Composition for preventing or treating dental erosion

Abstract

The present invention relates to a composition of pH in the range 2.0 to 4.5 comprising at least one fluoride source and at least one other agent for use in prevention and/or treatment of dental erosion.

Claims

1. A composition comprising, at least one bifluoride selected from the group consisting of NaHF.sub.2, KHF.sub.2, and NH.sub.4HF.sub.2; and benzoic acid; wherein the composition is a toothpaste and the at least one bifluoride is provided in the toothpaste in particulate form; wherein the pH of the composition is in the range from 2.0 to 4.5, and wherein the total amount of benzoic acid present in the composition is between about 0.1% and about 0.5% by weight; and the total amount of the at least one bifluoride is between about 0.01% and about 0.5% by weight.

2. The composition according to claim 1, wherein the pH of the composition is in the range from 2.5 to 4.0.

3. The composition according to claim 2, wherein the pH of the composition is in the range from 3.0 to 3.5.

4. The composition according to claim 2, wherein the pH of the composition is about 3.5.

5. The composition according to claim 1, wherein the total amount of benzoic acid present in the composition is between about 0.2% and 0.3% by weight.

6. The composition according to claim 1, wherein the total amount of the at least one bifluoride present in the composition is about 0.15% by weight.

7. The composition according to claim 1, wherein the at least one bifluoride is NaHF.sub.2.

8. A method for preventing and/or treating dental erosion, preventing demineralization or subsurface demineralization of the dental enamel, and/or enhancing remineralization of the dental enamel or the subsurface dental enamel, the method comprising administering to a subject in need thereof a composition comprising one or more bifluoride(s) selected from the group consisting of NaHF.sub.2, KHF.sub.2, and NH.sub.4HF.sub.2; and benzoic acid; wherein the composition is a toothpaste and the at least one bifluoride is provided in the toothpaste in particulate form; wherein the pH of the composition is in the range from 2.0 to 4.5, and wherein the total amount of benzoic acid present in the composition is between about 0.1% and about 0.5% by weight; and wherein the total amount of the at least one bifluoride is between about 0.01% and about 0.5% by weight.

9. The method of claim 8, wherein the pH of the composition is in the range from 2.5 to 4.0.

10. The method of claim 8, wherein the pH of the composition is in the range from 3.0 to 3.5.

11. The method of claim 8, wherein the pH of the composition is about 3.5.

12. The method of claim 8, wherein the total amount benzoic acid present in the composition is about 0.2% and 0.3% by weight.

13. The method of claim 8, wherein the total amount of the at least one bifluoride present in the composition is about 0.15% by weight.

14. The method of claim 8, wherein the at least one bifluoride is NaHF.sub.2.

Description

DESCRIPTION OF THE FIGURES

(1) Preferred embodiments of the present invention will now be illustrated in more detail with reference to the accompanying figures.

(2) FIG. 1 illustrates SEM pictures of an untreated HA disc before and after etching.

(3) FIG. 2 shows an EDS spectra of an untreated HA disc.

(4) FIG. 3 illustrates SEM pictures of a HA disc treated with a solution of Table 1 before and after etching, and compared to FIG. 1 this HA disc is protected from the etching.

(5) FIG. 4 shows an EDS spectra of the HA disc after treatment with the solution of Table 1.

(6) FIG. 5 depicts SEM pictures (×5000) taken to analyse the HA surface before and after etching with citric acid.

(7) FIG. 6 depicts a SEM picture (×5000) taken to analyse the HA surface after HF treatment.

(8) FIG. 7 depicts SEM pictures (×5000) taken to study the effect of HF treatment and subsequent citric acid etching on the enamel surface.

DETAILED DESCRIPTION OF THE INVENTION

(9) Experiments were performed to study the compositions' effect on dental erosion.

(10) A Comparison Example was performed to show that polished HA discs are an appropriate in vitro model for studying effects of fluoride solutions and etching on enamel.

