Aqueous zinc oral care composition with fluoride

Abstract

The present invention describes a dental composition comprising a homogenous solution of a stable zinc complex with an amine-containing ligand and a fluoride anion source, a method for treating or preventing caries activity on a tooth surface using the dental composition, and a kit thereof.

Description

Background Art

[0001] Dental caries is a disease in which tooth decay occurs due to an interaction with acids produced by bacteria. Silver salts are known to have antibacterial properties and fluoride salts are known to remineralize tooth surfaces. Both silver and fluoride compositions have been shown individually to help prevent and inhibit caries activity.

[0002] Silver ammonium fluoride has been used to treat surfaces affected by caries; however, reaction with saliva results in the formation of silver phosphate. Silver phosphate is light-sensitive and permanently stains teeth black when exposed to light. Silver fluoride (without a diamine stabilizer) is extremely unstable in aqueous solution and rapidly decomposes to form metallic silver.

[0003] Zinc salts are also known to have antibacterial properties and do not present the problem of photosensitivity, i.e., zinc complexes do not darken when exposed to light. Overall, zinc and fluoride have the potential to create promising dental caries treatments. However, zinc fluoride, as well as other zinc complexes, are insoluble in aqueous solutions. In fact, even with water-soluble zinc precursors, zinc fluoride will typically precipitate from solution.

[0004] There is a need for a way to formulate aqueous solutions of zinc and fluoride to treat caries activity. The present disclosure describes a dental composition that provides a zinc complex stabilized with an amine-containing ligand in an aqueous solution with fluoride ions. Summary of the Invention

[0005] In one embodiment, a dental composition is described. The dental composition can include a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4 weight percent relative to the weight of the dental composition, and water. The dental composition can have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25°C.

[0006] In one embodiment, a method for treating or preventing caries activity on a tooth surface is described. The method may include providing a dental composition comprising a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4 weight percent relative to the weight of the dental composition, and water. The dental composition may have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25° C. The method may include contacting the dental composition with the tooth surface.

[0007] In one embodiment, a kit is described. The kit may include a dental composition comprising a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4% by weight relative to the weight of the dental composition, and water. The dental composition may have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25°C. The method may include contacting the dental composition with a tooth surface. The kit may also include instructions for a user to perform the method of providing and contacting the dental composition with a tooth surface. DETAILED DESCRIPTION

[0008] As used herein, "about" refers to ±10% of a given value. For example, "about 10" refers to 9 to 11.

[0009] As used herein, "zinc carboxylate" refers to a zinc complex having one or more carboxylate ligands, such as -OC(O)-R.

[0010] As used herein, a "homogeneous solution" refers to a solution that is visually clear or transparent. No particles or turbidity are observed in the homogeneous solutions described herein. A homogeneous solution does not include dispersions, suspensions, etc.

[0011] Dental compositions

[0012] In many embodiments, a dental composition is described. The dental composition can include a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4 weight percent relative to the weight of the dental composition, and water. The dental composition can have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25°C.

[0013] In some embodiments, the dental composition can consist essentially of the zinc carboxylate, the amine-containing ligand, the fluoride source, and water. In fact, no thickener, silica, or polymer vehicle may be required.

[0014] In some embodiments, the zinc carboxylate is present in an amount effective to provide zinc at a weight percent of about 5% to about 15% by weight relative to the weight of the dental composition. For example, the zinc carboxylate can provide zinc at a weight percent of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, or a value within a range between any of the foregoing values ​​(e.g., between about 8 and about 15, between about 10 and about 12, etc.), relative to the weight of the composition.

[0015] In some embodiments, the amine-containing ligand is present in an amount between about 5% and about 30% by weight relative to the weight of the dental composition. For example, the amine-containing ligand can be present in an amount of about 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, or 30% by weight, or a value within a range between any of the foregoing values ​​(e.g., between about 8 and about 16, between about 10 and about 15, etc.).

[0016] In some embodiments, the zinc carboxylate and the amine-containing ligand are present in amounts to provide a molar ratio of about 1:2 to about 1:3. In some embodiments, the molar ratio is 1:2. In other embodiments, the molar ratio is greater than 1:2.

