Phosphonate and N-halamine compositions for removing dental tartar - Patents.com

Abstract

Provided herein are compositions and methods comprising phosphonates, N-halamines or combinations thereof for dental care, particularly for removing calculus, including mature calculus.

Description

[Technical field]

[0001] Provided herein are compositions and methods comprising phosphonates, N-halamines or combinations thereof for dental care, particularly for removing calculus. [Background technology]

[0002] Dental calculus (tartar) is a solid material that hardens (calcifies) on the teeth due to plaque accumulation.

[0003] Dental plaque grows naturally on tooth surfaces and forms part of the host defense against exogenous microorganisms by acting as a colonization barrier. This barrier effect is known as colonization resistance. Plaque contains approximately 80% water and 20% solids. Approximately half of the dry weight of plaque is bacterial and salivary proteins. Approximately 25% of the plaque dry weight is in the plaque matrix, in addition to its high concentration of proteins, carbohydrates, and lipids.

[0004] Dental calculus is a hardened surface that provides more surface area for plaque to adhere to. More plaque can mean more gum disease, bad breath and cavities. Therefore, removing calculus is an important step towards long-term oral health. Another drawback of tartar is its ability to easily absorb stains due to its porous quality.

[0005] Uncontrolled bacteria in dental plaque lead to the formation of oral biofilms located on the teeth and subgingival surfaces. It can induce local inflammation (gingivitis) and even the development of periodontal disease. Various oral bacteria, such as Streptococcus mutans and Porphyromonas gingivalis, are involved in the development of caries and periodontitis. A very frequent bacterial infection is associated with candidiasis (Candida albicans).

[0006] There are two types of dental calculus: (i) supragingival calculus, which forms above the gum line. It is yellow or tan in color and is visible on the surface of the teeth; and (ii) subgingival calculus, which forms below the gum line, in the grooves (spaces) between the teeth and the gum line. It is typically not visible to the naked eye unless gum recession has already occurred.

[0007] Furthermore, there are two stages of dental calculus: (i) incipient (immature) calculus; and (ii) mature calculus. Incipient calculus refers to the early stage of forming calculus, which is mostly inorganic brucite CaHPO4.2H2O. Incipient calculus is softer in nature and therefore can be scraped off with white dentifrice and toothbrush. Mature calculus refers to the later stage of forming calculus, which contains at least one of octacalcium phosphate Ca4H(PO4)3.2H2O in the intermediate phase, which further contains hydroxyapatite Ca 10 It is transformed into (OH)2(PO4)6 and / or whitlockite Ca9(PO4)6XPO4. Mature tartar is also known as hard tartar. Early calculus is a chalky, spongy like mineralized plaque that adheres to the tooth surface. At its early stage, tartar is relatively soft and has a weaker adhesive strength to the tooth surface. Furthermore, early tartar is more prone to being disrupted by toothbrush strokes and by chemicals - e.g., ingredients in tartar control toothpastes. If early tartar is left untreated, it will accumulate and become more mineralized layers, hard crystals, and firmly adhere to the tooth surface and is considered mature tartar.

[0008] Once mature calculus forms on a tooth, it can only be removed by a dental professional; regular brushing and flossing are ineffective at removing it, whereas early stage calculus is more susceptible to tartar control dentifrices. Mature calculus is removed through a process known as debridement, with handheld instruments or using ultrasonic devices to remove calculus. Dental calculus should be removed periodically to maintain healthy teeth.

[0009] Today, there is a wide range of products marketed for removing tartar (mouth rinses, toothpastes, chewing gum, etc.) labeled "tartar control" or "tartar defense," however, there are no products specifically designed to remove mature calculus.

[0010] Many studies have shown that pyrophosphates are commonly used in products to remove tartar; however, the present inventors (FIGS. 6-9) show that pyrophosphonates do not remove mature tartar.

[0011] Bisphosphonates are non-hydrolyzable pyrophosphate analogs with high affinity for calcium ions due to their ability to form bidentate and / or tridentate chelates with calcium ions. As a result, bisphosphonates cause strong interactions with dentin, enamel and bone. To date, the wide clinical use of approved bisphosphonates is for the treatment of bone diseases associated with bone fragmentation, such as bone malignancies, osteoporosis, Paget's disease, etc. In addition to their strong affinity for calcium ions in bone minerals, bisphosphonates (especially those with OH) promote osteoblast activity while strongly inhibiting osteoclasts, thus contributing to enhanced bone formation.

[0012] N-halamines are a class of compounds containing one or more nitrogen-halogen covalent bonds and are known for their antimicrobial activity. N-halamines have several advantages, including long-term stability in aqueous solution, specificity, low toxicity, relatively low cost, and efficient regeneration ability to carry halogens. The latter is a unique property that distinguishes N-halamines from other antimicrobial agents.

[0013] Peri-implantitis disease is an inflammatory process that affects the soft and hard tissues around an implant, which results in loss of supporting bone. As with natural teeth, bacteria can build up on the base of the implant, below the gum line. Over time, the bacteria can irritate and inflame the gum tissue, causing tissue damage and, if not caught early, deteriorating the bone structure underneath the implant.

[0014] Periodontal disease, also known as gum disease, is a set of inflammatory conditions that affect the tissues surrounding the teeth, generally caused by bacteria in the mouth that infect the tissues around the teeth.

[0015] Provided herein is the efficient use of polyphosphonates (bisphosphonates, tetraphosphonates, polymeric phosphonates) and / or N-halamines to remove calculus, especially mature calculus, without the need for a dental professional. Furthermore, the compositions of the present invention also treat and prevent dental caries or treat peri-implantitis or periodontal disease. Summary of the Invention

[0016] In some embodiments, the invention provides a dental care composition for use in removing mature tartar from a dental surface of a subject, comprising at least one polyphosphonate or a salt thereof in an amount of 0.05%-30% by weight of the composition; and a pharma- ceutically acceptable carrier. In another embodiment, the dental care composition further comprises an N-halamine.

[0017] In one embodiment, the dental care compositions of the invention comprise a polyphosphonate or salt thereof, the polyphosphonate comprising a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, a polymeric bisphosphonate, or a polymeric tetraphosphonate.

[0018] In one embodiment, the polyphosphonate is in the form of nanoparticles or microparticles.

[0019] In one embodiment, the dental care composition of the invention comprises a polyphosphonate represented by the following structure, or a salt thereof: [ka] In the formula, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl; [ka] or [ka] and L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; the amino acid side chain is attached to the carbon; and said alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain is each substituted or unsubstituted.

[0020] In another embodiment, the polyphosphonate is a bisphosphonate compound represented by the following structure (γ-Glu-BP) or a salt thereof: [ka]

[0021] In another embodiment, the polyphosphonate is a polymeric bisphosphonate that includes a monomer in the bisphosphonate represented by the following structure, or a salt thereof: [ka]

[0022] In another embodiment, the polyphosphonate is a tetraphosphonate compound represented by the following structure or a salt thereof: [ka] During the ceremony, L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; the side chain of the amino acid is attached to the carbon; and said alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain is substituted or unsubstituted.

[0023] In another embodiment, the tetraphosphonate compound is represented by the following structure: (succinyl tetraphosphonate (SUTP) or an alkali salt thereof:; or malonic acid tetraphosphonate or an alkali salt thereof): [ka] or [ka]

[0024] In another embodiment, the dental care composition further comprises an N-halamine compound, an N-halamine-based polymer, or an N-halamine-based particle in an amount of 0.1%-10% by weight of said composition.

[0025] In some embodiments, provided herein is a dental care composition for use in removing tartar from a subject's tooth surface, comprising at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle in an amount of 0.1%-10% by weight of the composition; and a pharma- ceutically acceptable carrier. In another embodiment, the tartar is mature tartar.

[0026] In another embodiment, the N-halamine compound comprises a halogenated primary amine, a halogenated secondary amine, a halogenated amide, or a halogenated urea.

[0027] In another embodiment, the N-halamine based particles are in the form of core / shell silica halamine-urea particles, represented by the following structure: [ka] wherein X is independently a halide and k is 1-10.

[0028] In another embodiment, the N-halamine polymer is represented by the structure: [ka] [ka] or [ka] wherein X is independently a halide and n is 2-100.

[0029] In some embodiments, provided herein is a dental care composition for use in treating or preventing dental caries and / or for treating or preventing peri-implantitis or periodontal disease, the composition comprising at least one N-halamine-based polymer or N-halamine-based particle in an amount of 0.1-10% by weight of the composition, and a pharma- ceutically acceptable carrier, wherein the N-halamine-based polymer is represented by the structure: [ka] [ka] or [ka] The N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: [ka] wherein X is independently a halide and k is 1-10.

[0030] In another embodiment, the dental care composition comprises an N-halamine provided herein and a polyphosphonate or salt thereof provided herein.

[0031] In one embodiment, the dental care compositions provided herein are formulated as a solution, paste, gel, spray, foam, toothpaste, mouthwash, dental tray, tooth filler, dentifrice, dissolving or non-dissolving thin film, dissolving or non-dissolving dental strip, as an edible film former, drop, chewing gum, or as a coating on a dental implant.

[0032] In one embodiment, the present invention provides a succinyl tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka] or a malonyl tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka]

[0033] In some embodiments, the invention provides dental care compositions comprising a succinyl or malonyl tetraphosphonate compound of the invention or an alkali salt thereof and a pharma- ceutically acceptable carrier.

