets having a mass of approximately 1963-2048mg, and a circular pill shape with diameter of 16mm and a thickness of 8.69mm, as well as a circular pill shape with a diameter of approximately 16mm and a thickness of 8.49mm (shown in schematic form in Figures 1 C and D, respectively). The formulations are manufactured into tablets having amass of approximately 1963-2048mg, and a circular pill shape with a diameter of approximately 16mm (shown in schematic form in Figures 1C and D, respectively).

[0144] The formulations provide localized and advantageous antibiotic, antiinflammatory and remineralizing activity in the mouth. They also stimulate saliva production, which also aids in remineralization. The formulations also provide a decrease in biofilm and bacterial concentration in the mouth, which can lead to a decrease in dental caries. The formulations provide an anti-inflammatory effect on the gums, which can lead to a decrease in periodontal disease.

[0145] EXAMPLE 2: Other formulations of the chewable tablet

[0146] Formulations 3-6 can be prepared utilizing the ingredient ratios detailed in Table 2. They are further detailed in Table 3 below:Table 2. Formulations of the invention.Table 3: Formulations of the invention without an outer coating.

[0147] The method of preparing formulations 3 and 4 will be very similar to that of formulations 1 and 2, and such method is detailed below. The method of preparation regarding formulations 5 and 6 is still under development.

[0148] To prepare the gum in formulations 3 and 4 of Table 1, Natural gum base (Chicle tree sap, candelilla wax, and natural citrus complex; AB natural base SA SV, Mexico, catalog #: NB-PW-060), Xylitol (Now foods Guelph, CA, catalog #: 86983), and Sorbitol (Royal command, China, catalog #: 152538) can be melted at ~100°C and continuously stirred until homogonous. Vegetable glycerin (Glycerin supplier, Houston, US), calcium carbonate (Now foods, Bloomindale, USA, catalog #: NOW81245), and soy lecithin (Molecular ingredients,imported by Qualifirst foods, China, catalog #: 152128) are added to the homogeneous mixture and stirred until the solution is once again homogeneous. The mixture is removed from the heat and as it is cooling to room temperature, a stir stick can be used to remove and aliquot 1.87 ± 0.04g of gum which is then manually shaped into a dragee or pill shape. Once cooled to room temperature the gum pieces are placed in a tube containing a blend of resveratrol (Liftmode, Chicago, USA, catalog #: RE-SVEL-0005), MBE (Liftmode, Chicago, US, catalog #: AG-OBAX-7XJV), and HA (for example 2 only, Fluidinova, Portugal, nanoXIM.CarePowder) and subsequently gently shaken. Once removed from the tube, the gum pieces present a coated outer layer of the blended powders. Once the powder has been added the average mass will be 2.02 ± 0.07g.

[0149] In addition to the above method, the respective ingredients can be used in a tablet press, such as the PRLT-Single, Double, Triple, and Core Tablet press (PTK-GB Limited, England).

[0150] In another formulation example, formulation 7 includes: Gum base, Sorbitol, Xylitol, Maltitol, Natural and artificial flavors, Magnesium stearate, hydroxyapatite, Resveratrol, Magnolia bark extract, Sucralose, Vegetable glycerin, Artificial Colors (FD&C Blue # 1 lake OR Gum Arabic, Blue # 1), and Silicon dioxide.

[0151] Formulation 7 provides a suitable and agreeable, chewable product, that lasts more than 20 minutes while chewing without any loss in texture. The formulations are manufactured into tablets having a mass of approximately 1963-2048mg, as well as a circular pill shape with a diameter of approximately 16mm (shown in schematic form in Figures 1C and D, respectively).

[0152] The formulations provide localized and advantageous antibiotic, antiinflammatory and remineralizing activity in the mouth. They also stimulate saliva production, which also aids in remineralization. The formulations also provide a decrease in biofilm and bacterial concentration in the mouth, which can lead to a decrease in dental caries. The formulations provide an anti-inflammatory effect on the gums, which can lead to a decrease in periodontal disease.

[0153] Formulation 7 leads to the decrease in salivary bacterial levels of Peptostreptococcus stomatis - contributes to gum inflammation and bad breath, Porphyromonas endodontalis , and Atopobium parvulum. Further the formulation leads to anincreased level of nitrate producing bacteria which are Haemophilus parainfluenzae, Neisseria flavescens, Rothia mucilaginosa, Veillonella atypica, and Veillonella dispar.