[0017] In some embodiments, the fluoride anion source is present in an amount effective to provide an amount of fluoride of at least about 10%, at least about 15%, or at least about 20% by weight relative to the weight of the dental composition.

[0018] In some embodiments, the fluoride anion source is present in an amount effective to provide fluoride in an amount ranging from about 4% to about 20% by weight. For example, the fluoride anion source can provide fluoride in an amount of about 4, 6, 8, 10, 12, 14, 16, or 20% by weight relative to the weight of the dental composition, or a value within a range between any of the foregoing values ​​(e.g., between about 14 and about 10, or between about 8 and about 16, etc.).

[0019] In some embodiments, water is present in an amount of about 20% to about 50% by weight relative to the weight of the dental composition. For example, water can be present in an amount of about 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, or 50, or a value within a range between any of the foregoing values ​​(e.g., between about 28 and about 50, between about 36 and about 40, etc.).

[0020] In some embodiments, the pH of the dental composition can be at least 8, at least 9, at least 10, at least 11, or at least 12. In some embodiments, the dental composition can have a pH of about 8 to about 10. In some embodiments, the pH can be 9.

[0021] Zinc carboxylate

[0022] In some embodiments, the zinc carboxylate is selected from one or more of zinc citrate, zinc gluconate, zinc maleate, zinc acetate, zinc fumarate, zinc adipate, and zinc propionate.

[0023] In some embodiments, the zinc carboxylate is zinc citrate.

[0024] Amine-containing ligands

[0025] In some embodiments, the amine-containing ligand may include one or more of an amino acid and ammonia.

[0026] In some embodiments, the amine-containing ligand can include one or more amino acids.

[0027] In some embodiments, the amine-containing ligand is selected from one or more of the following: histidine, isoleucine, leucine, lysine, tyrosine, tryptophan, methionine, phenylalanine, aspartic acid, glycine, arginine, glutamic acid, valine, alanine, threonine, cysteine, proline, and asparagine.

[0028] In some embodiments, the amine-containing ligand can be arginine.

[0029] In some embodiments, the amine-containing ligand is ammonia (H3N).

[0030] In other embodiments, the amine-containing ligand may include an amine of the formula R3N, wherein one or more R is C 1-4 alkyl.

[0031] Fluoride anion source

[0032] In some embodiments, the fluoride anion source is selected from one or more of sodium fluoride, ammonium fluoride, silver fluoride, stannous fluoride, and potassium fluoride.

[0033] In some embodiments, the fluoride anion source is selected from one or more of ammonium fluoride, silver fluoride, stannous fluoride, and potassium fluoride.

[0034] In other embodiments, the fluoride source is not sodium fluoride.

[0035] In some embodiments, the fluoride anion source is ammonium fluoride.

[0036] Method for treating or preventing dental caries activity

[0037] In many embodiments, a method for treating or preventing caries activity on a tooth surface is described. The method may include providing a dental composition comprising a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4 weight percent relative to the weight of the dental composition, and water. The dental composition may have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25° C. The method may include contacting the dental composition with the tooth surface.

[0038] In many embodiments, the dental composition can include any of the dental compositions described herein.

[0039] In some embodiments, the method can further include allowing the dental composition to contact the tooth surface for a period of time from about 10 seconds to about 15 minutes. For example, the dental composition can be allowed to contact the tooth surface for a period of time in seconds of about 10, 20, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, 480, 540, 600, 660, 720, 780, 840, or 900, or a value within a range between any of the foregoing values ​​(e.g., between about 30 and about 60, between about 90 and about 300, etc.).

[0040] In some embodiments, the method can include applying the dental composition with a dropper, needle, pipette, tray, or swab.

[0041] Reagent test kit

[0042] In many embodiments, a kit is described. The kit may include a dental composition comprising a zinc carboxylate, an amine-containing ligand, a fluoride anion source effective to provide fluoride in an amount of at least 4% by weight relative to the weight of the dental composition, and water. The dental composition may have a pH of at least 8 and be a homogeneous solution at a temperature of about 20-25°C. The method may include contacting the dental composition with a tooth surface. The kit may also include instructions for a user to perform the method of providing and contacting the dental composition with a tooth surface.