[0034] The subject matter which is regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification, however, the invention, both as to organization and method of operation, together with its objects, features, and advantages, may best be understood by reference to the following detailed description when read in conjunction with the accompanying drawings. [Brief description of the drawings]

[0035] [Figure 1] Shown are photographs of teeth with mature calculus before and after treatment with 10 mg / mL succinyl tetraphosphonate, SUTP (Figure 1A: pre-treatment; Figure 1B: post-treatment); and 1 mg / mL SUTP (Figure 1C: pre-treatment; Figure 1D: post-treatment). [Diagram 2] Photographs of a human tooth with mature calculus before (FIG. 2A) and after (FIG. 2B) poly(styryl bisphosphonate) NPs (Poly(StBP) NPs) treatment (1 mg / ml) are shown. [Diagram 3] Photographs of human teeth with mature calculus before (FIG. 3A) and after (FIG. 3B) γ-Glu-BP treatment (1 mg / ml) are shown. [Figure 4] Shown are photographs of a tooth with mature calculus before and after treatment with 7.5 mM Si-Urea-Cl NPs (Figure 4A: before treatment and Figure 4B: after treatment) and 2 mM Si-Urea-Cl NPs (Figure 4C: before treatment and Figure 4D: after treatment). [Diagram 5]Shown are photographs of teeth with mature calculus before and after treatment with 20 mM PMAA-Cl (Figure 5A: pre-treatment; Figure 5B: post-treatment); and 2 mM PMAA-Cl (Figure 5C: pre-treatment; Figure 5D: post-treatment). [Figure 6] Photographs of teeth with mature calculus before and after treatment with succinyl tetraphosphonate (SUTP) at a concentration of 1 mg / ml are shown. [Figure 7] Photographs of teeth with mature calculus before and after treatment with sodium pyrophosphate tetrabasic having a concentration of 1 mg / ml are shown. [Figure 8] Photographs of teeth with mature calculus before and after treatment with sodium pyrophosphate dibasic having a concentration of 1 mg / ml are shown. [Figure 9] Photographs of three solutions at a concentration (1 mg / ml) after tooth brushing are shown: SUTP solution (FIG. 9A), sodium pyrophosphate dibasic solution (FIG. 9B) and sodium pyrophosphate tetrabasic solution (FIG. 9C). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.

[0037] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.

[0038] composition In some embodiments, the invention provides dental care compositions comprising at least one polyphosphonate or a salt thereof, an N-halamine or a combination thereof; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma- ceutically acceptable carrier.

[0039] In some embodiments, the invention provides dental care compositions comprising at least one polyphosphonate or a salt thereof, an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or any combination thereof; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma-ceutically acceptable carrier.

[0040] In some embodiments, the invention provides dental care compositions comprising at least one polyphosphonate or salt thereof, and a pharma- ceutically acceptable carrier, hi other embodiments, the polyphosphonate comprises a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, a polymeric bisphosphonate, or a polymeric tetraphosphonate.

[0041] In some embodiments, the invention provides dental care compositions comprising: a tetraphosphate compound or an alkali salt thereof and a bisphosphonate compound or a salt thereof.

[0042] In some embodiments, the invention provides dental care compositions comprising: a tetraphosphate compound or an alkali salt thereof and a polymeric bisphosphonate or a salt thereof.

[0043] In some embodiments, the invention provides dental care compositions comprising at least one polyphosphonate or a salt thereof and a pharma- ceutically acceptable carrier.

[0044] In some embodiments, the invention provides dental care compositions comprising: at least one N-halamine compound, N-halamine-based polymer, N-halamine-based particle, or combinations thereof, and a pharma- ceutically acceptable carrier.

[0045] In some embodiments, the invention provides dental care compositions comprising: at least one polyphosphonate and at least one of an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle; and a pharma- ceutically acceptable carrier.

[0046] The invention provides a dental care composition comprising: a copolymer comprising a phosphonate backbone and an N-halamine backbone, and a pharma- ceutically acceptable carrier.

[0047] In some embodiments, the invention provides dental care compositions for use in removing tartar from a subject's tooth surface, comprising at least one polyphosphonate, N-halamine compound, N-halamine-based polymer, N-halamine-based particle, or combination thereof; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma- ceutically acceptable carrier. In another embodiment, the tartar is early and mature tartar. In another embodiment, the tartar is mature tartar.

[0048] In some embodiments, the invention provides dental care compositions for use in removing mature tartar from a subject's tooth surface, comprising at least one polyphosphonate or a salt thereof, an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma-ceutically acceptable carrier; the polyphosphonate comprises a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, a polymeric bisphosphonate, or a polymeric tetraphosphonate.

[0049] In some embodiments, the invention provides a dental care composition for use in removing mature tartar from a dental surface of a subject, comprising at least one polyphosphonate or salt thereof, in an amount of 0.05%-30% by weight of the composition, and a pharma- ceutically acceptable carrier. In one embodiment, the polyphosphonate comprises a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, a polymeric bisphosphonate, or a polymeric tetraphosphonate.

[0050] In some embodiments, the invention provides a dental care composition for use in removing mature tartar from a tooth surface of a subject, comprising at least one polyphosphonate or salt thereof, in an amount of 0.05%-10% by weight of the composition, and a pharma- ceutically acceptable carrier. In one embodiment, the polyphosphonate comprises a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, a polymeric bisphosphonate, or a polymeric tetraphosphonate.

[0051] In another embodiment, the polyphosphonates or salts thereof provided herein are in the form of nanoparticles or microparticles.

[0052] In some embodiments, the invention provides a dental care composition for use in removing tartar from a subject's dental surface, comprising: at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle, in an amount of 0.1%-10% by weight of the composition; and a pharma- ceutically acceptable carrier.

[0053] In some embodiments, the invention provides a dental care composition for use in removing tartar from a subject's tooth surface, comprising at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle, or a combination thereof; or a combination of at least one polyphosphonate and an N-halamine compound, N-halamine-based polymer, or N-halamine-based particle; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma- ceutically acceptable carrier. In another embodiment, the tartar is mature tartar.

[0054] The invention provides a dental care composition for use in treating or preventing dental caries, comprising at least one N-halamine compound, N-halamine based polymer, or N-halamine based particle, or a combination thereof; or a combination of at least one polyphosphonate compound and an N-halamine compound, N-halamine based polymer, or N-halamine based particle; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharmaceutically acceptable carrier.The invention provides a dental care composition for use in treating or preventing peri-implantitis, comprising at least one N-halamine compound, N-halamine based polymer, or N-halamine based particle, or a combination thereof; or a combination of at least one polyphosphonate compound and an N-halamine compound, N-halamine based polymer, or N-halamine based particle; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharmaceutically acceptable carrier.

[0055] In some embodiments, the invention provides dental care compositions for use in treating or preventing periodontal disease comprising at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle, or a combination thereof; or at least one polyphosphonate compound and a combination of an N-halamine compound, an N-halamine-based polymer, or an N-halamine-based particle, an N-halamine-based polymer, an N-halamine-based particle, or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma-ceutically acceptable carrier.

[0056] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar (calculus) from a subject's tooth surface; or (ii) removing mature tartar (mature calculus) from a subject's tooth surface, comprising at least one polyphosphonate or salt thereof, and a pharma- ceutically acceptable carrier.

[0057] In another embodiment, a dental care composition comprising at least one polyphosphonate or salt thereof and a pharma- ceutically acceptable carrier for use in removing mature calculus from the dental surfaces of a subject.

[0058] In another embodiment, the subject's tooth surface is treated with octacalcium phosphate, Ca4H(PO4)3.2H2O, hydroxyapatite, Ca 10 A dental care composition comprising at least one polyphosphonate or a salt thereof and a pharma- ceutically acceptable carrier for use in removing (OH)2(PO4)6, Whitlockite Ca9(PO4)6XPO4, or any combination thereof. In another embodiment, the dental composition further comprises an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or a combination thereof.

[0059] In some embodiments, the invention provides a dental care composition for use in removing mature calculus from the tooth surfaces of a subject, comprising: a tetraphosphate compound or an alkali salt thereof and a bisphosphonate compound or a salt thereof, and a pharma- ceutically acceptable carrier.

[0060] In some embodiments, the invention provides a dental care composition for use in removing mature calculus from the tooth surfaces of a subject, comprising: a tetraphosphate compound or an alkali salt thereof and a polymeric bisphosphonate or a salt thereof, and a pharma- ceutically acceptable carrier.

[0061] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, comprising an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or combinations thereof, and a pharma- ceutically acceptable carrier. Each represents a separate embodiment of the invention. In another embodiment, the dental composition further comprises a polyphosphonate.

[0062] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surfaces; (ii) removing mature calculus from a subject's tooth surfaces; (iv) treating or preventing dental caries; (v) treating or preventing peri-implantitis; or (vi) treating or preventing periodontitis, comprising: an N-halamine, and a polyphosphonate or salt thereof; and a pharma- ceutically acceptable carrier. Each represents a separate embodiment of the invention.

[0063] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, comprising: a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma- ceutically acceptable carrier, each of which represents a separate embodiment of the invention.

[0064] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, comprising at least one polyphosphonate or salt thereof, an N-halamine, or a combination thereof or a combination thereof; or a copolymer comprising a phosphonate backbone and an N-halamine backbone; and a pharma- ceutically acceptable carrier. Each represents a separate embodiment of the invention.