[0154] EXAMPLE 3: Sample formulations of the solution

[0155] Formulation 8 was prepared utilizing the ingredient ratios shown in Table 4.Table 4: Formulation of the invention in a solution.

[0156] To prepare the solution in formulation 8 of Table 4, soy lecithin (Molecular ingredients, imported by Qualifirst foods, China, catalog #: 152128) resveratrol (Liftmode, Chicago, USA, catalog #: RE-SVEL-0005), MBE (Liftmode, Chicago, US, catalog #: AG- OBAX-7XJV), and HA (Fluidinova, Portugal, nanoXIM. CarePowder) were weighed out in a sterile Falcon™ tube. The respective amount of milliQ™ water was weighed out and the solution was subsequently gently shaken for approximately 20 minutes.

[0157] EXAMPLE 4: Testing on Human Saliva

[0158] Saliva samples taken from individuals (n=2) were analyzed using quantitative polymerase chain reaction (qPCR) by a third-party lab (Bristle®) after either a “control day” or an “experimental day”. During the control day individuals followed the following instructions:1. Do not brush your teeth the night before or in the morning2. Record a food diary of anything consumed throughout the day explicitly, including the timing.3. At the end of the day, before brushing your teeth, collect the saliva samples

[0159] During experimental days individuals followed the following instructions:1. Do not brush your teeth the night before or in the morning2. Use the same diet as the previous day and explicitly record a food diary of anything consumed throughout the day, including the timing.3. Chew 4 toothpods throughout the day for >10min. Record in your diary when you chew the pieces4. At the end of the day, before brushing your teeth, take the saliva samples

[0160] Saliva samples were collected following the manufacturer’s instructions and analyzed by qPCR by Bristle®. The percentage change in the microbiome species was calculated by subtracting the control day percentiles from the experimental percentiles.

[0161] Table 5 indicates qPCR results from two biological replicates of the saliva samples on either a control or an experimental day.Table 5. Bacterial levels reported in percentiles as provided by Bristle® recorded

[0162] The data demonstrated an increase in nitrate producing bacteria (Haemophilus parainfluenzae and Veillonella dispar combined with a decrease in bacteria species responsible for halitosis, and gum inflammation (Peptostreptococcus stomatis, Porphyromonas endodontalis , Atopobium parvulum).

[0163] EXAMPLE 5: Testing on human saliva - total bacterial load

[0164] An individual's saliva was obtained in a falcon tube. The individual then rinsed their mouth with 25mL of formulation 8 for 30 seconds. Immediately after discarding thesolution a saliva sample was taken, and again after 5 minutes a saliva sample was taken. The three saliva samples were then aliquoted (1 Opl) onto an agar plate in separate sections. The Agar plate was then incubated at 37°C for 48 hours and the number of colonies was counted. The same saliva experiment was conducted after chewing the tablet form of the invention after chewing one tablet for 5 minutes and another tablet immediately after for 10 minutes, from formulation 7. The results are delineated in Table 6.Table 6. Bacterial colonies before and after rinsing with the solution.

[0165] EXAMPLE 6: Salivary pH

[0166] Individuals' salivary pH was determined using pH strips over 15 minutes while chewing a tablet of formulation 7.

[0167] The salivary pH must be at or above 7.5 for remineralization to occur.Table 7. Salivary pH was determined after 1, 5, 10, and 15 minutes while chewing the tablet with formulation 7 (N=2).

[0168] EXAMPLE 7: Testing with disclosing tablets

[0169] Disclosing tablets are used to provide users an indication of how effectively they are brushing and flossing their teeth. Chewing disclosing tablets stains will stain the plaque on a user’s teeth and this stain then illustrates how well the user is brushing and flossing theirteeth. Disclosing tablets were used in the present study to demonstrate the effectiveness of the present oral compositions.

[0170] Individuals chewed disclosing tablets to stain plaque on their teeth. Individuals then chewed two chewable tablets for 5 minutes each. The chewable tables were either of formulation 7 or sugar / active ingredient-free tablets containing none of the active ingredients in the current invention as a control.

