Tooth remineralization composition

Description

[0001] The present invention relates to a composition for the remineralization of teeth and its use. The composition comprises calcium phosphate (CaP) glass and aqueous silica sol. Background of the invention

[0002] Calcium phosphate is one of the most valuable materials in the skeleton: as the main component of teeth and bones, it ensures hardness and stability. Remineralization (the reincorporation of minerals) in teeth therefore increases their hardness and resistance to cavities.

[0003] Numerous compositions for the remineralization of teeth are known in the state of the art.

[0004] For example, WO 2010 / 041073 A1 describes a film for use in the oral cavity, wherein the film comprises: a water-soluble polymeric film former; and a bioactive glass; wherein the film is able to adhere to at least one tooth in the oral cavity for a maximum time of approximately 60 minutes before the film dissolves or substantially dissolves, and wherein the film is able to remineralize the tooth. For example, the film comprises a water-soluble polymeric film former selected from methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and carboxymethylcellulose; and a bioactive glass comprising silicon dioxide, sodium oxide, calcium oxide, and phosphorus oxide.

[0005] EP 1 343 450 relates to a dental adhesive film for the local treatment of teeth by remineralization. This film consists of a water-soluble or swellable carrier material that adheres to the teeth and active ingredients stored in this material. The active ingredient in the film is a finely divided calcium salt, sparingly soluble in water, selected from the group consisting of phosphates, fluorides, fluorophosphates, and mixtures thereof, preferably hydroxyapatite and / or fluorapatite, with an average particle size between 10 and 300 nm. Furthermore, the carrier material preferably contains a protein component, preferably in the form of a composite material consisting of a calcium salt that is sparingly soluble in water and protein components.

[0006] EP 1 811 942 describes a dental composition comprising: an ethylene unsaturated compound with acid functionality; an ethylene unsaturated compound without acid functionality; and a calcium and phosphorus releasing glass, wherein the acid functionality comprises a phosphoric acid functionality.

[0007] WO 2019 / 068596 concerns a toothpaste composition comprising spherical, anhydrous, amorphous silica gel particles with a pore volume of less than 0.1 ml / g and an orally compatible carrier.

[0008] WO 2019 / 034348 discloses an oral care composition comprising a bioactive glass, a water-soluble and / or soluble calcium source, a phosphate source, and a physiologically acceptable carrier, wherein the bioactive glass and the water-soluble and / or soluble calcium source are present in a weight ratio (a:b) of 1:3 to 20:1; and wherein the calcium source is calcium chloride, calcium nitrate, calcium gluconate, calcium glycerophosphate, or mixtures thereof.

[0009] JPS 63-10039 A describes the use of a phosphate or silica sol embedding material with an average particle size of <=50 µm as an embedding material for dental casting to cast a calcium phosphate dental material.

[0010] US 2017 / 319455 A1 discloses a method for occluding dentinal tubules and remineralizing teeth with a toothpaste, wherein the toothpaste contains theobromine and at least one of bioactive glass and hydroxyapatite. Summary of the invention

[0011] The present invention is based on the objective of providing a composition by which dentin surfaces of teeth are completely protected and irregularities and defects on the dentin surfaces are significantly minimized.

[0012] The present invention relates to a composition for remineralizing teeth comprising or consisting of: a) Calcium phosphate (CaP) glass, and b) aqueous silica sol, wherein the composition comprises 30-35 wt% aqueous silica sol, 60-70 wt% water, and 2-3 wt% CaP glass based on the total amount of the components aqueous silica sol, water and CaP glass, wherein the aqueous silica sol is an aqueous colloidal suspension of nearly spherical polysilicic acid molecules with 10 wt% to 90 wt% SiO₂ 2 and the rest is water.

[0013] Preferably, the composition of the present invention is free of SiO2 as a glass component. Detailed description of the invention

[0014] As described above, the composition according to the invention for the remineralization of teeth comprises a) calcium phosphate (CaP) glass, and b) aqueous silica sol.

[0015] The composition according to the invention is used for the mineralization of teeth. The composition is applied to the necks of the teeth in the periodontal pockets using an instrument (e.g., cotton swab, brush, airflow). This forms a gel layer (SiO₂) containing very fine glass particles (calcium phosphate glass). This gel layer hardens and initially seals the exposed dentin tubules in the neck of the tooth.

[0016] In the following days, the calcium phosphate glass dissolves in the oral environment, and its ionic components are remineralized in the open dentin tubules, forming hydroxyapatite or calcium phosphate. This permanently seals them.