[0065] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, comprising an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or combinations thereof, and a pharma- ceutically acceptable carrier. Each represents a separate embodiment of the invention. In another embodiment, the dental composition further comprises a polyphosphonate.

[0066] In some embodiments, the invention provides dental care compositions for use in treating or preventing peri-implantitis or treating or preventing periodontitis, comprising an N-halamine compound, an N-halamine-based polymer, an N-halamine-based particle, or combinations thereof, and a pharma- ceutically acceptable carrier. Each represents a separate embodiment of this invention. In another embodiment, the dental composition further comprises a polyphosphonate or a salt thereof.

[0067] In some embodiments, the invention provides dental care compositions for use in (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, comprising: an N-halamine-based polymer, an N-halamine-based particle, or a combination thereof, and a pharma- ceutically acceptable carrier, wherein the N-halamine-based polymer is represented by the structure: [ka] [ka] or [ka] The N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: [ka] wherein X is a halide and k is 1-10. Each represents a separate embodiment of this invention. In another embodiment, the dental composition further comprises a polyphosphonate or a salt thereof.

[0068] In some embodiments, the dental care compositions of the present invention are for use in removing mature tartar from tooth surfaces. In some embodiments, the dental care compositions of the present invention are for use in removing or decomposing octacalcium phosphate, Ca4H(PO4)3.2H2O, from tooth surfaces. In some embodiments, the dental care compositions of the present invention are for use in removing or decomposing hydroxyapatite, Ca 10 For use in removing or decomposing (OH)2(PO4)6 and / or Whitlockite Ca9(PO4)6XPO4.

[0069] In some embodiments, removal of tartar using the dental care compositions of the present invention refers to removal of supragingival tartar, hi some embodiments, removal of tartar using the dental care compositions of the present invention refers to removal of subgingival tartar.

[0070] In some embodiments, removal of mature calculus using the dental care compositions of the present invention refers to removal of supragingival mature calculus. In some embodiments, removal of mature calculus using the dental care compositions of the present invention refers to removal of subgingival mature calculus.

[0071] The term "periodontal disease", also known as gum disease, is used herein to refer to a set of inflammatory conditions that affect the tissues surrounding the teeth. Generally, it is caused by bacteria in the mouth that infect the tissues surrounding the teeth. Periodontal disease also includes gingivitis or periodontitis.

[0072] In one embodiment, peri-implantitis disease is an inflammatory condition that affects the soft and hard gum tissues around a dental implant. As with natural teeth, bacteria can accumulate on the base of the implant, below the gum line. Over time, the bacteria can irritate and inflame the gum tissue, causing tissue damage and, if not caught early, deteriorating the bone structure under the implant.

[0073] In another embodiment, the compositions and methods of use provided herein comprise 0.01%-10% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.05%-30% by weight of a polyphosphonate. In another embodiment, the compositions comprise 0.05%-60% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.05%-2% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.05%-0.5% by weight of a polyphosphonate. In another embodiment, the compositions comprise 0.1%-0.5% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.1%-1% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.1%-0.2% by weight of a polyphosphonate. In another embodiment, the compositions comprise 0.1%-0.3% by weight of a polyphosphonate or a salt thereof. In another embodiment, the compositions comprise 0.1%-0.4% by weight of a polyphosphonate or a salt thereof. In another embodiment, the composition comprises 0.1%-0.6% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.1%-0.7% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.1%-0.8% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.1%-0.9% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.2% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.3% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.4% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.6% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.7% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-0.8% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05% by weight-0.9% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 1%-3% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 1%-5% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-1.5% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.1%-1.5% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 3%-10% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 1%-7.5% by weight of the polyphosphonate. In another embodiment, the composition comprises 2%-5% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 1%-5% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 4%-8% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 3%-10% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 5%-10% by weight of a polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.5-10% by weight of a polyphosphonate or salt thereof. In another embodiment, the composition comprises 0.05%-7.5% by weight of a polyphosphonate. In another embodiment, the composition comprises 0.05%-10% by weight of a polyphosphonate. In another embodiment, the composition comprises 0.05%-20% by weight of a polyphosphonate. In another embodiment, the composition comprises 0.In another embodiment, the composition comprises 0.05%-25% by weight of the polyphosphonate. In another embodiment, the composition comprises 1%-20% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 2%-10% by weight of the polyphosphonate. In another embodiment, the composition comprises 2%-20% by weight of the polyphosphonate. In another embodiment, the composition comprises 5%-30% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 10%-12% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 15-20% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 12-20% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 20-30% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 30%-40% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition comprises 40%-50% by weight of the polyphosphonate or salt thereof. In another embodiment, the composition is 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.0.4 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 ... .9% by weight, 3.0% by weight, 3.1% by weight, 3.2% by weight, 3.3% by weight, 3.4% by weight, 3.5% by weight, 3.6% by weight, 3.7% by weight, 3.8% by weight, 3 .9% by weight, 4.0% by weight, 4.1% by weight, 4.2% by weight, 4.3% by weight, 4.4% by weight, 4.5% by weight, 4.6% by weight, 4.7% by weight, 4.8% by weight, 4 .9% by weight, 5.0% by weight, 5.1% by weight, 5.2% by weight, 5.3% by weight, 5.4% by weight, 5.5% by weight, 5.6% by weight, 5.7% by weight, 5.8% by weight, 5 .9% by weight, 6.0% by weight, 6.1% by weight, 6.2% by weight, 6.3% by weight, 6.4% by weight, 6.5% by weight, 6.6% by weight, 6.7% by weight, 6.8% by weight, 6.9% by weight, 7.0% by weight, 7.1% by weight, 7.2% by weight, 7.3% by weight, 7.4% by weight, 7.5% by weight, 7.6% by weight, 7.7% by weight, 7.8% by weight, 7.9% by weight, 8.0% by weight, 8.1% by weight, 8.2% by weight, 8.3% by weight, 8.4% by weight, 8.5% by weight, 8 .6% by weight, 8.7% by weight, 8.8% by weight, 8.9% by weight, 9.0% by weight, 9.1% by weight, 9.2% by weight, 9.3% by weight, 9.4% by weight, 9.5% by weight, 9.6% by weight, 9.7% by weight, 9.8% by weight, 9.9% by weight, 10.0% by weight, 11% by weight, 11.5% by weight, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 35%, 40%, 45%, 50%, 55%, 60% by weight of the polyphosphonate or salt thereof, or any range thereof, each of which represents a separate embodiment of this invention.

[0074] In another embodiment, the composition comprises 0.1%-10% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.1%-2% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.5%-10% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.5%-2% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.1%-0.5% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.1%-1% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 1%-3% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 1%-5% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.1%-1.5% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 0.1%-1.5% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle.

[0075] In another embodiment, the composition comprises 2%-5% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 4%-8% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 3%-10% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition comprises 5%-10% by weight of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle. In another embodiment, the composition is 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 ... .6% by weight, 2.7% by weight, 2.8% by weight, 2.9% by weight, 3.0% by weight, 3.1% by weight, 3.2% by weight, 3.3% by weight, 3.4% by weight, 3.5% by weight, 3.6% by weight, 3.7% by weight, 3.8% by weight, 3.9% by weight Amount%, 4.0 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt%, 5.0 wt%, 5.1 wt%, 5.2 wt%, 5.3% by weight, 5.4% by weight, 5.5% by weight, 5.6% by weight, 5.7% by weight, 5.8% by weight, 5.9% by weight, 6.0% by weight, 6.1% by weight, 6.2% by weight, 6.3% by weight, 6.4% by weight, 6.5% by weight, 6. 6% by weight, 6.7% by weight, 6.8% by weight, 6.9% by weight, 7.0% by weight, 7.1% by weight, 7.2% by weight, 7.3% by weight, 7.4% by weight, 7.5% by weight, 7.6% by weight, 7.7% by weight, 7.8% by weight, 7.9% by weight %, 8.0% by weight, 8.1% by weight, 8.2% by weight, 8.3% by weight, 8.4% by weight, 8.5% by weight, 8.6% by weight, 8.7% by weight, 8.8% by weight, 8.9% by weight, 9.0% by weight, 9.1% by weight, 9.2% by weight, 9.3% by weight, 9.4% by weight, 9.5% by weight, 9.6% by weight, 9.7% by weight, 9.8% by weight, 9.9% by weight, or 10.0% by weight of N-halamine compound, N-halamine-based polymer, or N-halamine-based particle.Each represents a separate embodiment of the present invention.

[0076] In another embodiment, the composition of this invention comprises 0.05%-30% w / w of a polyphosphonate or salt thereof and 0.01%-10% w / w of an N-halamine compound, N-halamine-based polymer, or N-halamine-based particle.

[0077] In some embodiments, the dental care composition comprises a polyphosphonate and an N-halamine compound, an N-halamine-based polymer, or an N-halamine-based particle, wherein the amount of the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle is 0.1%-10% by weight of the composition.

[0078] The term "tartar" or "calculus" or "dental calculus" refers to the partially mineralized deposits on the tooth surfaces formed by the maturation of plaque. Tartar is a deposit of inorganic salts, mainly calcium carbonates and phosphates, mixed with bacterial food debris and desquamated epithelial cells.

