TW201618745A - Anti-sensitive composition for tooth - Google Patents

Abstract

The present disclosure relates to an oral care composition comprising hydroxyapatite, a polycarboxylic compound, soluble calcium and an orally acceptable carrier, an aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium and use thereof for relieving or preventing tooth sensitivity. The present disclosure discovers that the hydroxyapatite in the oral care composition can not only block the opening of the dentinal tubules, but also infiltrate into the dentinal tubules to a depth of tens of microns. The oral care composition can be prepared by mixing the aqueous mixture with the orally acceptable carrier. The aqueous mixture could be prepared by mixing the polycarboxylic compound, the hydroxyapatite and the soluble calcium in an aqueous solution.

Description

Tooth anti-allergy composition

The present invention relates to the field of oral care, and in particular to compositions useful for sealing dentinal tubules, methods for their preparation, and uses thereof.

Dentin hypersensitivity is a common and frequently-occurring disease in the department of stomatology, and it is also one of the common causes of clinical toothache. The pathogenesis of dentine hypersensitivity is not clear, but Brannstrom M, Astrom A. The hydrodynamics of the dentine; its possible relationship to dentinal pain. Int Dent J, 1972, 22(2): 219~227) The proposed fluid dynamics theory is now widely accepted. According to fluid dynamics, dentin tubule fluid is present in dentinal tubules. When various causes such as gingival recession or tooth acid erosion lead to excessive opening of dentinal tubules, various external stimuli (temperature, chemical, mechanical, etc.) will result. The body fluid in the dentinal tubules flows excessively inside and outside, and mechanically stimulates the endodontic nerve endings that are very sensitive to pressure, generating impulses and transmitting pain. Absi et al. (Absi EG, Addy M, Adams D. Dentine hypersensitivity: a study of the patency of dentinal tubules in sensitive and non-sensitivecervical dentine. J Clin Periodontol, 1987, 14(5): 280-284) The open number and average diameter of the dentinal tubules per unit area of the sensitive dentin surface are several times insensitive, resulting in the flow velocity of the dentin tubule fluid being more than 100 times higher than the insensitivity. So plug the dentinal tubules, Reducing the permeability of dentin to reduce the flow of liquid in the dentin is the fundamental way to treat dentin hypersensitivity.

Researchers have also conducted extensive research on desensitizing materials that are sensitive to the treatment of dentin by sealing dentinal tubules, such as strontium salts and oxalate materials, which have been used to form deposits on the surface of dentin. Block the essence of tubules. Although these materials can effectively block dentinal tubules in vitro, the friction of the teeth, such as brushing, can easily remove these deposits and re-expose the dentinal tubules. Therefore, the anti-allergic persistence of these materials needs further study.

Hydroxyapatite (HAP) is an important component of teeth and has good biocompatibility. Nano hydroxyapatite (Nano HAP) is considered to be a promising desensitizing material due to its small size effect. It is widely used in dental and oral care. . Citrate plays an important role in inhibiting HAP growth and controlling HAP size (Baoquan Xie and George H. Nancollas, How to control the size and morphology of apatite nanocrystals in bone. PNAS 2010, 107(52): 22369-22370). Citrate has good biocompatibility with human body and plays an important role in the growth and remineralization of hydroxyapatite. However, no blocking method has been found which can make hydroxyapatite penetrate into the dentinal tubule.

The present invention provides a composition, a preparation method and a use thereof that can enter the interior of a dentinal tubule to seal a dentinal tubule.

In one aspect, the invention provides an oral care composition comprising hydroxyapatite, a polycarboxy compound, soluble calcium, and an orally acceptable carrier. In some embodiments The hydroxyapatite in the oral care composition is capable of entering the dentinal tubules. In certain embodiments, the hydroxyapatite is capable of entering the dentinal tubules at least about 5 microns deep. In certain embodiments, the polycarboxy compound is selected from the group consisting of citrate compounds, such as potassium citrate, sodium citrate, and the like, polyaspartate, such as sodium polyaspartate, polyaspartate Potassium acid or the like, iminodisuccinate, such as potassium iminodisuccinate, sodium iminodisuccinate, etc., 2-phosphonobutane-1,2,4-tricarboxylate, for example 2-phosphonobutane-1,2,4-tricarboxylic acid tetrasodium, etc., polyacrylates, such as sodium polyacrylate, potassium polyacrylate, and the like.