[0043] In some embodiments, the dental composition is provided in one part.

[0044] In other embodiments, the dental composition is provided in more than one part.

[0045] In some embodiments, the instructions may further direct the user to combine more than one part to prepare the dental composition.

[0046] In some embodiments, the dental composition can include any of the dental compositions described herein.

[0047] In some embodiments, instructions may direct a user to perform any of the methods described herein.

[0048] Example

[0049] Although the objects and advantages of the present disclosure are further illustrated by the following examples, the specific materials and amounts thereof and other conditions and details recited in these examples should not be construed as unduly limiting the present disclosure. These examples are for illustrative purposes only and are not intended to limit the scope of the appended claims.

[0050] Table 1. Materials

[0051]

[0052] Examples EX1 to EX10 and Comparative Examples CE1 to CE4

[0053] All Example components were added to a plastic centrifuge tube. The composition was thoroughly mixed using a vortex mixer to form a suspension. The mixture was then heated to 60°C and mixing continued several times. The mixture was kept in a 60°C oven for 24 hours. During the warming period in the 60°C oven, the Example mixture was vortexed several times to form a solution. The Comparative Examples (CE) did not form a solution; zinc citrate and potassium zinc fluoride were not soluble in solution, and these Comparative Examples exhibited low water solubility compared to the Examples.

[0054] Table 2. Examples EX1 to EX5 and Comparative Examples CE1 and CE2

[0055]

[0056] Table 3. Examples EX6 to EX10 and Comparative Examples CE3 and CE4

[0057]

[0058] Remineralization and acid resistance testing

[0059] Enamel specimens were prepared from bovine teeth. Caries lesions were created in the enamel by immersing each specimen in a solution of 0.1 M lactic acid and 0.2% carbopol (pH 5) at 37°C for 24 hours. The specimens were randomly assigned to one of the following treatment solutions: artificial saliva (used as a control), silver ammonium fluoride (SDF) as a comparative solution, EX1, EX2, and EX3. A total of 10 specimens were prepared for each treatment solution.

[0060] The samples were processed by applying different test treatment liquids to the enamel lesions with a mini dental brush, rubbing the lesions with the mini dental brush for 10 seconds, waiting one minute, rinsing with artificial saliva, and storing in artificial saliva for 30 minutes at 37° C. The samples were then rinsed with artificial saliva again and placed in fresh artificial saliva at 37° C. for 24 hours.

[0061] The surface hardness of the treated samples was measured by a Vickers hardness tool (Vickers hardness number (VHN)). The average VHN and standard deviation of 10 samples per treatment were calculated.

[0062] To measure the retention of surface microhardness, the samples were then placed in a solution of 0.1 M lactic acid and 0.2% CARBOPOL (pH = 5) for 24 hours to create a demineralization challenge. The retention of any increased hardness was assessed by an acid challenge. The samples were subjected to the demineralization solution for 24 hours. The retention of microhardness after the acid challenge indicates the ability of the treatment to resist demineralization. The surface microhardness was measured after the acid challenge. Microhardness values ​​higher than the baseline measurement indicate that the enamel has been remineralized by the treatment. The samples were stored in artificial saliva at 37°C for 24 hours and then the hardness was measured. The samples were acid challenged with the demineralization solution and the hardness was measured again. The more resistant the enamel is to the challenge, the higher the retention of the surface microhardness value. The surface microhardness was measured using the same procedure as the baseline measurement. Any increase in microhardness after treatment indicates the ability of the treatment solution to remineralize the enamel.