[0079] The terms "mature calculus" and "mature tartar" refer to the later stage of calculus formation, which is composed of octacalcium phosphate Ca4H(PO4)3.2H2O, hydroxyapatite Ca 10 (OH)2(PO4)6 and / or Whitlockite Ca9(PO4)6XPO4. In another embodiment, mature calculus is also known as hard calculus. In another embodiment, mature calculus refers to calculus that needs to be removed by handheld instruments through a process known as debridement or by using ultrasonic devices to remove calculus.

[0080] The compositions of the invention are used to remove or dissolve calculus or tartar. In one embodiment, the compositions of the invention are used to remove mature calculus (mature tartar). The compositions can be applied to teeth by any known method. The compositions provided herein are formulated as dentifrices (including toothpastes), gels, mouthwashes, dissolving or non-dissolving thin films, dissolving or non-dissolving dental strips, as edible film formers, as drops and chewing gums, sprays, tooth filers, dental trays, solutions, pastes, foams, toothpastes, or tooth fillers.

[0081] In another embodiment, the composition is formulated as dragees, lozenges, dissolving lozenges, drops or chewing gum.In another embodiment, the composition of this invention is used as a coating for dental implants.

[0082] In another embodiment, the compositions of the invention are formulated as toothpastes, oral gels, poultices (e.g., dental dressings), pastes, mouthwashes, sprays, dentifrices, tooth powders, mouth rinses, chewing gums, lozenges, or impregnated flosses or brushes, tooth hardeners. The compositions can also be provided in dissolving and non-dissolving films. In other embodiments, the compositions of the invention are solutions, pastes, gels, mouthwashes, or creams.

[0083] In some embodiments, the polyphosphonate or salt thereof, N-halamine compound, N-halamine-based polymer, N-halamine particle, or copolymer comprising a phosphonate backbone and an N-halamine backbone is referred to herein as a calculus remover. In other embodiments, the calculus remover of the present invention is a particle. In other embodiments, the calculus remover of the present invention is encapsulated. In other embodiments, the calculus remover of the present invention is polymerized.

[0084] Polyphosphonates The term "polyphosphonate" as used herein refers to a bisphosphonate or salt thereof, a triphosphonate or salt thereof, a tetraphosphonate or salt thereof, a polymeric bisphosphonate or salt thereof, a polymeric triphosphonate or salt thereof, a polymeric tetraphosphonate or salt thereof or more.

[0085] In another embodiment, the dental care compositions of the invention comprise a polyphosphonate, the polyphosphonate comprising a bisphosphonate compound, a tetraphosphonate compound, a polymeric phosphonate, or a polymeric bisphosphonate, or a polymeric tetraphosphonate. In some embodiments, the polyphosphonate compounds provided herein are nanoparticles or microparticles.

[0086] In some embodiments, the polyphosphonate in the dental care composition of the present invention is represented by the structure of Formula I, or a salt thereof: [ka] During the ceremony, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, [ka] or [ka] and; L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; the side chain of the amino acid is attached to a carbon (C-OH); and said alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain is each substituted or unsubstituted.

[0087] In another embodiment, the polyphosphonate is a bisphosphonate compound in the compositions of this invention and is represented by the following structure (γ-Glu-BP) or a salt thereof: [ka]

[0088] In some embodiments, the polyphosphonate in the dental care compositions of the present invention comprises a polymeric bisphosphonate.

[0089] In some embodiments, the polyphosphonate is a polymeric bisphosphonate based on a bisphosphonate monomer represented by the following structure or an alkali salt thereof: [ka]

[0090] In some embodiments, the polyphosphonate in the dental care compositions of the present invention comprises a tetraphosphonate compound or an alkali salt thereof.

[0091] In another embodiment, the tetraphosphonate compound has the structure: [ka] or a salt thereof During the ceremony, L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; the side chain of an amino acid is attached to the carbon; and said alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain is substituted or unsubstituted.

[0092] In some embodiments, L of the polyphosphonates of this invention is an alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; the amino acid side chain is attached to the carbon. In another embodiment, L is a substituted or unsubstituted alkyl. In another embodiment, L is an unsubstituted alkyl. In another embodiment, L is a substituted alkyl. In another embodiment, L is a substituted or unsubstituted C2-C5 alkyl. In another embodiment, L is an unsubstituted C2-C5 alkyl. In another embodiment, L is a substituted C2-C5 alkyl. In another embodiment, L is a substituted or unsubstituted alkylaryl. In another embodiment, L is a substituted or unsubstituted alkynyl. In another embodiment, L is a substituted or unsubstituted aryl. In another embodiment, L is a substituted or unsubstituted alkylether. In another embodiment, L is a substituted or unsubstituted alkylthioether. In another embodiment, L is a substituted or unsubstituted alkylamide. In another embodiment, L is a substituted or unsubstituted alkylamine.

[0093] In another embodiment, L of formula I or the bisphosphonate or tetraphosphonate compounds provided herein is substituted or unsubstituted C1-C5 alkyl. In another embodiment, L is substituted or unsubstituted C2-C5 alkyl. In another embodiment, L is substituted or unsubstituted C2-C8 alkyl. In another embodiment, L is unsubstituted C2-C3 alkyl. In another embodiment, L is substituted C2-C3 alkyl.

[0094] In some embodiments, L in the polyphosphonates of the invention is an alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain, where the alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, or alkylamine is substituted or unsubstituted. The substituents are selected from halo, CN, NO2, alkyl, OH, COOH, amine, hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, or alkylsulfonyl groups. Any of the substituents can be unsubstituted or further substituted with any one of these aforementioned substituents.

[0095] In some embodiments, the polyphosphonates of the invention are encapsulated.

[0096] In another embodiment, the tetraphosphonate compound is represented by the following structure (succinyltetraphosphonate-SUTP) or an alkali salt thereof: [ka]

[0097] In another embodiment, the tetraphosphonate compound is represented by the following structure (malonyl tetraphosphonate) or an alkali salt thereof: [ka]

[0098] In some embodiments, provided herein is a dental care composition for use in removing tartar from a dental surface of a subject, comprising at least one polyphosphonate in an amount of 0.05%-30% by weight of said composition; and a pharma- ceutically acceptable carrier; the polyphosphonate comprises a bisphosphonate compound or a tetraphosphonate compound; the bisphosphonate is represented by the following structure or a salt thereof: [ka] In the formula, R a is an amino acid, the side chain of the amino acid being attached to the carbon; and the tetraphosphonate compound is represented by the following structures: succinyl tetraphosphonate (-SUTP) or an alkali salt thereof; or malonic acid tetraphosphonate or an alkali salt thereof: [ka] or [ka] In another embodiment, the tartar is mature tartar.

[0099] In one embodiment, the hydroxy groups of the polyphosphate can be ionized by the pH environment, while in another embodiment, the ionization of the hydroxy groups of the polyphosphate includes its alkali salt.

[0100] In another embodiment, the tetraphosphonate compound, bisphosphonate compound, polyphosphonate, or alkali salt of the structure of formula I is Li+, Na+, K+, Rb+, or Cs+. In another embodiment, the alkali salt is Na+.

[0101] In one embodiment, the present invention provides a succinyl tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka]

[0102] In one embodiment, the present invention provides a succinyl tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka] and a pharma- ceutically acceptable carrier. In another embodiment, the composition is a dental care composition.

[0103] In one embodiment, the present invention provides a succinyl tetraphosphonate compound represented by the following structure or an alkali salt thereof for use as a calculus remover: [ka] and a pharma- ceutically acceptable carrier. In another embodiment, the composition is for use as a mature calculus remover.

[0104] In one embodiment, the invention provides a dental care composition comprising a succinyl tetraphosphonate compound for use in treating teeth to remove mature tartar from the tooth surfaces of a subject.

[0105] In one embodiment, the invention provides a malonic acid tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka]

[0106] In one embodiment, the present invention provides a malonate tetraphosphonate compound represented by the following structure or an alkali salt thereof: [ka] and a pharma- ceutically acceptable carrier. In another embodiment, the composition is a dental care composition.

[0107] In one embodiment, the present invention provides a succinyl tetraphosphonate compound represented by the following structure or an alkali salt thereof for use as a calculus removing agent, an anti-caries agent, or a combination thereof: [ka] and a pharma- ceutically acceptable carrier.

[0108] In one embodiment, the invention provides a dental care composition comprising a malonate tetraphosphonate compound for use in treating teeth to remove tartar from the tooth surfaces of a subject. In another embodiment, the tartar is mature tartar.

[0109] N-Halamine The term "N-halamine" as used herein refers to N-halamine compounds, N-halamine-based polymers and / or N-halamine particles, unless specifically referred to.

[0110] In another embodiment, "N-halamine" refers to an N-halamine compound. In another embodiment, "N-halamine" refers to an N-halamine-based polymer. In another embodiment, "N-halamine" refers to an N-halamine-based particle.

[0111] In another embodiment, the N-halamine compound comprises a halogenated primary amine, a halogenated secondary amine, a halogenated amide, or a halogenated urea.

[0112] In another embodiment, the N-halamine-based particles are nanoparticles or microparticles.

[0113] In another embodiment, the N-halamine-based polymer is a nanoparticle or microparticle.

[0114] In another embodiment, the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle is encapsulated.

[0115] In some embodiments, the dental care compositions of the present invention include an N-halamine compound. In other embodiments, the N-halamine compound includes a halogenated primary amine, secondary amine, tertiary amine, primary or secondary amide, imine, or urea. In other embodiments, the N-halamine is an N-chloroamine. In other embodiments, the N-halamine is an N-bromoamine. In other embodiments, the N-halamine is an N-iodoamine. In other embodiments, the N-halamine is an N-fluoroamine.