In certain embodiments, the soluble calcium concentration (ppm) ranges from about 7.34 ppm to about 800 ppm. In certain embodiments, the molar concentration (mol/L) of soluble calcium: the molar concentration (mol/L) of carboxylate in the polycarboxy compound ranges from about 0.00178 to about 0.361.

In certain embodiments, the oral care composition is characterized by: 1) the weight percent (w/w) (by dry weight) of hydroxyapatite in the composition ranging from about 0.01% to about 50% 2) the weight percentage (w/w) of the polycarboxylate in the composition is from about 0.001% to about 30% by weight; and 3) the molar concentration of the carboxylate in the polycarboxy compound (mol/ L): The molar concentration (mol/L) of the hydroxyapatite molecule ranges from about 1.238 to about 99.041.

In certain embodiments, the hydroxyapatite weight percentage (w/w) ranges from about 0.1% to about 20% in the oral care composition. In certain embodiments, the weight percentage (w/w) of the polycarboxylate in the polycarboxy compound in the oral care composition ranges from about 0.01% to about 12% in the oral care composition. Preferably, it is from about 0.0874% to about 6.995%. In certain embodiments, the orally acceptable carrier comprises one or more of a thickening agent, a rubbing agent, a surfactant, a flavoring agent. In certain embodiments, The thickening agent includes one or more of xanthan gum, carrageenan or sodium carboxymethylcellulose. In certain embodiments, the flavoring agent comprises methyl salicylate and/or eugenol. In certain embodiments, the oral care composition further comprises one or more active ingredients. In certain embodiments, the active ingredient comprises an anti-caries agent, an anti-allergic agent, and/or an antibacterial agent. In certain embodiments, the anti-caries agent comprises a source of fluoride ions. In certain embodiments, the anti-sensitizer comprises a source of potassium ions. In certain embodiments, the oral care composition is a toothpaste, gel or mouthwash. In certain embodiments, the oral care composition is a dental patch, an oral spray, or a dentifrice.

In another aspect, the invention provides a method of preparing an oral care composition comprising mixing a polycarboxy compound, hydroxyapatite, soluble calcium, with an orally acceptable carrier.

In another aspect, the invention provides an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium. In certain embodiments, the molar concentration of the soluble calcium (mol/L) in the mixed solution: the molar concentration (mol/L) of the carboxylate in the polycarboxy compound ranges from about 0.00178- About 0.361. In some embodiments, the molar concentration (mol/L) of the carboxylate in the polycarboxy compound in the mixed solution: the molar concentration (mol/L) of the hydroxyapatite molecule ranges from About 1.238 to about 99.041. In certain embodiments, the hydroxyapatite has a particle size ranging from about 10 nm to about 100 nm, preferably from about 20 nm to about 50 nm, in the mixture. In certain embodiments, the pH of the mixture is from about 7 to about 14. In certain embodiments, the aqueous mixture further comprises a metal ion, such as a copper ion, a zinc ion, a silver ion, or any combination thereof. In certain embodiments, the metal ion is capable of interacting with a carboxyl group in a polycarboxy compound.

In another aspect, the invention provides a method of preparing an oral care composition comprising mixing the aqueous mixture with an orally acceptable carrier.

In another aspect, the invention provides a method of filling a dentinal tubule comprising contacting the dentin with an oral care composition provided herein to allow the hydroxyapatite to enter a dentinal tubule.

In certain embodiments, the oral care composition is a toothpaste, the method comprising brushing the toothpaste to allow the hydroxyapatite to enter a dentinal tubule. In certain embodiments, the oral care composition is a gel, the method comprising brushing with the gel, or contacting the tooth with the gel to allow the hydroxyapatite to enter a dentinal tubule . In certain embodiments, the oral care composition is a mouthwash, the method comprising contacting the teeth with the mouthwash to allow the hydroxyapatite to enter the dentin tubules.

In another aspect, the invention provides a dental material having dentinal tubules, wherein the dentin tubules are filled with hydroxyapatite.