[0171] Images of the teeth were taken after chewing the disclosing tablet prior and after 10 minutes of chewing the tablet in formulation 7 or the sugar / active ingredient-free control tablets. ImageJ was used to analyze the surface area coverage of the disclosing tablet stain. The results demonstrated that 10 minutes of chewing formulation 7 reduced plaque surface area by 48.9 ± 18.4% versus the control, which only removed 22.1 ± 10.2% of the plaque.REFERENCES1. Peres, M.A., Macpherson, L.M.D., Weyant, R.J. et al. Oral diseases: A global public health challenge. (2019) The Lance , 394(10194): 249-260.2. NJ Kassebaum, E Bernabe, M Dahiya, et al. Global burden of untreated caries. (2015) JDent Res; 94: 650-658.3. Pitchika, V., Pink, C., Volzke, H., et al. Long-term impact of powered toothbrush on oral health: 11-year cohort study. (2019) Journal of Clinical Periodontology, 46(7): 713- 722.4. Selwitz, R.H., Ismail, A.I., and Pitts, N.B. Dental caries. (2007) The Lancet; 369: 51-595. Momeni-Moghaddam, M., Hashemi, C., Fathi, A., et al. Diagnostic accuracy, available treatment, and diagnostic methods of dental caries in practice: a meta-analysis. (2022). Beni-Suef Univ J Basic Appl Sci; 11(62).6. Cate, J.M., and Featherstone, J.D. Mechanistic aspects of the interactions between fluoride and dental enamel. (1991). Crit Rev Oral Biol Med; 2: 283-296.7. Niu, J.Y., Yin, I.X., Wu, W.K.K., et al. Antimicrobial peptides for the prevention and treatment of dental caries: A concise review. (2001). Archives of Oral Biology; 122: 105022.8. Scannapieco, F.A., and Gershovich, E. The prevention of periodontal disease - an overview. (2020). Periodontology 2000; 84(1): 9-13.er, N.S., and Schure, R.S. Periodontal disease. (2020). StatPearls Publishing,Treasure Island (FL). ishengallis, G., Chavakis, T., and Lambris, J.D. Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. 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IntDentJ; 49(4):226-230. enberg M, Umezis, P, and Tian, M., Compressed mints and chewing gum containing magnolia bark extract are effective against bacteria responsible for oral malodor. J Agric Food Chem 2007; 55(23): 9465-9469. G. Cagetti, F. Cocco, G. Carta, C. Maspero, G. Campus, J. Funct. Foods 2020, 68,103891. M, Dodds MWJ, Greenberg MJ, Estrich C. Interaction of MBE with oral bacteria and salivary protein. J Dent Res 2010; 89(Spec Iss B): 3302. e C, Wang Q, Komarov GN, Adeyemi AA, Pender SM, Smith PW, Pender N, Inui T,Higham SM. Magnolia bark extract inhibits growth of oral bacteria in vivo. J Dent Res 2010; 89(Spec Iss B): 4315. re, M., and Duez, P. Biological activity and toxicity of the Chinese herb Magnoliaofficinalis Redher & E. Wilson (Houpo) and its constitutents. J Zhejiang Univ Sci B 2017; 18(3): 194-214. , J., Zhao, J., Zhang, M., et al. Optimization of the ultrasonic-assisted extraction of trans-resveratrol and its glucoside from grapes followed by UPLC-MS / MS using response surface methodology. Journal of food measurement and characterization 2022, 16; 1124-1136. one, D., Fuggetta, M.P., Ardito, F., et al. Resveratrol (3,5,4’-trihydroxystillbene) and its properties in oral diseases (Review). Experimental and Therapeutic Medicine (2017): 14(1); 3-9. nard SS, Xia C, Jiang BH, Stinefelt B, Klandorf H, Harris GK and Shi X: Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses. Biochem Biophys Res Commun. 309:1017-1026. 2003 anegan A, Shokuhian M, Jafari S, Shirazi F, Shahidi M. Anti-histaminic effects of resveratrol and silymarin on human gingival fibroblasts. Inflammation.2019;42(5): 1622-1629. DOI: 10.1007 / sl0753-019-01023-z ney, T.L. Evaluation of trans-resveratrol as a treatment for periodontitis. In L.Ardelean, & L. C. Rusu (Eds.), Oral Health Care - An Important Issue of the Modem Society [Working Title], IntechOpen 2021. https: / / doi.org / 10.5772 / intechopen.101477n, Y. T., Cheng, G. Y., Shih, Y. J., Lin, C. Y., Lin, S. J., Lai, H. Y., ... & Liu, L. F.(2017). Therapeutic applications of resveratrol and its derivatives on periodontitis. Annals of the New York Academy of Sciences, 1403(1), 101-108.x, J., Fabritius, H., Fabritious-Vilpoux, K., etal. Modes of action and clinical efficacy of particulate hydroxyapatite in preventative oral health care - State of the Art. The Open Dentistry Journal 2019: 13; 274-287. er., F., and Enax., J. Early childhood caries: epidemiology, aetiology, and prevention.Int J Dent 2018 : 1415873. ibfard, K., Ramalingam, K., Chedjieu, I., et al. Remineralization of early caries by a nano-hydroxyapatite dentifrice. J Clin Dent 2011; 22(5): 139-143.31. Memarpour, M., Shafiei, F., Rafiee, A., et al. Effect of Hydroxyapatite nanoparticles on enamel remineralization and estimation of fissure sealant bond strength to remineralized tooth surfaces: An in vitro study. BMC Oral Health 2019; 19(92).32. Wicaksono, D., Washio, J., Abiko, Y., et al. Nitrite Production from Nitrate and Its Link with Lactate Metabolism in Oral Veillonella spp. Applied and Environmental Microbiology 2020; 86(20).33. Doel, J. J., Benjamin, N., Hector, M. P., et al. Evaluation of bacterial nitrate reduction in the human oral cavity. European Journal of Oral Sciences, 2005; 113(1): 14-19.34. Rosier, B. T., Moya-Gonzalvez, E. M., Corell-Escuin, P., et al. Isolation and characterization of nitrate-reducing bacteria as potential probiotics for oral and systemic health. Frontiers in Microbiology 2020; 11.35. Gonzalez, A., Hyde, E. R., Sangwan, N., et al. Migraines Are Correlated with HigherLevels of Nitrate-, Nitrite-, and Nitric Oxide-Reducing Oral Microbes in the American Gut Project Cohort. 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[0172] The above disclosure generally describes the present invention. Although specific terms have been used herein, such terms are intended in a descriptive sense and not for purposes of limitation.