[0116] Examples of N-halamine compounds include N-chloroglycine, N-bromoglycine, N-iodoglycine, N-chlorosarcosine, N-bromosarcosine, N-iodosarcosine, N-chloro alpha aminoisobutyric acid, N-chlorotaurine, N-bromotaurine, N-iodotaurine, N-chloroaminomethanesulfonic acid, N-chloroethanolamine, N-chloro-N-acetylglycine, N-bromoethanolamine, N-iodo- ...bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromoethanolamine, N-bromo Alkanolamine, N-iodo-N-acetylglycine, N-bromo-N-acetylglycine, N-chloroalanine, N-chloro-β-alanine, N-bromo-β-alanine, N-chloroserine, N-bromoserine, N-iodocerine, N-chloro-N-phenylalanine, N-chloroisoleucine, N-chloro-norvaline, N-chloroleucine, N-bromoleucine, N-iodoleucine, N-chloroproline, N-bromoproline, N-iodoproline , N-chlorohydroxyproline, N-chloro omega-aminoundecanoic acid, N-chloroaspartic acid, N-bromoaspartic acid, N-chloroglutamic acid, N-iodoglutamic acid, N-chlorovaline, N-chlorotyrosine, N-bromo-tyrosine, N-iodotyrosine, N-chlorothreonine, N-chlorocysteine, N-chlorocystine, N-chloromethionine, N-chlorohistidine, N-chloroarginine, N-chloroglutamine, N -Bromoglutamine, N-chlorolysine, N-chloro gamma aminobutyric acid, N-chloro alpha, epsilon diaminopimelic acid, N-chloro-ornithine, N-chlorohydroxylysine, N-chloroanthranilic acid, N-chloro p-aminobenzoic acid, N-chlorosulfanilic acid, N-chlorophenylsulfamic acid, N-chloroaminopropanesulfonic acid, N-chloro-propanolamine, N-chloro-diethanolamine, N-chloroethylenediaminetetraacetic acid.

[0117] In some embodiments, the dental care compositions of the present invention include an N-halamine-based polymer, hi other embodiments, the N-halamine polymer forms nanoparticles or microparticles.

[0118] In another embodiment, the N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: [ka] wherein X is independently a halide and k is an integer from 1 to 10. In another embodiment, the halide is chloride.

[0119] In another embodiment, the N-halamine polymer is represented by the structure: [ka] [ka] or [ka] During the ceremony, X is independently a halide and n is 2 to 100. In another embodiment, the halide is chloride.

[0120] In some embodiments, k of the N-halamine based particles is an integer between 1-10. In other embodiments, k is an integer between 1-5. In other embodiments, k is an integer between 2-5. In other embodiments, k is an integer between 1-8. In other embodiments, k is an integer between 2-8. In other embodiments, k is an integer between 3-5. In another embodiment, k is an integer between 2-10. In another embodiment, k is 1. In another embodiment, k is 2. In another embodiment, k is 3. In another embodiment, k is 4. In another embodiment, k is 5. In another embodiment, k is 6. In another embodiment, k is 7. In another embodiment, k is 8. In another embodiment, k is 9. In another embodiment, k is 10.

[0121] In some embodiments, n of the N-halamine based polymer is an integer between 2-100. In other embodiments, n is an integer between 10-20. In other embodiments, n is an integer between 20-30. In other embodiments, n is an integer between 30-40. In other embodiments, n is an integer between 40-50. In other embodiments, n is an integer between 50-60. In other embodiments, n is an integer between 60-70. In other embodiments, n is an integer between 70-80. In other embodiments, n is an integer between 80-90. In other embodiments, n is an integer between 90-100. In other embodiments, n is an integer between 2-20. In other embodiments, n is an integer between 2-30. In other embodiments, n is an integer between 2-40. In other embodiments, n is an integer between 2-50. In other embodiments, n is an integer between 2-60. In other embodiments, n is an integer between 2-70. In other embodiments, n is an integer between 2-80. In other embodiments, n is an integer between 2-90. In another embodiment, n is an integer between 2-80. In another embodiment, n is an integer between 5-25. In another embodiment, n is an integer between 2-80. In another embodiment, n is an integer between 25-50. In another embodiment, n is an integer between 2-80. In another embodiment, n is an integer between 50-75. In another embodiment, n is an integer between 2-80. In another embodiment, n is an integer between 75-100.

[0122] In some embodiments, the dental care composition comprises an N-halamine based polymer (wherein the halogenation is on both the primary and secondary amides) and is represented by the following structure: [ka] wherein X is independently a halide and n is 2 to 100. In another embodiment, X is Cl.

[0123] In some embodiments, the dental care composition comprises a polymeric N-halamine and is represented by the following structure: [ka] or [ka] wherein X is independently a halide and n is an integer from 2 to 100. In another embodiment, X is Cl.

[0124] In some embodiments, provided herein is a dental care composition for use in removing tartar from a subject's tooth surface, comprising an N-halamine compound, an N-halamine-based polymer, or an N-halamine-based particle in an amount of 0.1%-10% by weight of said composition; and a pharma- ceutically acceptable carrier. In another embodiment, the tartar is mature tartar.

[0125] In another embodiment, the N-halamine compound comprises a halogenated primary amine, a halogenated secondary amine, a halogenated amide, or a halogenated urea.

[0126] In some embodiments, provided herein is a dental care composition for use in treating or preventing dental caries and / or for treating or preventing peri-implantitis or periodontal disease, comprising an N-halamine-based polymer or N-halamine-based particle in an amount of 0.1-10% by weight of said composition and a pharma- ceutically acceptable carrier, wherein the N-halamine-based polymer is represented by the structure: [ka] [ka] or [ka] The N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: [ka] where X is a halide and k is 1-10.

[0127] As used herein, the term "alkyl" refers, in one embodiment, to "C1-C 12 "alkyl" refers to straight-chain and branched, saturated or unsaturated (e.g., alkenyl, alkynyl) groups, the latter only if the number of carbon atoms in the alkyl chain is 2 or more, and may include mixed structures. Non-limiting examples are alkyl groups containing 1 to 6 carbon atoms (C1-C6 alkyl), or alkyl groups containing 1 to 4 carbon atoms (C1-C4 alkyl). Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amyl, tert-amyl, and hexyl. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, and the like. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like. Similarly, "C1-C 12 The term "alkylene" refers to a divalent radical of 1 to 12 carbons.

[0128] An alkyl group can be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, or alkylsulfonyl groups. Any of the substituents can be unsubstituted or further substituted with any one of these aforementioned substituents.

[0129] The term "aryl" as used herein alone or as part of another group refers to an aromatic ring system containing 6-14 ring carbon atoms. The aryl ring can be monocyclic, bicyclic, tricyclic, etc. Non-limiting examples of aryl groups are phenyl, naphthyl, e.g., 1-naphthyl and 2-naphthyl, etc. The aryl group can be unsubstituted or substituted through available carbon atoms with one or more groups such as halogen, hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo, cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, carboxamido, cyano, sulfonyl, sulfonylamino, sulfinyl, sulfinylamino, thiol, alkylthio, arylthio, or alkylsulfonyl groups. Any of the substituents can be unsubstituted or can be further substituted with any one of these aforementioned substituents.

[0130] The term "salt" refers to any known inorganic or organic salt. The term "salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and that are not biologically or otherwise undesirable. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, and the like. In another embodiment, the term "salt" refers to a pharmaceutically acceptable organic or inorganic base or residue of a base selected from the group consisting of alkali metals, alkaline earth metals, aluminum, zinc, and ammonium. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include NaOH, KOH, and the like. Salts derived from organic bases include NH4OH, NH3, and the like.

[0131] In another embodiment, the pharma- ceutically acceptable salt comprises an inorganic cation selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, aluminum, zinc, and ammonium. Each possibility represents a separate embodiment of the present invention.

[0132] In another embodiment, the salt is an alkaline salt.

[0133] The term "alkali salt" refers to an alkali cation. Alkali salts of polyphosphonates provided herein refer to those in which at least one of the OH groups on the phosphonic acid group is O-M+, where M+ is an alkali cation.

[0134] "Alkali cation" as used herein means Li + , Na + , K + , Rb + , or Cs + Shows.

[0135] In some embodiments, the dental care compositions of the present invention comprise a polymeric phosphonate. In other embodiments, the polymeric phosphonate forms nanoparticles or microparticles. It is well known that nanoparticles have a high surface area, which can increase the effectiveness of active groups on their surface.

[0136] "Halide," as used herein, refers to Cl, F, Br, or I. In one embodiment, the halide is chloride. In another embodiment, the halide is fluoride. In another embodiment, the halide is bromide. In another embodiment, the halide is iodide.

[0137] In some embodiments, the dental care compositions of the present invention comprise a copolymer, the copolymer comprising a polyphosphonate backbone and a poly N-halamine backbone. In other embodiments, the polyphosphonate backbone comprises a polybisphosphonate backbone. In other embodiments, non-limiting examples of polyphosphonate backbones include poly(styryl bisphosphonate) or polyethylene glycol bisphosphonate. In other embodiments, the copolymer is in the form of nanoparticles or microparticles.