In certain embodiments, wherein the dental material is a tooth. In certain embodiments, the hydroxyapatite has a filling depth in the dental tubule of at least about 5 microns, at least about 10 microns, at least about 15 microns, at least about 20 microns, at least about 30 microns, at least about 40 microns, at least about 50 microns, at least about 60 microns, or at least about 70 microns. In certain embodiments, the tubules have a diameter of from about 1 micron to about 4 microns, such as at least about 1 micron, at least about 2 microns, at least about 3 microns, at least about 4 microns.

In another aspect, the present invention provides the use of an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium in the preparation of an oral care composition for relieving or preventing tooth sensitivity.

In certain embodiments, the present invention provides an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium in the preparation of a mouth for filling dentinal tubules in a tooth Use in a cavity care composition.

In another aspect, the present invention provides a process for the preparation of an aqueous mixture comprising hydroxyapatite, a polycarboxy compound and soluble calcium as described herein, comprising the addition of a polycarboxy compound, hydroxyapatite and soluble calcium in an aqueous solution. Mixed in. In certain embodiments, the polycarboxy compound is selected from the group consisting of citrate, polyaspartate, iminodisuccinate, 2-phosphonate butane-1, 2,4- Tricarboxylate, polyacrylate.

Fig. 1 is a scanning electron microscope (SEM) image of a short rod-shaped Nano HAP material (raw material 1).

Fig. 2 is a scanning electron microscope (SEM) image of the needle-shaped Nano HAP material (raw material 2).

Figure 3 shows the results of the zeta potential of Nano HAP (raw material 1)-potassium citrate-soluble calcium suspension (suspension 1-I~1-VIII), wherein the ratio of Nano HAP to potassium citrate is 1.25:0. , 1.25:0.05, 1.25:0.5, 1.25:1, 1.25:2, 1.25:4, 1.25:8, and 1.25:16.

Figure 4 shows the results of the Zeta potential of Nano HAP (raw material 2)-potassium citrate-soluble calcium suspension (suspension 2-IV~2-XI), wherein the ratio of Nano HAP to potassium citrate is 1.25:0. , 1.25:0.05, 1.25:0.5, 1.25:1, 1.25:2, 1.25:4, 1.25:8, and 1.25:16.

Figure 5 is a scanning electron microscope (SEM) image perpendicular to the dentinal tubule observation surface model (Model A) at different magnifications. Among them, the fifth (a) is an SEM image of the model A magnified 500 times, and the fifth (b) is an SEM image of the model A magnified 5000 times.

Figure 6 is a scanning electron microscope (SEM) image of a model of different densities parallel to the dentinal tubule observation surface model (model B). Among them, the 6th (a) is a model B that is magnified 1000 times. SEM image; Figure 6(b) is an SEM image of model B magnified 10,000 times.

Fig. 7 is a scanning electron microscope (SEM) image of a dentinal tubule model (model A) treated separately by two commercially available Nano HAPs, and Fig. 7(a) and Fig. 7(b)(b) correspond respectively. The two Nano HAPs in Figures 1 and 2.

Figure 8 is a scanning electron microscope (SEM) image of a dentinal tubule model (Model A) treated separately with two commercially available Nano HAPs modified with citrate and soluble calcium. Figures 8(a) and 8(b) correspond to the two Nano HAPs in Figures 1 and 2, respectively.

Figure 9 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 1"-I (Nano HAP: potassium citrate = 2.25:0). Figures 9(a) and 9(b) It is an observation surface perpendicular to the dentinal tubule (model A), which is magnified 1000 times and 20000 times respectively. The 9th (c) and 9th (d) figures are observation planes parallel to the dentinal tubule (model B) , magnified 1000 times and 5000 times respectively.

Figure 10 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 1"-II (Nano HAP: potassium citrate = 2.25:0.6). Among them, Fig. 10(a) and Fig. 10(b) The figure is an observation surface perpendicular to the dentinal tubule (model A), which is magnified 1000 times and 20000 times respectively. The 10th (c) and 10th (d) figures are observation planes parallel to the dentinal tubules (model) B), magnified 1000 times and 10000 times respectively.