(11) Reference Example 1 shows SEM pictures of an untreated HA disc before and after etching (see FIG. 1), and EDS spectrum of the presence of oxygen (O), phosphor (P) and calcium (Ca) proving that hydroxyl apatite Ca.sub.5(PO.sub.4).sub.3(OH) is formed on the surface of the untreated HA disc (see FIG. 2).

(12) Example 1 shows corresponding date as presented in Reference Example 1 for a HA disc treated with a composition of the invention (see FIGS. 3 and 4).

(13) Reference Example 2 shows an experiment with a composition according to the prior art (WO 2005/110347) wherein the fluoride source is hydrogen fluoride (HF). No organic acids or salts thereof are added.

(14) Examples 1 to 10 show experiments with compositions of the invention wherein the fluoride source is HF. Different organic acids or salts thereof are present in the various compositions. The amounts of HF and organic acid(s)/salt(s) are varied, as well as the pH value.

(15) As can be seen from Examples 1 to 10, as shown by ICP-AES analysis, all compositions according to the invention are more effective in inhibiting dental erosion than the composition of Reference Example 2.

(16) Reference Example 3 shows an experiment with a composition wherein the fluoride source is a bifluoride (i.e. NaHF.sub.2). No organic acids or salts thereof are added.

(17) Examples 11 to 12 show experiments with compositions of the invention wherein the fluoride source is a bifluoride (i.e. NaHF.sub.2). Different organic acids are present in the various compositions.

(18) As can be seen from Examples 11 and 12, as shown by ICP-AES analysis, the compositions according to the invention are more effective in inhibition of dental erosion than the composition of Reference Example 2 not comprising an organic acid or salt thereof.

(19) Experimental Model

(20) The method used is an in vitro model consisting of hydroxyl apatite (HA) discs which serve as a model for tooth enamel. The model enables testing the effect on preventing enamel erosion after acid etching by using different solutions containing fluoride (F). As shown by the Comparison Example below, this is a good in vitro model for studying effects of aqueous fluoride solutions and etching on enamel.

(21) Analytical Methods

(22) Analyses were carried out by using low vacuum scanning electron microscopy (SEM) equipped with energy-dispersive X-ray spectroscopy (EDS) detectors for elemental analysis of disc surfaces and inductively coupled plasma atomic emission spectroscopy (ICP-AES) analysis of the etching solution.

(23) SEM

(24) In general, SEM produces images of a sample by scanning it with a focused beam of electrons. The electrons interact with atoms in the sample, producing various signals that can be detected and that contain information about the sample's surface topography and composition. Specimens can be observed in high vacuum, in low vacuum, in wet conditions. In the present analyses, low vacuum conditions have been used.

(25) EDS detectors as used in the present SEM, have analytical capabilities, and can provide several items of data at each pixel.

(26) In the examples below, SEM analysis enables a visual comparison of the surface layers, i.e. CaF.sub.2 layer formed upon fluoride treatment of the HA discs, as well as elemental analysis and comparison of the layer thickness. EDS is preferably run to compare the amount of fluoride (F), phosphor (P) and calcium (Ca) on the disc surface. An increase in Ca and F in combination with a decrease in P after fluoride treatment means that a CaF.sub.2 layer has been formed on the surface. After etching, peaks of Ca and F usually decrease and P increases.

(27) ICP-AES

(28) In general, ICP-AES is an analytical technique used for the detection of trace metals. It is a type of emission spectroscopy that uses the inductively coupled plasma to produce excited atoms and ions that emit electromagnetic radiation at wavelengths characteristic of a particular element. The intensity of this emission is indicative of the concentration of the element within the sample.

(29) In the examples below, erosion corresponds to surface dissolution and when HA is dissolved there are ions released into the acid. Difference in amount dissolved HA as Ca and P (mg/L) are found. The interpretation of the data is; when there is less Ca and P found in the citric acid after fluoride treatment compared to a citric acid etched control HA-disc, then the fluoride treatment has proven to protect the disc. That is, ICP-AES analysis measures the amount of Ca and P ions in the etching solutions. Ca and P concentration in mg/l or μg/l of etching solutions are compared to results of etching solution of an untreated reference HA disc and the percentage reduction of Ca and P is calculated. This percentages indicate how well the HA discs are protected from etching. The lower concentrations of Ca and P ions, the higher resistance against etching/erosion.

