Poly (dialkyl dimethyl ammonium fluoride)-novel anti-caries and remineralizing agent

Abstract

The present invention relates to a novel poly (dialkyldimethylammonium fluoride) (PDAF) compound which provides a repair material for stopping dental caries development, remineralizing dental caries lesion regions and inhibiting bacterial growth.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Application No. 63 / 511,792, filed on July 3, 2023, which is hereby incorporated herein in its entirety, including any tables, figures, or drawings. Background Art

[0003] Dental caries (i.e. tooth decay) is a prevalent non-communicable disease, particularly as global sugar consumption increases, caused by acids produced by bacteria that metabolize sugar. Severe dental caries can affect overall health and often cause pain and infection, which can lead to tooth extraction.

[0004] Poly(dialkyldimethylammonium chloride) (PDDACl) is an antibacterial agent. It consists of quaternary ammonium groups (R4N+) that can interact with negatively charged bacterial cell membranes through electrostatic attraction. This destroys the cytoplasmic membrane of bacterial cells, resulting in cell lysis. However, PDDACl does not have the properties of tooth remineralization.

[0005] Silver diamine fluoride (SDF) has been used to stop the progression of dental caries. It is a non-invasive method. In 2016, the U.S. Food and Drug Administration approved SDF as a treatment for severe early childhood dental caries. However, SDF causes permanent black staining on teeth. Therefore, there is an urgent need for a new composition that can both stop the progression of dental caries and remineralize carious lesions and eliminate black staining of teeth. Summary of the invention

[0006] The present invention relates to a new dental material suitable for managing tooth decay (e.g., caries). In certain embodiments, these compositions provide a composition comprising poly(dialkyldimethylammonium fluoride) (PDDAF) for preventing caries, remineralizing demineralized areas of carious lesions, inhibiting bacterial growth, or any combination thereof. In certain embodiments, PDDAF can be used in conjunction with a filler-reinforced resin composite for filling tooth decay. In certain embodiments, silicon filler nanoparticles loaded with PDDAF are added to a resin matrix by mechanical mixing and then photocured to prepare an antibacterial and remineralizing dental resin composite.

[0007] In certain embodiments, PDDAF is prepared from poly(dialkyl dimethyl ammonium chloride) chloride. PDDAF is synthesized by anion exchange reaction with silver fluoride (PDDACl + AgF → PDDAF + AgCl). A silver chloride precipitate is formed, which can be removed by, for example, filtration or centrifugation. Excess Ag +The ions are removed by photoreduction using zinc oxide nanoparticle photocatalyst. The silver particles formed can be filtered off. A PDDAF filtrate is obtained from which the PDDAF solid is collected by drying in an oven.

[0008] In certain embodiments, the subject composition can be applied to a subject. In certain embodiments, the subject composition can be applied to the oral cavity of a subject, including but not limited to the surface of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or more teeth. In certain embodiments, the tooth has caries, caries damage, or a combination of the two. In certain embodiments, the tooth does not have caries nor caries damage, and the subject composition can be used as preventive or preventive treatment. In certain embodiments, the subject composition can be applied to a subject at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more times. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1A-1B : Scanning electron microscope (SEM) image of poly (dialkyl dimethyl ammonium chloride) (PDDACl) ( Figure 1A ), and SEM images of poly(dialkyldimethylammonium fluoride) (PDDAF) ( Figure 1B ).

[0010] Figure 2A-2B : Energy dispersive X-ray spectroscopy (EDX) spectrum of PDDAC1 ( Figure 2A ), and the EDX spectrum of PDDAF ( Figure 2B ).

[0011] Figure 3 : Fluorine concentration versus potential calibration graph for 280,000 ppm poly(dialkyldimethylammonium fluoride) solution.

[0012] Figure 4 : SEM image, EDX spectrum and chemical structure of PDDAC1.

[0013] Figure 5 : SEM image, EDX spectrum and chemical structure of PDDAF.

[0014] Figure 6 : Poly(dialkyldimethylammonium fluoride) (PDDAF) solution.

[0015] Figure 7 : Fluorine concentration versus potential calibration graph for 350,000 ppm poly(dialkyldimethylammonium fluoride) solution.

[0016] Figures 8A-8D:SEM micrograph of dentin sample (magnified 5000 times): Fig. 8A )Polished dentin surface, ( Figure 8B )10% EDTA etched dentin surface, ( Figure 8C ) Remineralized dentin surface after immersion in simulated body fluid for 7 days with 38% silver diamine fluoride (SDF), ( Fig.8D ) poly(dialkyldimethylammonium fluoride) (PDDAF) remineralized dentin surface after immersion in simulated body fluid for 7 days. The volume of both solutions applied to the dentin surface was 15 μL.