Figure 11 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 1"-III (Nano HAP: potassium citrate = 2.25: 1.2). Among them, Figure 11(a) and Figure 11(b) The map is perpendicular to the observational view of the dentinal tubule (model A), magnified 1000 times and 20000 times respectively. The 11th (c) and 11th (d) are parallel to the observational view of the dentinal tubule (model) B), magnified 1000 times and 10000 times respectively.

Figure 12 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 1"-IV (Nano HAP: potassium citrate = 2.25:2). Among them, Fig. 12(a) and Fig. 12(b) Figure (b) is an observational view perpendicular to the dentinal tubule (model A), magnified 1000 times and 20000 times respectively. Figures 12(c) and 12(d) are parallel to the observation surface of the dentinal tubule Figure (model B), magnified 1000 times and 10000 times respectively.

Figure 13 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 2"-I (Nano HAP: soluble calcium = 2.25:4), wherein Figure 13(a) is a magnification of 2000 times vertical In the observational view of the dentinal tubule (model A), the 13th (b) is an observation plane parallel to the dentinal tubule (Model B) magnified 10,000 times.

Figure 14 is a scanning electron microscope (SEM) image of dentinal tubules treated with suspension 2"-II (Nano HAP: soluble calcium = 2.25: 56.97). Among them, Figure 14(a) and Figure 14(b) The figures are magnified 500 and 5000 times perpendicular to the observational view of the dentinal tubule (model A).

Figure 15 is a suspension of 2"-II (Nano HAP: soluble calcium = 2.25: 56.97), 2"-III (Nano HAP: soluble calcium = 2.25: 113.94), 2"-IV (Nano HAP: soluble calcium = 2.25: 224.89) Scanning electron microscopy (SEM) image of dentin tubules treated with 2"-V (Nano HAP: soluble calcium = 2.25: 323.84). Among them, the 15th (a) is an observation surface (parameter B) parallel to the dentinal tubule treated by the suspension 2"-II with a magnification of 10000 times, and the suspended liquid is magnified 10000 times by the 15th (b) 2"-III treatment parallel to the observational view of the dentinal tubule (model B), Figure 15 (c) is a 10,000-fold observation of the observation of the 2"-IV suspension parallel to the dentinal tubule ( Model B), Figure 15(d) is an observational view (model B) parallel to the dentinal tubules treated with a 2"-V suspension of 5000 times magnification.

Figure 16 shows a paste prepared in accordance with the preparation process of the present invention.

The present invention provides a composition, a preparation method and a use thereof that can enter the interior of a dentinal tubule to seal a dentinal tubule.

Dentin is an important part of the tooth. Dentinal tubules are arranged in the dentin, radiating from the end of the pulp to the enamel interface. It is generally believed that when the dentinal tubules are exposed to the opening of the dentin surface, the endodontic nerve endings are excited when exposed to cold, heat, acid, sweetness, mechanical or chemical stimuli, resulting in transient pain, ie dentin sensitive symptoms. Studies have shown that dentinal tubules are more open and have an average diameter larger in dentin-sensitive individuals than dentin-insensitive individuals. Therefore, dentin sensitivity can be alleviated or treated by blocking the dentinal tubules to reduce the permeability of the dentin.

An important component of dentin is hydroxyapatite, or HAP for short. HAP has good biocompatibility and can be used to block dentinal tubules, but the sealing efficiency in actual use is not ideal, which greatly limits the application of HAP in the sealing of dentinal tubules. The invention improves the affinity of the HAP and the dentin surface by changing the surface characteristics of the HAP, so that it can penetrate into the dentinal tubules deeply, which greatly improves the use efficiency of the HAP desensitizing material, and fundamentally achieves a long-lasting effective anti-allergy. .

In particular, the present invention provides a composition of HAP, a polycarboxy compound, and soluble calcium that is capable of promoting deep penetration of HAP into dentinal tubules. Polycarboxylates have good biocompatibility with human body and play an important role in the growth and remineralization of HAP. Calcium is a conformational ion of HAP and has an important influence on the surface chemical structure and surface electrical properties of HAP. The study found that the combination of these three components allows HAP to penetrate deep into the dentinal tubules, providing the possibility of dentin-sensitive eradication.