[0138] The term "backbone" refers to the monomeric unit that contains the N-halamine or phosphonic acid groups, respectively, of the copolymer.

[0139] In some embodiments, the invention provides dental care compositions comprising at least one polyphosphonate, N-halamine or combination thereof; or a copolymer comprising a polyphosphonate backbone and a poly N-halamine backbone; and a pharma-ceutically acceptable carrier, the polyphosphonate, N-halamine and / or copolymer are encapsulated. In another embodiment, the polyphosphonate is encapsulated. In another embodiment, the N-halamine is encapsulated. In another embodiment, the copolymer is encapsulated. In another embodiment, provided herein are compositions encapsulated in the form of core-shell silica urea particles.

[0140] Non-limiting examples of encapsulating the calculus remover of the present invention can be found in US10508126.

[0141] The term "removing mature calculus" in this invention refers to removing octacalcium phosphate Ca4H(PO4)3.2H2O, hydroxyapatite Ca from the tooth surface of the subject. 10 This indicates the removal or decomposition of (OH)2(PO4)6 and / or whitlockite Ca9(PO4)6XPO4.

[0142] In some embodiments, the term "remove" refers to the complete removal of tartar or mature tartar from a subject's tooth surfaces.

[0143] In another embodiment, the removal of tartar to mature tartar represents at least 50% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 60% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 70% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 75% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 80% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 85% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 90% from the tooth surface. In another embodiment, the removal of tartar to mature tartar represents at least 95% from the tooth surface.

[0144] In some embodiments, complete removal of tartar or mature tartar is after repeated administration or application of the compositions of this invention.

[0145] In some embodiments, complete removal of tartar or mature tartar is achieved after repeated administration or application of the compositions of this invention followed by brushing.

[0146] A pharma- ceutically acceptable carrier for the dental care composition of this invention refers to a suitable carrier, a suitable vehicle, that can be used to apply the composition to the oral mucosa.

[0147] Suitably, in the compositions of the present invention, the orally acceptable vehicle may contain other ingredients such as flavourings, colouring agents, sweeteners, humectants, thickeners, binders and surfactants.

[0148] Binders and thickeners can be added to ensure physical integrity in pastes, gels, films and liquid pastes. Preferred thickeners and binding agents include, for example, natural and synthetic gums such as xanthan and acacia gums, carrageenans, alginates, cellulose ethers and esters such as carboxymethylcellulose, polyoxyalkyl polymers such as pluronic polymers, certain polymers exemplified by PVP materials, carboxyvinyl polymers, and silica.

[0149] In addition, the orally acceptable vehicle may optionally contain surfactants, sweeteners, flavoring agents, anti-caries agents (in addition to the fluoride ion source provided as a phosphatase enzyme inhibitor), anti-plaque agents, anti-microbial agents, such as cetylpyridinium chloride, dental desensitizing agents, colorants and pigments.

[0150] The compositions of the invention may also be formulated as mouthwashes or rinses, which may contain up to 95% water, up to 30% alcohol, flavors, polyalcohols, anticaries agents, plaque removers, sweeteners, dyes and lakes.

[0151] The active ingredients can also be incorporated into currently existing formulations, non-limiting examples of which include Cepacol (Lakeside Pharmaceuticals), Plax (Pfizer), Scope (Procter & Gamble), and the like.

[0152] In some embodiments, the composition of this invention is a solution. In other embodiments, the solution has a pH of 3.0-9.5. In other embodiments, the solution is acidic. In other embodiments, the solution is basic.

[0153] method This invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; and (v) treating or preventing periodontitis, by administering the compositions provided herein, each of which represents a separate embodiment of the invention.

[0154] The present invention provides a method for removing tartar from dental surfaces by administering / applying the compositions of the present invention to the dental surface in need thereof.

[0155] The invention provides a method for removing mature tartar (mature calculus) from a subject's tooth surface by administering / applying a composition of the invention to the tooth surface in need.The invention provides a method for removing mature tartar (mature calculus) from a subject's tooth surface by repeated administration or application of a composition of the invention to the tooth surface in need.

[0156] The present invention provides a method for treating or preventing dental caries by administering / applying the compositions of the present invention to a tooth surface in need thereof.

[0157] The present invention provides a method for treating or preventing peri-implantitis by administering / applying the compositions of the present invention to a tooth surface in need thereof.

[0158] The present invention provides a method for treating or preventing periodontal disease by administering / applying the compositions of the present invention to a tooth surface in need thereof.

[0159] In other aspects, the invention provides methods of treating a tooth by applying a composition of this invention to a tooth in need thereof to (i) remove tartar from a subject's tooth surface; (ii) remove mature calculus from a subject's tooth surface; (iii) treat or prevent dental caries; (iv) treat or prevent peri-implantitis; or (v) treat or prevent periodontitis, while leaving the remainder of the tooth unaffected (e.g., dentin or enamel are completely unaffected). Each represents a separate embodiment of the invention.

[0160] In another aspect, the invention provides methods of treating teeth by applying a composition of the invention to a subject's teeth in need of removing or reducing tartar from the tooth surface, thereby preventing the buildup of plaque and / or tartar, while leaving the remainder of the tooth unaffected (e.g., the dentin or enamel are completely unaffected). Each represents a separate embodiment of the invention.

[0161] In other aspects, this invention provides methods of treating teeth to (i) remove tartar from a subject's tooth surface; (ii) remove mature calculus from a subject's tooth surface; or (iii) treat teeth to treat or prevent caries by applying the compositions of this invention to teeth in need thereof, thereby minimizing or completely eliminating the need for mechanical removal with drills, burrs and hand tools. Each represents a separate embodiment of this invention.

[0162] In another aspect, the invention provides a method of treating teeth to remove tartar from a subject's tooth surfaces by applying the compositions of the invention to the teeth in need thereof, thereby preventing the accumulation of plaque and / or tartar, thereby minimizing or completely eliminating the need for mechanical removal with drills, burrs and hand tools. In another embodiment, the tartar is mature tartar.

[0163] The invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) preventing the accumulation of calculus formation on a subject's tooth surface; (iv) treating or preventing dental caries; (v) treating or preventing peri-implantitis; or (vi) treating or preventing periodontitis by administering a composition comprising a polyphosphonate or salt thereof provided herein to a tooth in need thereof.

[0164] The invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) preventing the accumulation of tartar formation on a subject's tooth surface; (iv) treating or preventing dental caries; (v) treating or preventing peri-implantitis; or (vi) treating or preventing periodontitis, by administering a composition comprising an N-halamine provided herein to a tooth in need thereof.

[0165] This invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) preventing the accumulation of calculus formation on a subject's tooth surface; (iv) treating or preventing dental caries; (v) treating or preventing peri-implantitis; or (vi) treating or preventing periodontitis by administering a combination of an N-halamine and a polyphosphonate, wherein the N-halamine and polyphosphonate are administered in either order, sequentially or concomitantly, each representing a separate embodiment of the invention.

[0166] This invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iiii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis by administering a combination of an N-halamine and a copolymer comprising a phosphonate backbone and an N-halamine backbone, where the N-halamine and the copolymer are administered in either order, sequentially or concomitantly, each representing a separate embodiment of this invention.

[0167] This invention provides methods for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis by administering a combination of a poly-phosphante and a copolymer comprising a phosphonate backbone and an N-halamine backbone, where the poly-phosphante and the copolymer are administered in either order, sequentially or concomitantly, each representing a separate embodiment of this invention.

[0168] Regimen In some embodiments, the invention provides a regimen for removing tartar from a subject's teeth, the regimen comprising applying a dental care composition of the invention to the teeth. In some embodiments, the invention provides a regimen for removing tartar from a subject's teeth, the regimen comprising applying a dental care composition of the invention to the teeth followed by brushing. In some embodiments, the invention provides a regimen for removing tartar from a subject's teeth, the regimen comprising repeated application of a dental care composition of the invention to the teeth. In some embodiments, the invention provides a regimen for removing tartar from a subject's teeth, the regimen comprising repeated application of a dental care composition of the invention to the teeth followed by brushing.

[0169] The invention provides a regimen for (i) removing tartar from a subject's tooth surfaces; (ii) removing mature calculus from a subject's tooth surfaces; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, the regimen comprising applying a dental care composition of the invention to a tooth, optionally followed by brushing the teeth.

[0170] The invention provides a regimen for (i) removing tartar from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis, the regimen comprising applying a dental care composition of the invention onto a dental implant.

[0171] In one embodiment, the regimen for (i) removing calculus from a subject's tooth surface; (ii) removing mature calculus from a subject's tooth surface; (iii) treating or preventing caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis comprises applying a provided dental care composition to a tooth for 2 minutes, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, or 1 hour. In another embodiment, the regimen for (i) removing or reducing calculus from a subject's tooth surface; (ii) removing or reducing mature calculus from a subject's tooth surface; (iii) treating or preventing caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis comprises applying the dental care composition of the invention to a tooth once a day, twice a day, once a week, or twice a week, optionally followed by brushing.

[0172] In another embodiment, a regimen for (i) removing or reducing tartar from a subject's tooth surfaces; (ii) removing or reducing mature calculus from a subject's tooth surfaces; (iii) treating or preventing dental caries; (iv) treating or preventing peri-implantitis; or (v) treating or preventing periodontitis comprises applying the dental care composition of this invention to the teeth once a day, twice a day, once a week, or twice a week, wherein the composition is applied by applying a mouthwash, or by applying a toothpaste, or by applying a dental tray.