[0017] Figures 9A-9D :EDX spectrum of dentin block surface:( Fig.9A )Polished dentin surface, ( Fig. 9B )10% EDTA etched dentin surface, ( Fig. 9C ) Remineralization of dentin surface (forming mineral calcium phosphate and silver chloride) after immersion in simulated body fluid for 7 days with 38% silver diamine fluoride (SDF), ( Fig.9D ) poly(dialkyldimethylammonium fluoride) (PDDAF) remineralized dentin surface (forming mineral calcium phosphate and calcium fluoride (or fluorapatite)) after immersion in simulated body fluid for 7 days.

[0018] Figures 10A-10C : Agar diffusion test showing the zone of inhibition: Fig. 10A For water; Fig. 10B for PDDAF; Fig. 10C Note the 38% SDF staining on and around the paper disk after anaerobic incubation at 37°C for 24 hours. The volume of water, SDF and PDDAF solutions applied was 20 μL.

[0019] Fig.11 : Evaluation of the staining effect of PDDAF on demineralized tooth sections after 2 weeks. Negative control: water, positive control: 38% SDF.

[0020] Fig.12 : Cytotoxicity IC50 test of PDDAF and 38% SDF. DETAILED DESCRIPTION

[0021] Selected Definitions

[0022] As described below, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Furthermore, to the extent that "includes," "including," "has," "having," or variations thereof are used in the detailed description and / or claims, these terms are intended to be used inclusively in a manner similar to "comprising." The transitional terms / phrases (and any grammatical variations thereof) "comprise," "comprising," "including," "essentially consisting of," "consisting essentially of," "including," and "comprising" may be used interchangeably.

[0023] The phrases “consisting essentially of” or “consisting essentially of” indicate that the claim covers embodiments that include the specified materials or steps as well as those that do not materially affect the basic and novel characteristics of the claim.

[0024] The term "approximately" refers to within an acceptable error range for a particular value, as determined by a person of ordinary skill in the art, which depends in part on how the value is measured, i.e., the limitations of the measurement system. When "approximately" is used in the context of compositions containing amounts of ingredients, these compositions contain the declared amounts of components with a variation (error range) of 0-10% around the value (X ± 10%). In other cases, the term "approximately" is used to provide a variation (error range) of 0-10% around a given value (X ± 10%). It is apparent that this variation represents a range, up to 10% above and below a given value, e.g., X ± 1%, X ± 2%, X ± 3%, X ± 4%, X ± 5%, X ± 6%, X ± 7%, X ± 8%, X ± 9%, or X ± 10%.

[0025] In this disclosure, the range is stated in abbreviated form to avoid having to list every value in the range in detail. Any appropriate value can be selected in an appropriate range as an upper limit, a lower limit or the end point of the range. For example, the range of 0.1-1.0 represents the end point values ​​of 0.1 and 1.0, and intermediate values ​​such as 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, and all intermediate ranges contained in 0.1-1.0, such as 0.2-0.5, 0.2-0.8, 0.7-1.0, etc. It is foreseeable that there are values ​​with at least two significant figures in the range, for example, the range of 5-10 represents all values ​​between 5.0 and 10.0 and between 5.00 and 10.00, including the end point value. When using ranges in this article, the combinations and sub-combinations of ranges (e.g., sub-ranges within the disclosure range) and specific embodiments thereof are clearly included.

[0026] As described below, the term "subject" refers to an animal in need or desire of the benefit provided by a therapeutic compound. As described below, the term "animal" can be, for example, a human, pig, horse, goat, cat, dog, ape, chimpanzee, orangutan, guinea pig, hamster, cow, or sheep. These benefits can include, but are not limited to, treating a health condition, disease, or disorder; preventing a health condition, disease, or disorder; immune health; enhancing the function of a body organ, tissue, or system. In the context of the present invention, the preferred subject is a human. The subject can be of any age or developmental stage, including an infant, toddler, adolescent, teenager, adult, or elderly.

[0027] As described below, the term "treat" refers to eradicating, reducing, ameliorating or reversing to any extent the signs or symptoms of a health condition, disease or disorder, including but not limited to completely curing the condition, disease or disorder. Treatment can be a cure, amelioration or partial amelioration of the disease. "Treatment" can also include improving or enhancing a condition or feature, for example, bringing the function of a particular system of the body to a higher state of health or homeostasis.

[0028] "Decrease" means a negative change of at least 1%, 5%, 10%, 25%, 50%, 75% or 100%.

[0029] "Increase" means a positive change of at least 1%, 5%, 10%, 25%, 50%, 75% or 100%.