Oral care composition

In one aspect, the application provides an oral care composition comprising hydroxyapatite, a polycarboxy compound, soluble calcium, and an orally acceptable carrier. In certain embodiments, the hydroxyapatite in the oral care composition is capable of entering dentin tubules. In certain embodiments, the hydroxyapatite is capable of entering the dentinal tubules at least about 5 microns deep.

"Enter" as used in this application means that the hydroxyapatite penetrates deep into the dentinal tubules at least about 5 microns deep, for example, at least about 10 microns, at least about 20 microns, at least about 25 microns, at least about 30 microns, at least about 35 microns, at least about 40 microns, at least about 50 microns, and the like. The hydroxyapatite entering the dentinal tubule can effectively reduce the permeability of the dentin and reduce the liquid flow in the dentin. It is generally believed that the plugging into the dentinal tubules has a more pronounced and lasting effect than the deposition on the surface of the dentinal tubules, thereby more effectively treating dentin hypersensitivity.

The present invention unexpectedly finds that polycarboxylates and soluble calcium can modify the surface of hydroxyapatite to enhance the interaction of hydroxyapatite with teeth or dentin or dentinal tubules, not only depositing hydroxyapatite The dentin surface allows it to penetrate deep into the dentinal tubules.

The invention also unexpectedly finds that the polycarboxy compound and the soluble calcium can also modify the surface of the hydroxyapatite, and the modified hydroxyapatite is more uniformly dispersed, and not only has better sealing of the dentinal tubule opening. The effect can be deep into the dentin tubules. Even some hydroxyapatite, which has no blocking effect due to poor physical properties, can have a good effect of blocking the opening of the dentinal tubule and deep into the dentinal tubule after adding the polycarboxyl compound and soluble calcium. .

In certain embodiments, the hydroxyapatite described herein is a nano hydroxyapatite. Nano-hydroxyapatite has better adsorption and remineralization properties due to its small size effect, and the effect of sealing the opening of the dental canal is better, and the dentinal tubule can be deeply penetrated in the technical solution of the present invention.

"Nano-hydroxyapatite" as used herein refers to hydroxyapatite having a particle size of less than 1 micron. In certain embodiments, the hydroxyapatite has a particle size ranging from about 10 nm to about 100 nm in the oral care composition. The hydroxyapatite particles in the oral care composition can be observed and counted under an electron microscope. For example, the oral care composition can be diluted with water or other suitable solvent, and the hydroxyapatite can be separated from the micron-sized abrasive or other micron-sized insoluble solids by various centrifugation rates or other means well known in the art and dried. Take appropriate samples, place them on the sample stage, observe under an electron microscope, count the total number of hydroxyapatite particles in the selected field of view, and count the hydroxyapatite particles in the preset particle size range. The particle size of the hydroxyapatite particles is a percentage of the total number of particles. In certain embodiments, at least about 50%, about 60%, about 70%, about 80%, or about 90% of the hydroxyapatite particles have a particle size of no more than about 100 in the oral care composition. Nano; or at least about 50%, about 60%, about 70%, about 80%, or about 90% of the hydroxyapatite particles have a particle size of no more than about 90 nm; or at least about 50%, about 60% , about 70%, about 80%, or about 90% of the hydroxyapatite particles have a particle size of no more than about 80 nanometers; or at least about 50%, about 60%, about 70%, about 80%, or about 90 % of the hydroxyapatite particles have a particle size between about 10 nanometers and about 100 nanometers; or at least about 50%, about 60%, about 70%, about 80%, or about 90% of the hydroxyapatite The particle size of the particles is between about 20 nanometers and about 100 nanometers; or at least about 50%, about 60%, about 70%, about 80%, or about 90% of the particle size of the hydroxyapatite particles are about 30 nm to about 100 Between the nanoparticles; or at least about 50%, about 60%, about 70%, about 80%, or about 90% of the hydroxyapatite particles have a particle size between about 40 nanometers and about 100 nanometers.