COMPARISON EXAMPLE

(30) Equipment

(31) A low vacuum scanning electron microscope, JEOL JSM 6610 LV, was used for studying surfaces.

(32) SEM pictures were taken with 5000 times magnification (SEM×5000).

(33) Hydroxyl Apatite (HA) Discs

(34) HA discs were prepared. The discs had one polished side and one unpolished. The discs were stored at room temperature and kept dry.

(35) 3 drops of 2% citric acid were placed on a HA disc using a pipette. The 3 drops were allowed to etch the HA disc for 15 minutes at room temperature. The contours of the drops were clearly defined and there was obviously a surface tension. The HA disc was then rinsed in distilled water and then left to dry on tissue paper. FIG. 5 depicts SEM pictures (×5000) taken to analyse the HA surface before and after etching with citric acid.

(36) A HA disc were immersed in a solution comprising 0.15% hydrogen fluoride (HF) at pH 2.58 for 5 minutes in 37° C. during gentle agitation (50 ml plastic bottle was used). The disc was rinsed in distilled water and left to dry on tissue paper for a few minutes. 3 droplets of 2% citric acid were placed on the surface by using a syringe, and the etching was allowed for 15 minutes. Visual inspection of the disc surface showed that after treatment with HF solution, the surface tension had decreased and the droplets of acid floated out compared to the disc that was not HF treated. The disc was then rinsed in distilled water. FIG. 6 depicts a SEM picture (×5000) taken to analyse the HA surface after HF treatment.

(37) Ex vivo Human Tooth

(38) A human ex vivo tooth (premolar) was received from a dentist practice. The tooth was stored in Ringer solution and kept in refrigerator.

(39) The effect of the HF treatment on HA surfaces was verified using an ex vivo human premolar tooth. The tooth had been split into two halves before the experiment (tooth 1:1 and tooth 1:2). The two tooth halves were rinsed with distilled water. One tooth half was placed in a 50 ml plastic bottle containing 2% citric acid and then allowed to incubate at 37° C. for 15 minutes under gentle agitation. The tooth was then rinsed with distilled water for a few minutes and then put on tissue paper to dry. The other tooth half was immersed in a solution comprising 0.15% hydrogen fluoride (HF) at pH 2.58 for 5 minutes at 37° C. under gentle agitation (50 ml plastic bottle). The tooth half was rinsed with distilled water and then immersed in 2% citric acid and then allowed to incubate at 37° C. for 15 minutes under gentle agitation. The tooth was then rinsed with distilled water and left to dry on tissue paper for a few minutes.

(40) FIG. 7 depicts SEM pictures (×5000) taken to study the effect of HF treatment and subsequent citric acid etching on the enamel surface.

(41) The SEM pictures depicted in FIG. 7 show that the enamel is clearly protected from etching by the CaF.sub.2 layer formed during HF treatment.

(42) Conclusion of Comparison Example

(43) Polished HA discs appear to be a good in vitro model for studying effects of fluoride solutions and etching on enamel.

Materials, Conditions and Routines used in the following Reference Examples and Examples

(44) 2% citric acid (pH 2.2) was used as etching solution.

(45) Distilled water or tap water was used for rinsing.

(46) All steps of the experiments were performed at 20 to 25° C.

(47) Fluoride solutions were weighed into plastic beakers and one or more HA discs were placed into each beaker for 5 minutes. Then the discs were moved to a container with water to be rinsed for at least 5-10 seconds.

(48) Etching solution was weighed into plastic bottles and one fluoride treated HA discs were placed in each bottle for 15 minutes. Then the discs were moved to a container with water to be rinsed for at least 5-10 seconds.

(49) The disc surface after etching were analysed with SEM.