[0030] As described below, an "isolated" or "purified" compound is substantially free of other compounds. In certain embodiments, the purified compound is at least 60% by weight (dry weight) of the compound of interest. More preferably, the preparation is at least 75%, more preferably at least 90%, and most preferably at least 99%, by weight of the compound of interest. For example, a purified compound is at least 90%, 91%, 92%, 93%, 94%, 95%, 98%, 99% or 100% (by weight) of the desired compound. Purity is measured by any appropriate standard method, for example, by column chromatography, thin layer chromatography or high performance liquid chromatography (HPLC) analysis.

[0031] As described below, the terms "therapeutically effective amount," "therapeutically effective dose," "effective amount," and "effective dose" are used to refer to an amount or dose of a compound or composition thereof that, when administered to a subject, is capable of treating or ameliorating a condition, disease, or disorder in the subject, or is capable of providing an enhancement of the health or function of an organ, tissue, or body system. In other words, the amount is "therapeutically effective" when administered to a subject. The actual amount will vary depending on a variety of factors, including, but not limited to, the specific condition, disease, or disorder being treated or ameliorated; the severity of the condition; the specific organ, tissue, or body system for which the health or function is desired to be enhanced; the patient's weight, size, age, and health; and the route of administration.

[0032] As described below, the terms "prevent," "reduce," "inhibit," "block," "prevent," "mitigate," or "relieve," when referring to a compound, mean that the compound reduces the occurrence, severity, size, volume, or associated symptoms of caries and / or carious lesions by at least about 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, or 100%, compared to the condition in which caries and / or carious lesions would normally exist in the absence of administration of the compound or a composition comprising the compound.

[0033] As described below, "caries", "tooth decay" or "cavities" is a disease involving the deterioration of tooth structure involving a series of demineralization / neutralization / remineralization processes of the dentin hard tissue in both primary and permanent teeth. Caries is usually caused by bacteria in the mouth that produce acids through the anaerobic metabolism of sugars and fermentable carbohydrates. The acids produced dissolve the hydroxyapatite of the dentin hard tissue, i.e. demineralization. The remineralization process is a repair mechanism to restore the crystal lattice of hydroxyapatite. When the rate of demineralization exceeds the remineralization, this results in caries.

[0034] As described below, "carious lesions" are visible macroscopic destruction of hard tooth structure resulting from the carious process. Surfaces or holes and areas may have softened walls or floors.

[0035] In some embodiments of the present invention, the method includes applying multiple doses of the composition of the present invention. The method may include applying a composition of a therapeutically effective dose comprising a compound or a composition thereof as described above once a week, once a month, once a quarter, twice a year, once a year, or less frequently. In addition, treating a subject with a therapeutically effective amount of the composition of the present invention may include a single treatment or a series of treatments. It will also be understood that the effective dose of the compound or a composition thereof for treatment may increase or decrease during a specific treatment. Changes in dosage may be caused and become apparent by the results of diagnostic assays, which are used to determine the presence (or absence) of caries and / or carious lesions, which are known in the prior art. Specifically, identification of caries and / or carious lesions includes, for example, intraoral radiographs.

[0036] In this article, the statement of any chemical group listed in the definition of a variable includes defining the variable as any single group or listed group combination. In this article, the statement of any embodiment of a variable or aspect includes the embodiment as any single embodiment or combination with other embodiments or parts thereof.

[0037] Any composition or method provided herein can be used in combination with one or more of any other composition or method provided herein.

[0038] Other features and advantages of the invention will be apparent from the following description of the preferred embodiments and from the claims.All references cited herein are incorporated herein by reference.

[0039] Poly(dialkyldimethylammonium fluoride) fluoride compositions

[0040] Provided herein are cationic polymer fluoride compounds that can treat caries, carious lesions, or a combination of both.

[0041] In certain embodiments, the compound of the present invention is a poly(dialkyldimethylammonium fluoride) fluoride according to formula (I):

[0042] Formula (I)

[0043]

[0044] wherein n is approximately 50 to approximately 10,000, approximately 53 to approximately 3,092, approximately 100 to approximately 1,855, or approximately 1,484.

[0045] In certain embodiments, the compound of the present invention is a poly(dialkyldimethylammonium fluoride) fluoride according to formula (II):

[0046] Formula (II)

[0047]

[0048] In one embodiment, the subject composition is formulated as an orally consumable product, such as a food, capsule, tablet, or liquid.An oral drug is any physiologically active substance that is delivered by initial application directly to an oral surface, preferably a tooth surface.