[0173] The following non-limiting examples are presented to more fully describe certain embodiments of the invention, but should in no way be construed as limiting the broad scope of the invention. Those skilled in the art can easily devise numerous variations and modifications of the principles disclosed herein without departing from the scope of the invention.

[0174] Working Example Example 1 Synthesis of succinyl tetraphosphonate (SUTP, Scheme 1) [ka] Scheme 1: Synthesis of SUTP: a) P(OSiMe3)3, THF, 0 °C to RT b) MeOH, NaOH, RT Succinyl dichloride (3.5 ml, 5 g, 0.03 mol) was dissolved in THF (100 ml) under nitrogen and placed in an ice bath. Tris(trimethylsilyl) phosphite (46.8 ml, 41.8 g, 0.14 mol) was added and the resulting yellow mixture was then allowed to reach RT and then stirred for 24 hours. The mixture was then evaporated to dryness and then methanol (200 ml) was added to give an orange solution which was then stirred at RT for 24 hours to give a white precipitate. The white solid was collected by Buckner filtration and washed with methanol (100 ml) to give a yellow filtrate which was dried under vacuum to give the desired compound, succinyl tetraphosphonate (SUTP, Figures 1A-1D).

[0175] Example 2 Synthesis of γ-Glu-BP (Scheme 2) [ka] Scheme 2: Synthesis of γ-Glu-BP: a) AcOH, 145° C., 1.5 h, 44.4%. b) Ac2O, 100° C., 2 h, 91.6%. c) P(OSiMe3), THF, RT, on d) MeOH, RT 2 h, 83.3% (for 2 steps). E) HCl 6M, reflux, on, 98.7%. Synthesis of γ-N-phthaloylglutamic acid - Step a N-phthaloyl glutamic acid was synthesized as follows (Scheme 2-Step a): Acetic acid (34 ml) was added to a 500 ml round bottom flask containing phthalic anhydride (12.88 g, 0.087 mol) and L-glutamic acid (17 g, 0.11 mol), giving a cloudy solution. The solution was heated at 145° C. for 1.5 hours, giving a clear, colorless solution. The solution was allowed to cool to room temperature and then evaporated to give a colorless oil. Double distilled water (DDW) (334 ml) was then added to the oil and heated to 100° C., giving a clear, colorless solution. The solution was then allowed to cool to room temperature, 32% HCl (6 ml) was added, and the mixture was refrigerated overnight. The resulting solid was filtered and dried to give the desired product (10.7 g, 44.4% yield).

[0176] Synthesis of N-phthaloylglutamic anhydride - step b N-phthaloylglutamic anhydride was synthesized as follows: A suspension of N-phthaloylglutamic acid (10 g, 0.036 mol) in acetic anhydride (40 ml) was heated at 100° C. for 2 h to give a clear colorless solution, which was then cooled to room temperature and evaporated to give the desired compound, a white pinkish solid (8.6 g, 91.6% yield).

[0177] Synthesis of N-Pht-Glu-BP - steps c, d N-phthaloylglutamic anhydride (8 g, 0.031 mol) was dissolved in 200 ml of dry tetrahydrofuran (THF) under nitrogen to give a clear off-white solution. Tris(trimethylsilyl) phosphite (20 g, 0.07 mol) was then added to the solution and stirred overnight. The resulting clear colorless solution was evaporated to give a clear pinkish oil, which was then dissolved in methanol (150 ml) and stirred for 2 hours to give a clear colorless solution. The methanol solution was evaporated and the resulting orange oil was washed with diethyl ether (700 ml) and dried to give the desired compound (10.8 g, 83.3% yield).

[0178] Synthesis of γ-Glu-BP – Step e N-Pht-Glu-BP (10.8 g, 0.036 mol) was dissolved in HCl solution (6 M, 190 ml) and the clear, colorless solution was refluxed overnight. The solution was cooled to room temperature and then refrigerated for 4 hours. The resulting white crystals of phthalic acid were filtered and the clear, colorless filtrate was evaporated to give the desired compound (5.9 g, 98.7% yield).

[0179] Example 3 Synthesis of monomeric styryl bisphosphonates (StBP, Scheme 3) [ka] Scheme 3: Synthesis scheme of StBP monomer StBP monomer was prepared as described below (Scheme 3): Oxalyl chloride (35 ml, 2M) and N,N dimethylformamide (1 drop) were added to 4-vinylbenzoic acid (27 mmol), which was dissolved in anhydrous DCM (100 ml) and stirred overnight at room temperature (RT) to produce 4-vinylbenzoyl chloride. The solution was evaporated to produce a yellow oil, which was then dissolved in anhydrous THF (100 ml). Tris(trimethylsilyl) phosphite (77 mmol) was added and the mixture was stirred overnight at RT. The solution was evaporated to give the desired compound. Anhydrous methanol (100 ml) was added, followed by a solution of 60 ml of NaOH (3.24 g) in methanol and stirred for 2 h at RT. The product was filtered, the excess reagents were washed with methanol and dried in vacuum (2 mmHg). The resulting solid residue (StBP monomer) was characterized by nuclear magnetic resonance (NMR) spectroscopy, 1 H, 13 C and 31 The compounds were analyzed by P NMR (Bruker DMX-600 spectrometer, 600.1, 150.9 and 242.9 MHz, respectively), Fourier transform infrared (FTIR-IR) analysis (Bruker ALPHA-FTIR, QuickSnap™, Germany), and elemental analysis (Perkin-Elmer 2400 Series II analyzer, Microanalysis Lab., Institute of Chemistry of The Hebrew University of Jerusalem, Jerusalem, Israel).

[0180] Example 4 Synthesis of crosslinked poly(styryl bisphosphonate) nanoparticles (Poly(StBP) NPs, Scheme 4) [ka] Scheme 4: Synthesis of poly(StBP) NPs. Poly(StBP) NPs with a dry diameter of 65±7 nm (hydrodynamic diameter of 149±15 nm) were synthesized by a dispersion copolymerization process using a total monomer concentration of 5% (w / v): 57.25 mg of StBP monomer as described in Example 3, and 62.5 mg of TEGDMA [triethylene glycol dimethacrylate] in 0.3 M aqueous HCl solution (2.5 ml) containing 1-propanol (40% (v / v)). In addition, 6.25 mg of PPS (5% (w / w)) [potassium persulfate] as initiator and 25 mg of 360K molecular weight PVP [polyvinylpyrrolidone] (1% w / v) as stabilizer were added to the monomer solution.

[0181] Prior to polymerization, the vial containing the mixture was purged with N2 to remove air and shaken overnight at 80°C. The resulting particles were washed of excess reagents by extensive dialysis cycles (1,000 kD cutoff) with DDW. The particle dispersion was concentrated using hollow fiber diafiltration (750 kD polysulfone membrane, Spectrum Labs MiniKros® Sampler Plus P / N M4AB-260-01P).

[0182] Example 5 Chloramine nano / microparticles [ka] Scheme 6: Synthesis of crosslinked P(MAA-MBAA) NPs Preparation of crosslinked P(MAA-MBAA) nanoparticles (Scheme 6): Crosslinked P(MAA-MBAA) nanoparticles with hydrodynamic sizes ranging from 18±2 to 460±60 nm (Scheme 6). P(MAA-MBAA) nanoparticles were prepared by surfactant-free dispersion copolymerization of monomers MAA and MBAA in water as the continuous phase. Briefly, P(MAA-MBAA) nanoparticles of 27±3 nm hydrodynamic diameter were formed by dissolving 4.4 g of MAA, 3.6 g of MBAA (2% w / v total monomers), and 240 mg of PPS in 400 mL of distilled water.

[0183] The 1 L round-bottom flask containing this solution was stirred at 100° C. for 1 h using a mechanical stirrer (200 rpm). MAA and MBAA residues were then removed from the nanoparticle aqueous dispersion by extensive dialysis against water. Dry P(MAA-MBAA) nanoparticles were obtained by lyophilization.

[0184] The percent conversion of monomer to P(MAA-MBAA) nanoparticles (polymerization yield) was calculated using the following equation:

number

[0185] Chlorination of P(MAA-MBAA) nanoparticles (Scheme 7) [ka] Scheme 7: Chlorination of crosslinked P(MAA-MBAA) NPs Aqueous sodium hypochlorite solution (5 mL, 4% w / v) was added to an aqueous dispersion of P(MAA-MBAA) nanoparticles (5 mL, 15 mg / mL), which was shaken for 1 h at room temperature. Excess sodium hypochlorite was removed from the P(MAA-MBAA)-Cl nanoparticle dispersion by extensive dialysis against water.

[0186] The amount of bound Cl in the P(MAA-MBAA)-Cl nanoparticles was determined by iodometric / thiosulfate titration according to the literature

[32] using the following equation:

number

[0187] Example 6 Preparation of core and core-shell silica halamine-urea particles (Scheme 8) Preparation of core and core-shell silica urea particles [ka] Scheme 8: Synthesis of SiO2-Urea N / MP SiO2-UreaN / MPs were prepared using a modified Stober polymerization process of tetraethyl orthosilicate (TEOS) and 1-[3-(trimethoxysilyl)propyl]urea (TMSPU). In a typical experiment, core particles were prepared by adding different amounts of absolute ethanol, deionized water, ammonium hydroxide, TEOS and TMSPU to a tube and shaking at room temperature for 4 hours. The formed SiO2-UreaN / MPs were then transferred to water by ethanol evaporation.