[0173] All publications, patents and patent applications cited above are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

[0174] Although preferable embodiments of the invention have been described herein in detail, it will be understood to those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

Claims

CLAIMS1. An orally administrable composition comprising: a) at least one antibiotic agent; b) at least one anti-inflammatory agent; c) optionally, a remineralizing agent; and d) one or more additive or excipient, wherein the composition is formulated for topical delivery of active ingredients to mucous membranes and surfaces in the oral cavity of a subject.

2. The composition of claim 1, wherein the at least one antibiotic agent comprises an antibiotic that has activity against Peptostreptococcus stomatis, Porphyromonas endodontalis , Atopobium parvulum, Haemophilus parainfluenzae, Neisseria flavescens, Rothia mucilaginosa, Veillonella atypica, Veillonella dispar or a combination of two or more thereof.

3. The composition of claim 2, wherein the at least one antibiotic comprises magnolia bark extract (MBE), or magnolol and / or honokiol.

4. The composition of any one of claims 1 to 3, wherein the at least one antiinflammatory agent comprises a non-steroidal anti-inflammatory agent.

5. The composition of claim 4, wherein the at least one anti-inflammatory agent comprises a compound that disrupts or downregulates TLR4 related pathways in the subject.

6. The composition of claim 4, wherein the at least one anti-inflammatory agent comprises a red grape extract, a red wine extract, an extract of polygonum cuspidatum, 3,5,4'- trihydroxystillbene, resveratrol, a derivative of resveratrol, or a combination of two or more thereof.

7. The composition of any one of claims 1 to 6, wherein the at least one antibiotic comprises MBE and the at least one anti-inflammatory agent comprises resveratrol or a derivative thereof.