[0017] This reduces tooth sensitivity to hot / cold or sweet / sour stimuli and halts periodontal disease. Additionally, it soothes the periodontal pockets in the oral mucosa and, ideally, leads to the regression of periodontal-damaged pockets.

[0018] A silica sol such as used herein is an aqueous colloidal suspension of nearly spherical polysilicic acid molecules containing 10% to a maximum of 90% by mass, preferably 15–50% by mass, silicon dioxide, with the remainder being water. An example of the aqueous silica sol used according to the invention is the product marketed under the name KÖSTROSOL®, manufactured by Chemiewerk Bad Köstritz GmbH. This product can be chemically defined as an aqueous, colloidal, weakly alkaline silica dispersion. The components of the composition are as follows: Components CAS No. EINECS No. Mass % amorphous 7631- 231- 15 - 50 Silica 86-9 545-4 Water 7732- 231- 44,5 - 84,5 18-5 791-2

[0019] The CaP glass is preferably ground and sieved, and has a particle size < 100 µm. In a preferred embodiment, the particle size of the CaP glass has a D 50 < 35, preferably < 20, or < 10 µm and / or a D 90 < 90, preferably < 20 µm.

[0020] The particle size is preferably determined by sieve analysis (e.g., using a sieve tower), with the particle size distribution being based on mass. This means that, for example, with a D50 = 10 µm, 50% of the particles by mass in a given sample will have a size < 10 µm and 50% of the particles by mass will have a size > 10 µm. Similarly, with a D90 = 20 µm, the mass fraction of particles in a given sample with a size < 20 µm would be 90% and the mass fraction of particles with a size > 90 µm would be 10%.

[0021] Sieve analysis is described, for example, in the German standard DIN 66165. This standard consists of two parts: DIN 66165-1 defines the fundamentals, and DIN 66165-2 describes the procedure for sieve analysis.

[0022] The composition according to the invention further preferably contains demineralized water and / or dilute hydrochloric acid. The demineralized water is preferably boiled for sterilization. Thus, the preferred components of the composition according to the invention are calcium phosphate (CaP) glass, aqueous silica sol, demineralized water, and dilute hydrochloric acid (for pH adjustment). For example, the dilute hydrochloric acid can be prepared from 1.62 g of 35% hydrochloric acid to 100 g of demineralized water. The preferred pH value of the composition is approximately pH 6.6–6.7.

[0023] In a further embodiment, the composition according to the invention further contains chlorhexidine digluconate and / or dilute hydrochloric acid.

[0024] Chlorhexidine digluconate is commonly used for the prevention and treatment of infectious diseases, for example, minor wounds and injuries, minor burns, gingivitis, and other inflammatory and infectious diseases of the mouth and throat. The active ingredient is chlorhexidine, an antiseptic agent from the group of disinfectants, used for the prevention and treatment of infectious diseases and for oral hygiene. This chlorinated biguanide derivative is particularly effective against bacteria. Its effects are based on the disruption of cell membrane function.

[0025] Chlorhexidine digluconate is added to the composition in pharmaceutically standard dosages (0.1 - 0.2% w / w).

[0026] The calcium phosphate (CaP) glass used according to the invention is preferably produced from equimolar amounts of CaCO₃ and P₂O₅. A detailed example of the production of the calcium phosphate glass according to the invention can be found in the following embodiments.

[0027] The composition according to the invention for the remineralization of teeth comprises the following components: SiO2 sol 30-35% w / w, water 60-70% w / w, and CaP glass 2-3% w / w based on the total amount of the components SiO2 sol, water and CaP glass.

[0028] Optionally, a small amount of diluted HCl or chlorhexidine digluconate can be added for pH adjustment.

[0029] The pH of the composition is preferably approximately pH 6.6-6.7.

[0030] For example, the composition includes the following proportions of the components in the dry matter: Mass fraction Ca in the dry matter: 20.4 wt% Mass fraction P in the dry matter: 31.2 wt% Mass fraction Si in the liquid component (Köstrosol): 4.67 wt% Mass fraction Si in the total mixture: 4.55 wt%

[0031] According to another aspect of the present invention, the composition described above is used for the remineralization of teeth. As already described above, the composition is applied to the necks of the teeth in the periodontal pockets using an instrument. This forms a gel layer (SiO₂) containing very fine glass particles (calcium phosphate glass). This gel layer hardens and initially seals the exposed dentin tubules in the neck of the tooth. In the following days, the calcium phosphate glass dissolves in the oral environment, and its ionic components are remineralized, forming hydroxyapatite or calcium phosphate in the open dentin tubules. Brief description of the illustrations