(50) The citric acid solution used in the studies was subjected to ICP-AES analysis.

REFERENCE EXAMPLE 1

(51) A low vacuum scanning electron microscope, JEOL JSM 6610 LV, was used for studying surfaces and equipped with EDS for elemental analysis.

(52) SEM pictures (SEM×1000) of an untreated HA disc before (on the left) and after etching (on the right) are shown in FIG. 1.

(53) In FIG. 2 an EDS spectrum of an untreated HA disc showing the presence of oxygen (O), phosphor (P) and calcium (Ca) in proportions telling that it is hydroxyl apatite Ca.sub.5(PO.sub.4).sub.3(OH) on the surface.

REFERENCE EXAMPLE 2

(54) A solution consisting of the ingredients shown in the table below was prepared:

(55) TABLE-US-00001 TABLE (Reference solution 2) Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Purified water up to 100 NaOH Adjustment of pH to 3.5

(56) The following results were obtained.

(57) TABLE-US-00002 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Reference solution 2 60 66

EXAMPLE 1

(58) A solution consisting of the ingredients shown in table 1 was prepared:

(59) TABLE-US-00003 TABLE 1 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glycine 0.20 Sodium benzoate 0.15 Sweetener, viscosity 36 improver, taste etc. Purified water 63 HCl or NaOH Adjustment of pH to 3.5

(60) The total amount of fluoride in the composition was 0.14%.

(61) A low vacuum scanning electron microscope, JEOL JSM 6610 LV, was used for studying surfaces and equipped with EDS for elemental analysis.

(62) SEM pictures of a HA disc treated with the solution of Table 1 before (on the left, SEM×200) and after etching (on the right, SEM×1000)) are shown in FIG. 3. The protective layer is somewhat affected after 15 min etching but mainly intact and the tooth beneath is protected.

(63) EDS spectrum of the HA disc after treatment with the solution of Table 1 showing the presence of F and Ca in proportions telling that it is CaF.sub.2 is shown in FIG. 4 The amounts of O and P are supressed due to the covering layer of is CaF.sub.2 but still visible in the spectra because EDS penetrates deeper into the specimen than the layer. The spectrum also shows that the layer does not consist of fluorapatite Ca.sub.5(PO.sub.4).sub.3F due to the proportions in the spectrum.

(64) Amount released P and Ca compared to control (untreated) was noted and the treatment with the solution of Table 1 had a major protective impact as showed by the reduction of amount eroded ions:

(65) $\%\mathrm{reduction}=\frac{\left(\mathrm{release}\mathrm{from}\mathrm{Control}\left(\mathrm{untreated}\right)-\mathrm{treated}\right)}{\mathrm{release}\mathrm{from}\mathrm{Control}}\times 100$

(66) TABLE-US-00004 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 1 73 79

EXAMPLE 2

(67) A solution consisting of the ingredients shown in table 1 except that the amount of sodium benzoate was increased to 0.30% and the amount of purified water was decreased accordingly, was prepared and tested. The total amount of fluoride in the composition was 0.14%, and the acidity was adjusted to pH 3.5.

(68) The surfaces of the HA discs treated with the present solution before and after etching were significantly improved over that treated by the solution of Table 1.

(69) The following results were obtained.

(70) TABLE-US-00005 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Example 2 79 85

EXAMPLE 3

(71) A solution consisting of the ingredients shown in table 3 was prepared:

(72) TABLE-US-00006 TABLE 3 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glycine 0.90 Purified water up to 100 HCl or NaOH Adjustment of pH to 3.5

(73) The total amount of fluoride in the composition was 0.14%.

(74) The following results were obtained.

(75) TABLE-US-00007 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 3 72 61

EXAMPLE 4

(76) A solution consisting of the ingredients shown in table 4 was prepared:

(77) TABLE-US-00008 TABLE 4 Ingredient Amount in % (w/w) Hydrogen fluoride 0.48 Glycine 0.56 Purified water up to 100 HCl or NaOH Adjustment of pH to 3.51

(78) The total amount of fluoride in the composition was 0.5%.