8. The composition of claim 7, wherein the MBE comprises > about 95% by weight magnolol and honokiol.

9. The composition of any one of claims 1 to 8, wherein the composition comprises the remineralizing agent and, optionally, wherein the remineralizing agent comprises a fluoride or non-fluoride remineralizing agent, or a combination thereof, wherein the non-fluoride remineralizing agent is optionally hydroxyapatite (HA) (e.g., nano-HAs), a-tricalcium phosphate (TCP), -TCP ( -TCP), functionalized tri calcium phosphate, amorphous calcium phosphate, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), bioglass (e.g., bioactive glass (45 S5)), xylitol, dicalcium phosphate dehydrate (DCPD) or a combination thereof, preferably HA.

10. The composition of claim 9, wherein the at least one antibiotic, the at least one antiinflammatory agent, and the remineralizing agent are present in a ratio of about 1:2:2, respectively, by weight.

11. The composition of any one of claims 1 to 10, further comprising one or more additional active agent.

12. The composition of claim 12, wherein the additional active agent is an antioxidant (e.g., ascorbic acid), antiseptic (e.g., chlorhexidine), antifungal agent (e.g., hydrogen peroxide, clotrimazole, nystatin, miconazole, or a combination thereof), analgesic / anesthetic (e.g., lidocaine), antihistamine / anti cholinergic, antacid (e.g., magnesium hydroxide / aluminum hydroxide to coat the mouth), or a combination of two or more thereof.

13. The composition of any one of claims 1 to 12, wherein the one or more additive or excipient comprises a preservative, sweetening agent, astringent, humectant, fragrance, thickener, emulsifier, softening agent (e.g., glycerine), stabilizer (e.g. poloxamer 334), plasticizer, filler, binding agent, wax, pigment, buffering agent, chelating agent, natural oil (or “essential” oil), colourant, or natural or artificial flavouring agent.

14. The composition of any one of claims 1 to 13, wherein the composition is in the form of a chewable composition (e.g., a chewable tablet or a chewing gum), a liquid solution (e.g.,a mouthwash or a rinse), a paste, a powder, a gel, a friable tablet, an edible fdm, a lozenge, a spray.

15. The composition of claim 14, which is a chewable composition comprising a chewable core and an outer coating.

16. The composition of claim 15, wherein the active ingredients are present in the outer coating or in both the outer coating and the chewable core.

17. The composition of claim 15 or 16, wherein the chewable core comprises a gum base comprising chicle, jelutung, guttakay rubber, a natural or synthetic resin, a natural or synthetic wax crown gum, nispero, rosidinha, jelutong, pendare, perillo, niger gutta, tunu, butadiene-styrene polymer, isobutylene-isoprene copolymer, petroleum wax, polyethylene, polyisobutylene, or a combination of two or more thereof.

18. The composition of any one of claims 15 to 17, wherein the gum base comprises about 0.1-10% by weight resveratrol and 0.1-10% by weight MBE.

19. The composition of any one of claims 15 to 18, wherein the active ingredients make up 1% to 95%, preferably about 3.75%, by weight of the total weight of the outer coating.

20. The composition of claim 14, which is a liquid solution, optionally wherein the liquid solution comprises water as a solvent for dissolving the active ingredients.

21. The composition of claim 20, wherein the one or more additive or excipient comprises a surfactant.

22. The composition of claim 21, wherein the surfactant is soy lecithin.

23. The composition of any one of claims 20 to 22, wherein the solvent in the solution is present at an amount ranging from about 99.9 to about 60% weight per volume.

24. The composition of any one of claims 20 to 23, which comprises about 1.8% (w / v) resveratrol, about 3% (w / v) MBE, and about 6% (w / v) HA.

25. The composition of any one of claims 1 to 24, wherein the composition decreases the total bacterial load within the oral cavity of the subject following use.

26. The composition of any one of claims 1 to 24, for improving oral health or for preventing or treating an oral disease or disorder in the subject.

26. A method for improving oral health or for preventing or treating an oral disease or disorder a subject, said method comprising administering to the subject the composition according to any one of claims 1 to 24.

27. The method according to claim 26, wherein the oral disease or disorder is periodontal disease, such as gingivitis or stomatitis, or dental caries.

28. The method according to claim 26, wherein the oral disorder is halitosis.

29. The method according to any one of clams 26 to 28, wherein administering the composition comprises maintaining the composition in the oral cavity of the subject for at least 10 seconds, at least 20 seconds, at least 30 seconds or at least 1 minute before swallowing or expelling the composition.

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