[0032] Figure 1 (Left) Loading the oven; (Right) Programming the oven. Figure 2 : SEM images (magnification 2500) of treated dentin surfaces after 0d, 1d, 7d and 14d. Figure 3 : Dentin surfaces with vertically running dentin canals before (0d) and after (14d) treatment with the composition according to the invention. Figure 4 : Topographic SEM image of the untreated (0d) and treated (14d) dentin surface. Figure 5 : Cross-section through dentin tubules of a dentin surface treated with the composition according to the invention after 14d (in the image above). Examples 1. Production of calcium phosphate glass 1.1 Production of the glass raw mixture

[0033] To produce one crucible filling of calcium phosphate glass, 101.09 g CaCO 3 (1.00 mol) and 141.94 g P 2 O 5 (1.00 mol) are required.

[0034] 25.27 g of CaCO3 (0.250 mol) were weighed out and placed in an agate mortar. Using a ceramic spatula, 35.48 g of P2O5 (0.250 mol; caution, highly hygroscopic!) were then quickly weighed out and added to the CaCO3 in the agate mortar.

[0035] The mixture is rubbed thoroughly for 2 minutes. Then it is allowed to rest for 5 minutes and is subsequently rubbed again for another 2 minutes.

[0036] The mixture is placed in the aluminum oxide crucible and another portion of 25.27 g CaCO3 and 35.48 g P2O5 is prepared as described above, etc. Due to the capacity of the agate mortar, larger quantities must not be ground at once to ensure thorough mixing. 1.2 Preparation of the kiln (glass melting)

[0037] The oven is as described in Fig. 1 The oven is shown loaded. The oven is closed and the sintering program is selected with a heating rate of 0°C-1050°C: 300K / h.

[0038] See Figure 1(Left) Loading the oven; (Right) Programming the oven. 1.3 Glass casting

[0039] It is a heat-resistant bucket with cold tap water (Do not use demineralized water to avoid leaching of the glass!).

[0040] The crucible is grasped with tongs (check a secure grip), held until just above the bucket (avoid splashing), and the molten glass is poured into the cold water. The process must be carried out safely but quickly to prevent the molten glass from cooling down in the crucible.

[0041] Afterwards, the crucible should be placed back in the ceramic dish in the oven, the oven closed, and allowed to cool freely.

[0042] The solidified glass should be removed from the water as soon as possible and dried in a drying oven at 40°C for 16 hours. Afterwards, it can be ground. 1.4 Glass grinding

[0043] The solidified glass is coarsely crushed and then distributed between two aluminum oxide grinding beakers. Aluminum oxide grinding balls (3 medium balls, d = 1.5 cm, 4 small balls, d = 1 cm) are added, and the glass is ground in a planetary ball mill at 200 rpm for 4 hours. To ensure that no larger particles remain (glass fragments and larger grains may occur!), the ground glass is sieved in a sieve tower using a 200 µm sieve. To determine the mean particle size, a sample is taken and measured using a laser granulometer (D 50 < 25 µm). 2. Preparation of the mixture components 2.1 Chemicals

[0044] Köstrosol® < 0830 (aqueous silica sol, see "Köstrosol 830 data sheet") demineralized water (DI water), boiled for sterilization dilute hydrochloric acid (1.62 g 35% hydrochloric acid per 100 g DI water) calcium phosphate glass (ground and sieved; particle size < 100 µm, see Chapter 1) 20% chlorhexidine digluconate (optional) 2.2 Devices

[0045] Sartorius CP324S analytical balance, Brand Transferpette S (volume 500 - 5000 µl), Brand Transferpette S (volume 100 - 1000 µl), Portamess 911 pH meter (Knick), 150 ml beakers (for preparing the liquid component), 1 small rolled-rimmed vial (for weighing calcium phosphate glass), 12 rolled-rimmed vials (50 mm x 20 mm, 15 ml capacity) for the application units, 12 matching lids, 12 magnetic stir bars (10 x 6 mm), multipoint stirrer (VarioMag)

[0046] Beakers, rolled-rimmed glasses, and magnetic stir bars are boiled in deionized water for sterilization. The lids are disinfected with Bacillol® (a cleaning agent based on 2-propanol, 1-propanol, and ethanol). 2.3 Production of the liquid component

[0047] Weigh out 26.8 g of Köstrosol® and 53.2 g of boiled water. Then combine both components and stir for approximately 15 minutes. 2.4 Preparation of the suspensions

[0048] For each application unit, 5 g of the liquid component is used. Weighing is performed on the Sartorius CP324S analytical balance. 4710 µl of the liquid component (density: 1.06 g / ml) are pipetted into the 12 round-rimmed vials using the Brand Transferpette S (volume 500–5000 µl). Subsequently, 0.125 g of the solid component (calcium phosphate glass) is weighed in a small round-rimmed vial on the Sartorius CP324S analytical balance and transferred into the 12 round-rimmed vials containing the liquid component.