(79) The following results were obtained.

(80) TABLE-US-00009 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Example 12 89 86

EXAMPLE 5

(81) A solution consisting of the ingredients shown in table 5 was prepared:

(82) TABLE-US-00010 TABLE 5 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glycine 0.20 Purified water up to 100 HCl or NaOH Adjustment of pH to 2.58

(83) The total amount of fluoride in the composition was 0.14%.

(84) The following results were obtained.

(85) TABLE-US-00011 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 5 61 83

EXAMPLE 6

(86) A solution consisting of the ingredients shown in table 6 was prepared:

(87) TABLE-US-00012 TABLE 6 Ingredient Amount in % (w/w) Hydrogen fluoride 0.95 Glycine 1.34 Purified water up to 100 HCl or NaOH Adjustment of pH to 3.87

(88) The total amount of fluoride in the composition was 1%.

(89) The following results were obtained.

(90) TABLE-US-00013 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 6 65 71

EXAMPLE 7

(91) A solution consisting of the ingredients shown in table 7 was prepared:

(92) TABLE-US-00014 TABLE 7 Ingredient Amount in % (w/w) Hydrogen fluoride 0.95 Glycine 1.34 Sodium benzoate 0.30 Purified water up to 100 HCl Adjustment of pH to 3.9

(93) The following results were obtained.

(94) TABLE-US-00015 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 7 67 81

EXAMPLE 8

(95) A solution consisting of the ingredients shown in table 8 was prepared:

(96) TABLE-US-00016 TABLE 8 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glycine 0.20 Glycolic acid 0.30 Purified water up to 100 NaOH Adjustment of pH to 3.5

(97) The following results were obtained.

(98) TABLE-US-00017 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 8 76 77

EXAMPLE 9

(99) A solution consisting of the ingredients shown in table 9 was prepared:

(100) TABLE-US-00018 TABLE 9 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glutamic acid 0.30 Purified water up to 100 NaOH Adjustment of pH to 3.5

(101) The following results were obtained.

(102) TABLE-US-00019 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 9 69 70

EXAMPLE 10

(103) A solution consisting of the ingredients shown in table 10 was prepared:

(104) TABLE-US-00020 TABLE 10 Ingredient Amount in % (w/w) Hydrogen fluoride 0.15 Glycine 0.20 Lactic acid 0.30 Purified water up to 100 NaOH Adjustment of pH to 3.5

(105) The following results were obtained.

(106) TABLE-US-00021 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 10 66 70

REFERENCE EXAMPLE 3

(107) A solution consisting of the ingredients shown in the table below was prepared:

(108) TABLE-US-00022 TABLE (Reference solution 3) Ingredient Amount in % (w/w) NaHF.sub.2 corr. to 0.14% F Purified water up to 100 HCl Adjustment of pH to 3.5

(109) The total amount of fluoride in the composition was 0.14%.

(110) The following results were obtained.

(111) TABLE-US-00023 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Reference solution 3 47 56

EXAMPLE 11

(112) A solution consisting of the ingredients shown in table 11 was prepared:

(113) TABLE-US-00024 TABLE 11 Ingredient Amount in % (w/w) NaHF.sub.2 corr. to 0.14% F Glycine 0.20 Purified water up to 100 HCl or NaOH Adjustment of pH to 3.5

(114) The following results were obtained.

(115) TABLE-US-00025 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 11 55 66

EXAMPLE 12

(116) A solution consisting of the ingredients shown in table 12 was prepared:

(117) TABLE-US-00026 TABLE 12 Ingredient Amount in % (w/w) NaHF.sub.2 corr. to 0.14% F Benzoic acid 0.30 Purified water up to 100 HCl or NaOH Adjustment of pH to 3.5

(118) The following results were obtained.

(119) TABLE-US-00027 ICP Citric acid etch 15 min 2% citric acid etch (room temp) Product Reduction Ca % Reduction P % Solution of Table 12 73 81