[0063] Table 4. Enamel microhardness (VHN) and remineralization test results

[0064] deal with Saliva control SDF EX1 EX2 EX3 Baseline average 45.6 45.9 46.8 47.3 47.7 Baseline standard deviation 7.1 7.3 7.3 7.2 7.2 Processing average 61.5 75.8 81 97.5 102.4 Processing standard deviation 12.5 16.4 11.8 19.1 19.5 Acid Challenge Average 46.1 68.2 55.1 72.8 77.1 Acid challenge standard deviation 9.9 16.3 9.5 16.1 22.5 Average saliva remineralization 57 88.0 84.2 92.9 115.6 Saliva remineralization standard deviation 12.7 22.3 10.1 22.3 23.9 Second Acid Challenge Average 42.2 68.4 54.9 73.9 80.8 Second acid challenge standard deviation 8.5 15.7 10.3 15.8 21.7

[0065] Fluoride uptake test

[0066] Enamel specimens were prepared from bovine teeth. Caries lesions were created in the enamel by immersing each specimen in a solution of 0.1 M lactic acid and 0.2% carbopol (pH 5) at 37°C for 24 hours. The specimens were randomly assigned to one of the following treatment liquids: artificial saliva (used as a control), silver ammonium fluoride (SDF) for comparison, EX1, EX2, and EX3. A total of 10 specimens were prepared for each treatment group.

[0067] The samples were processed by applying different test treatment liquids to the enamel lesions with a mini dental brush, rubbing the lesions with the mini dental brush for 10 seconds, waiting one minute, rinsing with artificial saliva, and storing in artificial saliva for 30 minutes at 37° C. The samples were then rinsed with artificial saliva again and placed in fresh artificial saliva at 37° C. for 24 hours.

[0068] A microdrill biopsy was obtained from each sample to measure the amount of fluoride transferred to the enamel. To test the incorporation of fluoride in the teeth, the samples were further subjected to an acid challenge. The samples were placed in a solution of 0.1 M lactic acid and 0.2% CARBOPOL (pH = 5) at 37°C for 24 hours to simulate an acid challenge. A microdrill biopsy was obtained from each sample to measure the amount of fluoride in the enamel after the acid challenge. The values ​​in μg F / cm are reported in Table 5. 2 The result is the unit.

[0069] Table 5. Fluoride uptake after treatment with the example solutions (μg F / cm 2 )

[0070]

[0071] Examples EX11 to EX13 and Comparative Example CE5

[0072] Commercially available SDF was used in combination with the zinc complex solution of Example EX3 to prepare additional examples. The following examples illustrate the use of the example compositions on tooth surfaces. Bovine tooth samples were prepared in the following manner to serve as test surfaces for example treatment. Bovine teeth were maintained in acrylic resin molds and polished with 120 grit sandpaper to expose the dentin, and then polished with 320 grit sandpaper to smooth the dentin surface. A drop of each example composition was placed on the prepared bovine dentin surface and then exposed to blue LED light using a 3M ELIPAR DEEPCURE-S LED curing lamp (available from 3M Company of St.Paul, MN, USA) with a maximum wavelength of 450 nm and an output of approximately 1500 mW / cm 2 Examples EX11-EX13 show that while silver ammonia fluoride can be used as an additional fluoride source and will have the antimicrobial benefit of zinc in the composition, the final condition is less aesthetically pleasing than examples that do not darken upon exposure to light, such as EX3.

[0073] Table 6. Examples EX11 to EX13 and Comparative Example CE5

[0074] Components Example 11 EX12 EX13 EX3 CE5 EX3 76.9 62.5 50 100 0 SDF 23.1 37.5 50 0 100 total 100 100 100 100 100 The formed solution yes yes yes yes yes Darkening of teeth after blue light exposure yes yes yes no yes

[0075] Example EX14 and Comparative Example CE6

[0076] Additional examples were prepared by combining the zinc fluoride complex of EX3 or SDF with a photocurable methacrylate mixture.

[0077] Table 7. Example EX14 and Comparative Example CE6

[0078] Components Example 14 CE6 EX3 28.5 0 SDF 0 9.1 HEMA 35.4 45 BisGMA 35.4 45 IRGACURE 819 0.7 0.9 total 100 100 Cures to a hard material upon light exposure yes yes Darkening on teeth after light exposure no yes

[0079] Zone of Inhibition Antimicrobial Testing

[0080] A multi-species zone of inhibition test was performed according to the following steps to evaluate the antimicrobial efficacy of the examples: Human saliva was used as the bacterial source.

[0081] 1. Use sterile 6 mm diameter round filter paper discs.