In certain embodiments, the weight percentage (w/w) of hydroxyapatite in the oral care composition ranges from about 0.01% to about 50%, more preferably about 0.1, in the oral care composition. % - about 20%. For example, the weight percent (w/w) of hydroxyapatite in the oral care composition can range from about 0.01% to about 40%, from about 0.01% to about 30%, from about 0.01% to about 20%, from about 0.01. % - about 15%, about 0.01% to about 10%, about 0.01% to about 5%, about 0.1% to about 20%, about 0.1% to about 15%, about 0.1% to about 10%, about 0.1% - From about 5%, from about 0.1% to about 4.5%, from about 0.75% to about 4.5%, from about 0.75% to about 5%, from about 0.75% to about 10%, from about 0.75% to about 15%, from about 0.75% to about 20% %, from about 1% to about 4.5%, from about 1.25% to about 4.5%, from about 1.5% to about 4.5%, from about 1.8% to about 4.5%, or from about 2.25% to about 4.5%, and the like. In certain embodiments, the weight percentage (w/w) of hydroxyapatite in the oral care composition is about 0.75%, about 1%, about 1.25%, about 1.5% in the oral care composition. , about 1.8%, about 2.25%, about 4.5%, and numerical ranges arbitrarily combined at the above-mentioned points, as these numerical ranges are listed one by one in the present application. In some embodiments, the amount of hydroxyapatite in the oral care composition can be calculated from the formulation of the oral care composition.

"Soluble calcium" as used in this application refers to calcium which is not present in the form of a precipitate in a solvent such as water or a substrate such as a toothpaste. The soluble calcium may include calcium present in ionic form, calcium present as a complex or chelate when dispersed in a solvent or matrix, and calcium in the form of a dispersible conjugate (eg, bound to a protein) calcium). Soluble calcium is primarily distinguished from calcium in the form of insolubles, such as calcium in hydroxyapatite crystals. Soluble calcium can be obtained in an appropriate manner. In certain embodiments, the soluble calcium is derived from hydroxyphosphorus Impurities in the limestone raw material, such as soluble calcium remaining in the preparation of hydroxyapatite due to incomplete reaction. In certain embodiments, the soluble calcium is derived from the decomposition products of hydroxyapatite, for example, hydroxyapatite may decompose to produce soluble calcium under acidic conditions or under the action of some chelating agents or both. In certain embodiments, the soluble calcium is derived from an exogenously added calcium-containing compound, for example, the soluble calcium-containing compound can be dispersed in a solvent, preferably in water or an aqueous solution, to form soluble calcium. The solid of the soluble calcium-containing compound may be a solid form of a calcium-containing compound powder, crystals or the like suitable for dispersion and dissolution.

The soluble calcium concentration can be determined by methods well known to those skilled in the art, such as atomic absorption spectroscopy, inductively coupled plasma emission spectroscopy, and the like. In certain embodiments, the soluble calcium concentration is tested using inductively coupled plasma optical emission spectroscopy (ICP-AES). In the method, the solution to be tested is formed into an aerosol by an atomizing device, and is sprayed into the plasma torch through a quartz tube, and the sample is decomposed to form an atomic state and an ion state of the excited state, and the particles of the excited state are released when returning to the stable ground state. A certain amount of energy, which is expressed as a spectrum of a certain wavelength, determines the characteristic line and intensity of each element. Compared with the standard solution, the type and quantity of the elements contained in the sample can be known. The method generally comprises the steps of accurately weighing a certain amount of an oral care composition sample (such as a toothpaste or gel or mouthwash) and dissolving in water, taking the supernatant after centrifugation, and digesting the supernatant to completely digest the solution. The organic matter, and then the emission line and intensity of the calcium element in the obtained digestion product, can be inferred from the standard curve of the calcium ion standard solution to infer the concentration of soluble calcium in the sample. Digestion can be carried out using suitable methods known in the art, including but not limited to digestion with high purity concentrated nitric acid, or microwave digestion, etc., as long as the organics in the supernatant are completely digested and no other calcium source is introduced.