[0049] An oral consumable product according to the present invention is any preparation or composition suitable for consumption, nutrition, oral hygiene or pleasure, and is intended to be introduced into the oral cavity of a human or animal, kept therein for a period of time, and then either swallowed (e.g., food or tablets ready for consumption), or removed again from the oral cavity (e.g., chewing gum or oral hygiene products or medical mouthwashes or gels). Although an oral medicament can be formulated as an oral consumable product, and an oral consumable product can comprise an oral medicament, the two terms are not meant to be used interchangeably here.

[0050] Products for oral consumption include all substances or products intended to be ingested by humans or animals in a processed, semi-processed or unprocessed state. This also includes substances added to products for oral consumption (especially food and pharmaceutical products) during production, handling or processing, which are intended to be introduced into the oral cavity of humans or animals.

[0051] Orally consumable products may also include substances intended to be swallowed by humans or animals and digested in an unchanged, prepared or processed state; therefore, orally consumable products according to the present invention also include packaging, coatings or other packaging intended or expected to be swallowed with the product.

[0052] In one embodiment, the oral consumable product is a capsule, tablet, syrup, emulsion or liquid suspension containing a desired oral delivery substance. In another embodiment, the oral consumable product can include a powder form of an oral delivery substance, which can be mixed with water or other liquids to produce a drinkable oral consumable product.

[0053] In some embodiments, the oral consumables according to the present invention may comprise one or more formulations intended for nutrition or pleasure. These include in particular baked products (e.g., bread, dry biscuits, cakes and other pastries), sweets (e.g., chocolate, chocolate bar products, other bar products, fruit chewing gum, coated tablets, hard caramels, toffee and chewing gum), alcoholic or non-alcoholic beverages (e.g., cocoa, coffee, green tea, black tea, oolong tea, white tea, black or green tea beverages rich in green tea or black tea extracts, Rooibos tea, Honeybush tea, other herbal teas, lemonade containing fruit juice, isotonic beverages, soft drinks, fruit drinks, juices, vegetable juices and fruit or vegetable juice preparations), instant beverages (e.g., instant cocoa drinks, instant tea drinks and instant coffee drinks), meat products (e.g., ham, fresh or raw sausage products, seasoned or cured fresh meat or salted meat products), eggs or egg products (e.g., dried whole eggs, egg whites and egg yolks), cereal products (e.g., breakfast cereals, muesli bars and precooked instant rice products), dairy products (e.g., full-fat or reduced-fat or fat-free milk drinks, rice pudding, yogurt, kefir, cream cheese, soft cheese, hard cheese, dried milk powder, whey, butter, buttermilk and partially or completely hydrolyzed products containing milk protein), products from soy protein or other soy fractions (e.g., soy milk and products made therefrom, beverages containing isolated or enzyme-treated soy protein, beverages containing soy flour, preparations containing soy lecithin, fermented products such as tofu or tempeh and mixtures with fruit preparations, and optional flavoring substances), fruit preparations (e.g., jams, fruit ice creams, fruit spreads and fruit fillings), vegetable preparations (e.g., ketchup, sauces, dried vegetables, deep-frozen vegetables, pre-cooked vegetables and boiled vegetables), snacks (e.g., baked or fried potato chips (chips) or potato dough products and extruded products based on corn or peanuts), products based on fats and oils or emulsions (e.g., mayonnaise, remoulade and condiments), other ready-made meals and soups (e.g., dry soups, instant soups and pre-cooked soups), seasonings (e.g., seasonings for sprinkling on), sweetener compositions (e.g., tablets, sachets and other preparations for sweetening or whitening beverages or other foods). These compositions can also be used as semi-finished products for the production of other compositions for nutritional or hedonic purposes.

[0054] The subject composition may further comprise one or more pharmaceutically acceptable carriers and / or excipients, and may be formulated into preparations, for example, in solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols.

[0055] In certain embodiments, PDDAF can be used to prepare an antimicrobial and remineralizing hydrogel containing carboxymethyl cellulose (CMC) and a crosslinking agent (eg, citric acid).

[0056] In certain embodiments, PDDAF can be encapsulated in polymethyl methacrylate (PMMA) nanoparticles.

[0057] In certain embodiments, PDDAF may be mixed with a methyl methacrylate (MMA) solution and an azobisisobutyronitrile (AIBN) initiator.

[0058] In certain embodiments, PDDAF can be used in combination with filler-reinforced resin composites for filling caries. In certain embodiments, silica filler nanoparticles loaded with PDDAF are added to a resin matrix by mechanical mixing and then photocured to prepare an antibacterial and remineralizing dental resin composite.

[0059] The term "pharmaceutically acceptable" as used herein means compatible with the other ingredients of a pharmaceutical composition and not deleterious to the recipient.