[0082] 2. Prepare the filter paper discs by dispensing the experimental and control solutions into a standard 96-well plate.

[0083] 3. Soak each sterilized paper disc by applying 10 μL of the corresponding solution to the disc. Each sample was run in triplicate and the final results were averaged.

[0084] 4. Divide the agar plate into equal parts according to the number of solutions to be tested. Label the parts with the names of the test solutions.

[0085] 5. Remove the agar plate lid and place the soaked filter paper samples on the agar. Then, gently push down on each sample filter paper disc to ensure it is in full contact with the agar surface. Be careful not to move the disc once it has made contact with the agar surface.

[0086] 6. The analyst continues placing the sample discs one at a time onto the agar surface until all discs have been placed into their respective sections of each agar plate, as described above.

[0087] 7. Once all the plates are in place, replace the lid, invert the agar plate, and place in a 37°C air incubator for 24 hours.

[0088] 8. After incubation at 37°C for 24 hours, measure the diameter of each zone of inhibition to the nearest millimeter using a ruler or caliper. Measure the zone of inhibition as the diameter from the edge of the last visible colony to the naked eye.

[0089] 9. During measurement, be careful not to touch the plate or agar surface. Sterilize the ruler between each measurement; measurements are performed in a biosafety cabinet.

[0090] Table 8. Inhibition zone antimicrobial test results

[0091] sample Average diameter of inhibition zone (mm) Standard deviation (n=3) 0.9% saline solution 6 0 CHG flush 11 1 SDF 13 0 EX1 17 2 EX2 18 0 EX3 17 4 EX4 17 1 EX11 14 1 EX12 14 2 EX13 14 1

[0092] Equivalent solutions

[0093] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A dental composition comprising the following components: zinc carboxylate; ammonia; a source of fluoride anions effective to provide fluoride in an amount of at least 4% by weight relative to the weight of the dental composition, and water, Optionally one or more amino acids, and optionally light-curable methacrylate mixtures, in: The dental composition has a pH of at least 8, and The dental composition is a homogeneous solution at a temperature of 20-25°C. 2 . The dental composition according to claim 1 , comprising the zinc carboxylate, ammonia, the fluoride source, and water.

3. The dental composition of claim 1, wherein the zinc carboxylate is selected from the group consisting of zinc citrate, zinc gluconate, zinc maleate, zinc acetate, zinc fumarate, zinc adipate, zinc propionate, hydrates thereof, and combinations thereof. The dental composition according to claim 1 , wherein the zinc carboxylate is zinc citrate.

5. The dental composition of claim 1, further comprising one or more amino acids.

6. The dental composition according to claim 5, wherein the amino acid is selected from the group consisting of histidine, isoleucine, leucine, lysine, tyrosine, tryptophan, methionine, phenylalanine, aspartic acid, glycine, arginine, glutamic acid, valine, alanine, threonine, cysteine, proline, asparagine, and combinations thereof. The dental composition according to claim 5 , wherein the amino acid is arginine.

8. The dental composition of claim 1, wherein the fluoride anion source is selected from the group consisting of sodium fluoride, ammonium fluoride, silver fluoride, stannous fluoride, potassium fluoride, and combinations thereof.

9. The dental composition of claim 1, wherein the fluoride anion source is ammonium fluoride.

10. The dental composition of claim 1, wherein the ammonia is present in an amount between 5% and 30% by weight relative to the weight of the dental composition.

11. The dental composition of claim 1 , wherein the zinc carboxylate is present in an amount effective to provide zinc in a range of 5% to 15% by weight relative to the weight of the dental composition.

12. The dental composition of claim 1, wherein the water is present in an amount of 20% to 50% by weight relative to the weight of the dental composition.

13. The dental composition of claim 1, wherein the ammonia is present in an amount of 10% to 15% by weight relative to the dental composition and provides a zinc:ammonia molar ratio of 1:2 to 1:

3.

14. Use of the dental composition according to any one of claims 1 to 13 for preparing a medicament for treating or preventing caries activity on a tooth surface.

15. A kit comprising: The dental composition according to any one of claims 1 to 13; as well as A set of instructions directing the user to contact the dental composition with the tooth surface.

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