[0188] Core / shell SiO2-urea NP / MP were prepared in two steps. First, core SiO2 NP / MP was prepared using modified Stober polymerization of tetraethyl orthosilicate (TEOS). Afterwards, 1-[3-(trimethoxysilyl)propyl]urea (TMSPU) was added to the tube and polymerized onto the previously generated SiO2N / MP. The formed SiO2-urea core / shell N / MP was then transferred to water by ethanol evaporation. Chlorination of core or core / shell SiO2-urea particles was achieved using bleach as previously described.

[0189] Example 7 Effects of SUTP, poly(StBP) NPs, and γ-Glu-BP on human teeth The effects of SUTP (Example 1), poly(StBP) NPs (Example 4), and γ-Glu-BP (Example 2) on human teeth were evaluated as follows:

[0190] The teeth were incubated in three separate aqueous solutions: SUTP, poly(StBP) NPs, and γ-Glu-BP (1 mg / ml, 4 ml, pH=4) for 1 h at RT. After 15 min of incubation, a new deposit of tartar was spontaneously observed. The teeth were then brushed with a toothbrush to remove the remaining tartar layer on the teeth and incubated overnight in new solutions of SUTP, poly(StBP) NPs, and γ-Glu-BP. The teeth were then washed with DDW and photographed. Figures 1-3 show the cleaning of tartar-stained teeth using SUTP (Figures 1A-1D), poly(StBP) NPs (Figures 2A-2B), and γ-Glu-BP (Figures 3A-3B) solutions.

[0191] Example 8 Effects of Halamine NPs on human teeth The effect of halamine nanoparticles (presented in Table 1) and SUTP compound on mature calculus removal on human teeth was studied. 5 mL of each aqueous suspension was added to a 20 mL vial, and a tooth with calculus was added to each vial. The solution was then stirred for 10 minutes at room temperature. After 10 minutes, the teeth were brushed using a soft toothbrush, and a photograph of the teeth was taken. [Table 1]

[0192] The activity of PMAA-Cl NPs to remove tartar from teeth is presented in Figures 5A-5D. Teeth treated with PMAA-Cl NPs at a concentration of 20 mM were completely clean after 10 minutes of agitation and brushing (shown in Figures 5A and 5B). Teeth treated with PMAA-Cl NPs at a lower concentration of 2 mM (Figures 5C and 5D) were partially clean, indicating the possibility of removing tartar. However, PMAA-Cl NPs at a concentration of 1 mM did not show any effect on tartar.

[0193] The activity of Si-Urea-Cl NPs on removing calculus from teeth is presented in Figures 4A-4D. Figures 4A and 4C present the teeth before treatment with Si-Urea-Cl NPs. Teeth treated with Si-Urea-Cl NPs at a concentration of 7.5 mM were completely clean after 10 minutes of agitation and brushing (Figure 4B). The lower concentration of 2 mM did not show a significant effect on calculus and the teeth appeared to be in their initial state (Figure 4D). It is possible that a longer agitation time would make the lower concentrations more effective.

[0194] The activity of SUTP to remove calculus from teeth is shown in Figures 1A-1D. Figures 1A and 1C present teeth before treatment with SUTP. Teeth treated with SUTP at a concentration of 10 mg / mL (pH 3-4) were completely clean after 10 minutes of agitation and brushing (Figure 1B). Teeth treated with SUTP at lower concentrations of 1 mg / mL (pH 3-4 and pH 6-7 (Figure 1D, respectively) were partially clean, showing promising potential for removing calculus. There was no effect on calculus when DDW was used (negative control).

[0195] Example 9 Comparison of the activity of succinyl tetraphosphonate and two types of technical pyrophosphate on human teeth. The effects of succinyl tetraphosphonate and two types of technical pyrophosphate on human teeth with mature tartar were compared as follows:

[0196] Human teeth were incubated in 5 ml of a solution of SUTP ((a) see structure below), sodium pyrophosphate tetrabasic ((b) see structure below) and sodium pyrophosphate dibasic ((c) see structure below) (1 mg / ml, pH=7) in PBS for 10 minutes and shaken. The teeth were then brushed with a toothbrush for 2 minutes. Images were acquired before and after treatment, FIG. 6 (with SUTP), FIG. 7 (with sodium pyrophosphate tetrabasic), and FIG. 8 (with sodium pyrophosphate dibasic). [ka]

[0197] As shown in Figure 6, significant mature calculus was removed in SUTP. Sodium pyrophosphate tetrabasic did not remove mature calculus (Figure 7). Sodium pyrophosphate dibasic also did not remove mature calculus (Figure 8).

[0198] In addition, solutions having a concentration of 1 mg / ml (FIG. 9) were obtained after brushing and showed cloudy solutions, however, the SUTP solution was significantly cloudier than the others at both concentrations, indicating significantly more calculus was removed from the teeth.

[0199] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art, and it is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. A tetraphosphonate compound represented by the following structure or a salt thereof: 【Chemistry 1】 During the ceremony, L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; The side chain of the amino acid is attached to the carbon; and Tetraphosphonate compounds wherein the alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chains are each substituted or unsubstituted.

2. The tetraphosphonate compound of claim 1, represented by the following structure: (succinyl tetraphosphonate (SUTP) or an alkali salt thereof; or malonic acid tetraphosphonate or an alkali salt thereof): 【Chemistry 2】 or 【Chemistry 3】

3. A dental care composition comprising at least one tetraphosphonate or salt thereof according to claim 1 or 2 in an amount of 0.05%-30% by weight of the composition; and a pharma- ceutically acceptable carrier.

4. The dental care composition of claim 3, wherein the tetraphosphonate is encapsulated.

5. The dental care composition of claim 3 or 4, wherein the composition further comprises at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle in an amount of 0.1%-10% by weight of the composition.

6. The dental care composition of claim 5, wherein the N-halamine compound comprises a halogenated primary amine, a halogenated secondary amine, a halogenated amide, or a halogenated urea.

7. The dental care composition of claim 5, wherein the N-halamine-based particles are nanoparticles or microparticles.

8. The N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: 【Chemistry 4】 The dental care composition of claim 5 or 7, wherein X is independently a halide and k is 1-10.

9. The N-halamine polymer is represented by the following structure: 【Chemistry 5】 【Chemistry 6】 or 【Chemistry 7】 6. The dental care composition of claim 5, wherein X is independently a halide and n is 2-100.

10. 10. The dental care composition of claim 8 or 9, wherein the halide is chloride.

11. The dental care composition of any one of claims 5-10, wherein the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle is encapsulated.

12. A composition described in any one of claims 3 to 11 for removing tartar from the dental surface of a subject.

13. The composition of claim 12, wherein the tartar is mature tartar.

14. 1. A dental care composition for removing mature tartar from a dental surface of a subject comprising at least one polyphosphonate or salt thereof in an amount of 0.05%-30% by weight of the composition; and a pharma- ceutically acceptable carrier, wherein the polyphosphonate compound is represented by the structure of Formula I, or a salt thereof: 【Chemistry 8】 During the ceremony, R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, 【Chemistry 9】 or 【Chemistry 10】 and L is an alkyl, aryl, alkylaryl, alkynyl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; The side chain of the amino acid is attached to the carbon; and The alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chains are each substituted or unsubstituted, or the polyphosphonate is in polymerized form as described below. 【Chemistry 11】

15. The polyphosphonate compound is a bisphosphonate compound represented by the following structure (γ-Glu-BP) or a salt thereof: 【Chemistry 12】 Alternatively, the polyphosphonate is a tetraphosphonate compound represented by the following structure or a salt thereof: 【Chemistry 13】 During the ceremony, L is an alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chain; The side chain of the amino acid is attached to the carbon; and 15. The dental care composition of claim 14, wherein the alkyl, alkylaryl, alkynyl, aryl, alkylether, alkylthioether, alkylamide, alkylamine, or amino side chains are each substituted or unsubstituted.

16. The dental care composition of claim 14 or 15, wherein the composition further comprises at least one N-halamine compound, N-halamine-based polymer, or N-halamine-based particle in an amount of 0.1%-10% by weight of the composition.

17. 17. The dental care composition of claim 16, wherein the N-halamine compound comprises a halogenated primary amine, a halogenated secondary amine, a halogenated amide, or a halogenated urea.

18. 17. The dental care composition of claim 16, wherein the N-halamine-based particles are nanoparticles or microparticles.

19. The N-halamine based particles are in the form of core / shell silica halamine-urea particles represented by the following structure: 【Chemistry 14】 19. The dental care composition of claim 16 or 18, wherein X is independently a halide and k is 1-10.

20. The N-halamine polymer is represented by the following structure: 【Chemistry 15】 【Chemistry 16】 or 【Chemistry 17】 17. The dental care composition of claim 16, wherein X is independently a halide and n is 2-100.

21. 21. The dental care composition of claim 19 or 20, wherein the halide is chloride.

22. The dental care composition of claim 16 or 20, wherein the N-halamine-based polymer is a nanoparticle or a microparticle.

23. The dental care composition of any one of claims 14-22, wherein the polyphosphonate is encapsulated.

24. The dental care composition of any one of claims 16-23, wherein the N-halamine compound, N-halamine-based polymer, or N-halamine-based particle is encapsulated.

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