[0060] The carriers and / or excipients according to the present invention may include any and all solvents, diluents, buffers (e.g., saline buffer, phosphate buffer, or alternatively Tris-HCl, acetate or phosphate buffer), water-in-oil or oil-in-water emulsions, aqueous compositions (with or without the inclusion of organic co-solvents, suitable for, e.g., intravenous use), solubilizers (e.g., polysantolide 65, polysantolide 80), colloids, dispersion media, carriers, fillers, chelating agents (e.g., EDTA or glutathione), amino acids (e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavors, fragrances, thickeners (e.g., carbomer, gelatin or sodium alginate), coatings, preservatives (e.g., thimerosal, benzyl alcohol, polyquaternary ammonium salts), antioxidants (e.g., ascorbic acid, sodium bisulfite), osmotic pressure regulators, absorption delaying agents, adjuvants, fillers (e.g., lactose, mannitol), etc. The use of carriers and / or excipients is well known in the pharmaceutical and supplement arts. Unless any conventional media or agent is incompatible with the target health promoting substance or with the composition, carrier or excipient, use of a carrier or excipient in the subject composition is contemplated.

[0061] The present invention also relates to a kit comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more compounds of the present invention in one or more containers. The kit of the present invention may also include one or more compounds, biomolecules or drugs. In one embodiment, the kit of the present invention includes a compound of the present invention.

[0062] The present invention also provides kits, including compounds of the subject invention and pharmaceutical formulations, which are packaged in suitable packaging materials, optionally in combination with instructions for using the kit components, e.g., instructions for performing the methods of the present invention. In one embodiment, the kit includes an amount of a compound of the present invention, and instructions on a label or package insert for administering the compound of the present invention to a subject in need of treatment. In a further embodiment, the kit includes an article of manufacture for delivering the compound of the present invention, e.g., topically, regionally, or systemically, to a subject.

[0063] As described below, the term "packaging material" refers to the physical structure used to store the components of the kit. The packaging material can sterilely hold the components and can be made of materials commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, etc.). The label or package insert can include appropriate written instructions, for example, for practicing the methods of the present invention, such as treating caries, carious lesions, or a combination of both, a detection method for identifying a subject having caries, carious lesions, or a combination of both, etc. Therefore, in additional embodiments, the kit includes a label or package insert containing instructions for practicing the methods of the present invention in solution, in vitro, in vivo, or ex vivo.

[0064] Thus, the instructions may include instructions for practicing any of the methods of the invention described herein. For example, the pharmaceutical composition may be contained in a container, package, or dispenser with instructions for administering the drug to a subject to treat caries or carious lesions. The instructions may also include appropriate routes of administration, dosage information, satisfactory clinical endpoints or any adverse symptoms that may occur, storage information, expiration date, or any information required by regulatory agencies such as the Food and Drug Administration or the European Medicines Agency for use in human subjects.

[0065] The instructions may be on "printed matter", for example, on paper or cardboard within the kit, on a label attached to the kit or packaging material, or attached to a bottle or tube containing the kit components. The instructions may include an audio or video tape, and may also be contained on a computer-readable medium such as a magnetic disk (hard disk), an optical disc such as a CD or DVD-ROM / RAM, a Blu-ray disc, or a computer-readable medium. TM , electronic storage media such as RAM and ROM, and hybrids of these, such as magneto-optical storage media.

[0066] The kit may also include a buffer, preservative, or agent to stabilize the subject invention compounds. Each component of the kit may be enclosed in a separate container or in admixture, and all of the various containers may be located in a single or multiple package.

[0067] Methods for treating caries and / or carious lesions

[0068] In certain embodiments, the compounds of the present invention can be used to treat dental caries, caries lesions, or a combination of the two in a subject. In certain embodiments, the cationic polymer backbone of the subject compound inhibits bacterial growth, while the fluoride of the subject compound remineralizes teeth. The basic principle of the antibacterial action of the cationic polymer of the subject compound is to be attracted to the bacterial cell membrane by electrostatic attraction. The cationic polymer of the subject compound contains positively charged groups, ammonium groups, and the bacterial cell membrane is negatively charged. The cationic polymer of the subject compound is attracted to the bacterial cell membrane by electrostatic attraction. This is followed by penetration into the bacterial cytoplasm and insertion into the phospholipid bilayer. This destroys the cytoplasmic membrane and causes cell lysis.

[0069] Fluoride ions diffuse into and are adsorbed to the surface of tooth enamel. It enhances tooth remineralization by attracting calcium and phosphate ions together to form fluorapatite crystals on the surface of enamel demineralized in carious lesions. Fluorapatite is more resistant to acid dissolution than hydroxyapatite and carbonate apatite. As a result, the newly formed minerals prevent tooth decay.