[0049] Suspensions were formed by combining the liquid and solid components. The rolled-rimmed vials are sealed with their corresponding lids. The samples are then stirred for approximately 1 hour on a multipoint stirrer (VarioMag) at 700-750 RPM. 2.5 pH measurement and HCI addition

[0050] After stirring for 1 hour, 300 µl of dilute hydrochloric acid are added to each sample using a Brand Transferpette S (volume 100-1000 µl). The 12 roll-top tubes are then resealed. The samples are stirred overnight. 2.6 Addition of chlorhexidine digluconate (20%)

[0051] Finally, chlorhexidine digluconate (20%) is added. Weighing is performed on a Sartorius CP324S analytical balance. 50 µl of chlorhexidine digluconate (20%) is transferred into each of the 12 samples using a Brand Transferpette S (volume 100–1000 µl). The individual weighings are documented. After the addition of the chlorhexidine digluconate, the samples are resealed and stirred for another 5 minutes. A flaky precipitate forms. After standing for approximately 2 hours, the samples solidify. 3. Closure of dentin canals in in vitro experiments 3.1 Sample preparation

[0052] Tooth samples were polished perpendicular to the dentin tubules. Remineralizing suspension was applied to the cleaned and dried samples using cotton swabs. The suspension remained in contact with the tooth (dentin) for 10 minutes. The samples were then immersed in saline solution for defined periods (0 days, 1 day, 7 days, 14 days) (the medium was changed daily). This setup simulated the oral environment. At the observation times, the samples were removed, dried, and analyzed using scanning electron microscopy (SEM). 3.2 Test results

[0053] The REM images in Fig. 2 The treated dentin surfaces are shown at the different observation times (0d, 1d, 7d, 14d). See Figure 2: SEM images (magnification 2500) of treated dentin surfaces after 0d, 1d, 7d and 14d.

[0054] At time 0d, only roughened enamel is present. Subsequently, the bioglass-based remineralization paste mentioned in the application example is applied. After 1d, a closed layer is still visible. After 7d, the coating begins to dissolve, and calcium and phosphate ions are released. These ions remineralize to calcium phosphate and, by exceeding the solubility product of calcium and phosphate, seal the dentin tubules beneath the coating.

[0055] After the coating has completely dissolved, two effects can be observed ( Figs. 3, 4 ).

[0056] Fig. 3 shows dentin surfaces with vertically oriented dentin canals before (0d) and after (14d) treatment with the composition according to the invention. Fig. 3 It can be seen that, compared to the untreated surface, the dentin channels are completely closed.

[0057] In Fig. 4It is evident that the unevenness and defects on the dentin surface were significantly minimized by the treatment. Fig. 4 shows a topographic SEM image of the untreated (0d) and treated (14d) dentin surface.

[0058] If a cross-section is made to the dentin canals ( Fig. 5 ), so their closure through treatment with the bioglass-based remineralization paste is clearly visible.

Claims

1. Composition for the remineralisation of teeth comprising: a) calcium phosphate (CaP) glass, and b) aqueous silica sol, wherein the composition comprises 30-35% by mass aqueous silica sol, 60-70% by mass water, and 2-3% by mass CaP glass relative to the overall quantity of the components aqueous silica sol, water and CaP glass, wherein the aqueous silica sol is an aqueous colloidal suspension of almost spherical polysilicic acid molecules with 10% by mass to 90% by mass SiC2 and the remainder water.

2. Composition according to claim 1, wherein the CaP glass is ground and sieved, and has a particle size < 100 µm.

3. Composition according to claim 2, wherein the particle size of the CaP glass has a D50 < 35 µm and / or a D90 < 90 µm.

4. Composition according to one or more of the preceding claims, which further contains fully demineralised water and dilute hydrochloric acid.

5. Composition according to one or more of the preceding claims, which further contains chlorhexidine digluconate and / or dilute hydrochloric acid.

6. Composition according to one or more of the preceding claims, wherein the calcium phosphate glass is produced from equimolar quantities of CaCO3 and P2O5.

7. Use of the composition according to one or more of the preceding claims for the remineralisation of teeth.