[0070] In certain embodiments, the subject composition can be applied orally to a subject. In certain embodiments, application includes rinsing, spraying, dripping, brushing, injecting, or any combination of these into the subject's oral cavity, preferably to the tooth surface.

[0071] In certain embodiments, the subject compounds can be administered prior to diagnosing a subject with caries, carious lesions, or a combination of the two, or for treating a subject that has been diagnosed with caries, carious lesions, or a combination of the two. In certain embodiments, the subject is a mammal. In preferred embodiments, the mammal is a human.

[0072] In certain embodiments, compounds and / or compositions of the subject invention may be used in methods of treating dental caries, carious lesions, or a combination of both.

[0073] In a preferred embodiment, a cationic polymer fluoride is designed to stop caries, remineralize carious lesions, and eliminate the formation of black staining. PDDAF is more photostable than SDF in forming stains. PDDAF does not form precipitates in the oral environment like SDF, for example, the formation of silver chloride. Silver chloride is unstable and forms black staining. This eliminates black staining on teeth after application. Therefore, the application of PDDAF can achieve good aesthetic results. PDDAF is an antibacterial organic polymer fluoride, and its chemical structure and antibacterial mechanism are different from the antibacterial inorganic SDF.

[0074] The therapeutic or preventive use of the subject compounds and compositions can be accomplished by any appropriate method of treatment and technique, which are currently or will be known to those skilled in the art. These compounds can be administered by any known appropriate route, including but not limited to, oral or intravascular (e.g., intravenous) administration. In a preferred embodiment, the compound or its composition can be administered orally. The administration of the compound can be performed continuously or at different intervals according to the judgment of those in the field.

[0075] In some embodiments, the amount of compound can be administered once a day for 1, 2, 3, 4, 5, 6, 7 days or longer. Treatment can continue as needed, for example, for weeks, months, years or decades. For example, in some embodiments, the composition initially applied contains the subject compound (e.g., PDDAF) at a concentration of about 1% to 99%, about 5% to 50%, about 12% to 38%, or about 30%. In order to provide such a concentration of compound for the desired treatment, the pharmaceutical composition of the present invention will contain about 0.1% to 99%, in particular 1% to 40% of the total weight of the compound, based on the total composition weight including the carrier or diluent.

[0076] Materials and Methods

[0077] PDDAF (poly(dialkyl dimethyl ammonium fluoride)) is prepared from poly(dialkyl dimethyl ammonium chloride) chloride. PDDAF is synthesized by anion exchange reaction with silver fluoride (PDDACl+AgF=>PDDAF+AgCl). A silver chloride precipitate is formed and removed by filtration. Excess Ag + The ions were removed by photoreduction using zinc oxide nanoparticle photocatalyst. The silver particles formed were filtered off. The PDDAF filtrate was obtained and PDDAF solid was obtained by drying in an oven.

[0078] PDDAF can be prepared from poly(dialkyldimethylammonium chloride) chloride (PDDACl) and silver fluoride via an anion exchange reaction.

[0079] In one example, the synthesis of PDDAF is carried out in aqueous solution. PDDAC1 (0.95 g) is added to 5 ml of deionized water. The mixture is heated to 50° C. under stirring until PDDAC1 is completely dissolved. Silver fluoride (0.8 g) is dissolved in 5 ml of deionized water. The silver fluoride solution is added dropwise to the PDDAC1 solution to form a white precipitate. The silver fluoride solution is continued to be added dropwise until no more white precipitate is formed. The white precipitate is separated by centrifugation.

[0080] Photoreduction was performed using zinc oxide nanoparticles (ZnO NPs) photocatalyst to remove excess silver ions. ZnO NPs (0.1 g) were added to the supernatant. The mixture was stirred for 15 minutes and then irradiated with ultraviolet light at 365 nm for 24 hours. The black silver precipitate formed was separated by centrifugation. The PDDAF supernatant was obtained. The PDDAF solid was obtained by drying in an oven. The PDDAF solution was prepared by dissolving the PDDAF solid in water at 37°C for 24 hours. The pH of the solution was adjusted to 9-11 using potassium hydroxide.

[0081] All patents, patent applications, provisional applications, and publications cited or referenced herein are hereby incorporated in their entirety, including all figures and tables, to the extent they are not inconsistent with the express teachings of this specification.

[0082] The following are some examples to illustrate the procedures for implementing the present invention. These examples should not be construed as limiting. Unless otherwise indicated, all percentages are weight percentages and all ratios of solvent mixtures are volume ratios.

[0083] Example 1 - Fluoride Ion Concentration Measurement of Cationic Polymer Fluoride

[0084] The fluoride concentration of a 280,000 ppm poly(dialkyldimethylammonium fluoride) solution was measured using a fluoride ion selective electrode connected to a potentiometer. The fluoride electrode was calibrated using standardized fluoride solutions of 100, 50, 10, and 1 ppm adjusted with an equal volume of total ionic strength adjustment buffer. A calibration plot of log[F-] versus potential was obtained ( Figure 3 ).

[0085] The PDDAF solution was diluted 500 times and the fluoride ion concentration was measured. Three measurements were performed and the average fluoride ion concentration was 41783.33±353.2ppm.

[0086] The fluoride concentration of a 350,000 ppm poly(dialkyldimethylammonium fluoride) solution was measured using a fluoride ion selective electrode connected to a potentiometer. The fluoride electrode was calibrated using an equal volume of total ionic strength adjustment buffer. A calibration plot of log [F-] versus potential was obtained ( Figure 7 ).

[0087] Measured fluoride ion concentrations (three samples):

[0088] sample Sample mV LogF / ppm F / ppm 1 -21.5 2.108223396 128.2990367 2 -22.7 2.128863586 134.5437678 3 -24.6 2.161543886 145.0587351

[0089] As a result, the fluoride ion concentration of the 350,000 ppm PDDAF solution = measured [F-] x 400 (measured after dilution):

[0090]

[0091]

[0092] The average fluoride ion concentration of the 350,000 ppm poly(dialkyldimethylammonium fluoride) solution = 54,386.67 ± 2766.48 ppm.

[0093] Example 2 - Remineralization properties of cationic polymer fluoride

[0094] The remineralization properties of a 280,000 ppm cationic polymer fluoride solution were examined. The concentration of 38% silver diamine fluoride was 300,000 ppm relative to silver fluoride. Dentin blocks measuring 4 mm x 4 mm x 2 mm were prepared (see Figure 8C-8D ,9C-9D).

[0095] Example 3 - Antimicrobial Activity of Cationic Polymer Fluorides

[0096] The antimicrobial activity of cationic polymer fluoride against Streptococcus mutans was evaluated using an agar diffusion test. The positive control was 38% silver diamine fluoride (300,000 ppm relative to AgF). The negative control was water. The concentration of cationic polymer fluoride was 280,000 ppm (see Figures 10A-10C ).

[0097] Example 4 - Dyeing Effect of Cationic Polymer Fluoride

[0098] We evaluated the staining effect of 280,000 ppm PDDAF solution on demineralized tooth sections. We applied 25 μL of PDDAF solution to demineralized tooth sections. Controls were water and 38% silver diamine fluoride (SDF). We found that 38% SDF darkened the demineralized tooth sections, while PDDAF solution did not discolor the tooth sections after 2 weeks (see Fig.11 ).

[0099] Example 5 - Cytotoxicity Test

[0100] We examined the cytotoxicity of 280,000 ppm PDDAF using human gingival fibroblasts (HGF-1) and stem cells from human exfoliated deciduous teeth (SHED1). Fig.12 The IC50 values ​​measured for PDDAF and 38% silver diamine fluoride (SDF) are shown. PDDAF was significantly less cytotoxic than SDF to HGF-1 and SHED1 cells. The results indicate that PDDAF is safe for human gingival fibroblasts and dental pulp cells.

[0101] It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes will be suggested to those skilled in the art under this enlightenment and should be included in the spirit and scope of this application and the appended claims. In addition, any element or limitation of any invention or embodiment disclosed herein may be combined with any and / or all other elements or limitations (alone or in any combination) or any other invention or embodiment disclosed herein, and all such combinations are considered within the scope of the invention without limitation.

[0102] Exemplary Embodiments

[0103] Example 1. A compound having the chemical formula (I), which is poly(dialkyldimethylammonium fluoride) (PDDAF):

[0104] Chemical formula (I)

[0105]

[0106] where n is between approximately 50 and 10,000.

[0107] Embodiment 2. The compound of embodiment 1, wherein n is 1484, according to chemical formula (II):

[0108] Chemical formula (II)

[0109]

[0110] Example 3. A composition comprising the compound of Example 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0111] Embodiment 4. A method of treating dental caries, carious lesions, or a combination thereof in a subject, the method comprising:

[0112] A composition is provided, comprising a compound of formula (I), which is poly(dialkyldimethylammonium fluoride) (PDDAF):

[0113] Chemical formula (I)

[0114]

[0115] where n is approximately between 50 and 10,000; and

[0116] The composition is administered orally to the subject.

[0117] Embodiment 5. The method of embodiment 4, wherein n is 1484.

[0118] Embodiment 6. The method of embodiment 4, wherein the subject is a mammal.

[0119] Embodiment 7. The method of embodiment 6, wherein the mammal is a human.

[0120] Embodiment 8. A method of treating dental caries, carious lesions, or a combination of both in a subject, the method comprising applying an effective amount of the composition of Embodiment 3 to the subject's teeth.

[0121] Embodiment 9. The method of any preceding embodiment, wherein applying the composition to the subject's teeth comprises rinsing, spraying, dripping, brushing, injecting, or any combination of these to the subject.

[0122] Embodiment 10. The method of any preceding embodiment, wherein the subject has dental caries.

[0123] Embodiment 11. The method of any preceding embodiment, wherein the subject has a carious lesion.

[0124] Embodiment 12. The method of any preceding embodiment, wherein the subject has both caries and carious lesions.

[0125] Embodiment 13. The method of any preceding embodiment, wherein the composition is applied to the subject prior to diagnosing the subject with caries, carious lesions, or a combination of both.

[0126] Embodiment 14. The method of any preceding embodiment, wherein the compound of formula (I) inhibits bacterial growth in the subject.

[0127] Embodiment 15. The method of any preceding embodiment, wherein the compound of formula (I) remineralizes the teeth of the subject.

[0128] Embodiment 16. The method of any preceding embodiment, wherein an effective amount of the composition is orally applied to the subject as a monotherapy.

[0129] Embodiment 17. The method of any one of embodiments 4 to 15, wherein an effective amount of the composition is orally applied to the subject as a series of treatments.

[0130] Embodiment 18. A kit for treating a subject having at least one of caries or carious lesions, comprising the composition of embodiment 3, and optionally a buffer, preservative, or agent for stabilizing the compound.

[0131] Embodiment 19. The kit of embodiment 18, wherein the kit is packaged in suitable packaging materials and includes instructions for administering the compound to a subject.

[0132] Embodiment 20. The kit of embodiment 19, wherein the instructions include paper or cardboard within the kit, a label attached to the kit, an audio or video tape, or a selected optical disc, optical CD, DVD-ROM / RAM, Blu-ray disc TM, electronic storage media including RAM and ROM, and any combination thereof.

[0133] References

[0134] Synthesis and characterization of a fluorinated cationic polymer, PHMB-F, with anti-caries and remineralizing properties. Biomaterials Science 2020; 9: doi:10.1039 / D0BM01627F. U.S. Patent; Patent No.: US9156772 B2 (Fluoride-releasing compositions) - 2015.

Claims

1. A compound having the chemical formula (I), which is poly(dialkyldimethylammonium fluoride) (PDDAF): Chemical formula (I) where n is between approximately 50 and 10,000.

2. The compound of claim 1, wherein n is 1484, according to chemical formula (II): Chemical formula (II) 3. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

4. A method of treating dental caries, carious lesions, or a combination thereof in a subject, the method comprising: A composition is provided, comprising a compound of formula (I), which is poly(dialkyldimethylammonium fluoride) (PDDAF): Chemical formula (I) wherein n is between about 50 and about 10,000; and the composition is orally administered to the subject.

5. The method of claim 4, wherein n is 1484.

6. The method of claim 4, wherein the subject is a mammal.

7. The method of claim 6, wherein the mammal is a human.

8. A method of treating dental caries, carious lesions, or a combination of both in a subject, the method comprising applying an effective amount of the composition of claim 3 to the subject's teeth.

9. The method of claim 4, wherein applying the composition to the subject's teeth comprises rinsing, spraying, dripping, brushing, injecting, or any combination thereof, to the subject.

10. The method of claim 4, wherein the subject has dental caries.

11. The method of claim 4, wherein the subject has a carious lesion.

12. The method of claim 4, wherein the subject has both caries and carious lesions.

13. The method of claim 4, wherein the composition is administered to the subject prior to diagnosing the subject with caries, carious lesions, or a combination of both.

14. The method of claim 4, wherein the compound of formula (I) inhibits bacterial growth in the subject.

15. The method of claim 4, wherein the compound of formula (I) remineralizes the teeth of the subject.

16. The method of claim 4, wherein an effective amount of the composition is orally administered to the subject as a monotherapy.

17. The method of claim 4, wherein an effective amount of the composition is orally administered to the subject as a series of treatments.

18. A kit for treating a subject having at least one of caries or carious lesions, comprising the composition of claim 3, and optionally a buffer, preservative or agent for stabilizing the compound.

19. The kit of claim 18, wherein the kit is packaged in suitable packaging material and includes instructions for administering the compound to a subject.

20. The kit of claim 19, wherein the instructions comprise paper or cardboard within the kit, a label attached to the kit, an audio or video tape, or a disk selected from the group consisting of an optical disc, an optical CD, a DVD-ROM / RAM, a Blu-ray disc, TM , electronic storage media including RAM and ROM, and any combination thereof.

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