In certain embodiments, the soluble calcium concentration (in ppm) ranges from about 7.34 ppm to about 800 ppm in the oral care composition. In the present application, ppm means the ratio of the quality of soluble calcium to the mass of the oral care composition, and the specific formula is ppm = (quality of soluble calcium / quality of oral care composition) x 1000000. Preferably, the soluble calcium concentration (ppm) ranges from about 7.34 ppm to about 739 ppm, from about 8.33 ppm to about 739 ppm, from about 8.92 ppm to about 739 ppm, from about 13.25 ppm to about 739 ppm, from about 14.4 ppm to about 739 ppm, From about 14.84 ppm to about 739 ppm, from about 28.4 ppm to about 739 ppm, from about 33.8 ppm to about 739 ppm, from about 43 ppm to about 739 ppm, from about 48.5 ppm to about 739 ppm, from about 48.71 ppm to about 739 ppm, from about 50.0 ppm to about 739 ppm, from about 56.97. Ppm - about 739 ppm, about 65.13 ppm to about 739 ppm, about 76.5 ppm to about 739 ppm, about 87.75 ppm to about 739 ppm, about 87.88 ppm to about 739 ppm, about 98.5 ppm to about 739 ppm, about 109.4 ppm to about 739 ppm, about 113.94 ppm - about 739 ppm, from about 157.87 ppm to about 739 ppm, from about 159.5 ppm to about 739 ppm, from about 162 ppm to about 739 ppm, from about 168 ppm to about 739 ppm, from about 185.34 ppm to about 739 ppm, from about 224.89 ppm to about 739 ppm, from about 234 ppm to about 739 ppm, From about 238.5 ppm to about 739 ppm, from about 308 ppm to about 739 ppm, from about 312 ppm to about 739 ppm, from about 323.84 ppm to about 739 ppm, from about 341 ppm to about 739 ppm, from about 354 ppm to about 739 ppm, from about 395.80 ppm to about 739 ppm, from about 415 ppm to about 739 ppm. From about 600 ppm to about 739 ppm. Preferably, the soluble calcium concentration (ppm) ranges from about 7.34 ppm to about 600 ppm, from about 7.34 ppm to about 395.80 ppm, from about 7.34 ppm to about 185.34 ppm, from about 7.34 ppm to about 87.88 ppm, and about 7.34 ppm. About 65.13 ppm, about 7.34 ppm to about 48.71 ppm, about 7.34 ppm to about 14.84 ppm, about 7.34 ppm to about 13.25 ppm, about 7.34 ppm - about 8.92 ppm. More preferably, the soluble calcium concentration (ppm) ranges from about 87.88 ppm to about 395.80 ppm, from about 87.88 ppm to about 185.34 ppm, from about 185.34 ppm to about 395.80 ppm.

The "polycarboxy compound" as used herein refers to a compound having at least two carboxyl groups in the chemical structural formula, or more preferably three or more carboxyl groups. The polycarboxylate can be ionized out of the polycarboxylate after being dissolved in water. In some embodiments, the polycarboxy compound is a citrate compound, ie, a compound that is capable of ionizing citrate after being dissolved in water. In some embodiments, the citrate compound is a citrate salt, such as potassium citrate or sodium citrate. In some embodiments, the polycarboxy compound is a polyaspartate, such as sodium polyaspartate (eg, having a molecular weight of 3000-5000 or 5000-8000). In some embodiments, the polycarboxy compound is 2-phosphonobutane-1,2,4-tricarboxylate, such as 2-phosphonobutane-1,2,4-tricarboxylic acid Sodium (PBTCA.Na4). In some embodiments, the polycarboxy compound is an imidodisuccinate, such as sodium iminodisuccinate, potassium iminodisuccinate. In some embodiments, the polycarboxy compound is a polyacrylate such as sodium polyacrylate (eg, having a molecular weight of 3000-5000). In some embodiments, the polycarboxy compound has the structure:

Polyaspartate,

PBTCA. Na ₄ ,

Sodium iminodisuccinate,

Sodium polyacrylate.

In certain embodiments, in the oral care composition, the molar concentration of the soluble calcium (mol/L): the molar concentration of the carboxylate in the polycarboxy compound (mol/L) ranges from about 0.00178 - about 0.361. The "molar concentration of carboxylate in a polycarboxy compound" as used herein refers to the molar concentration of the -C(=O)O- group in the polycarboxy compound. For example, suppose a molecule of a polycarboxy compound has N -C(=O)O- groups, when 1 mole of the polycarboxylate is used After the base compound is placed in an aqueous solution of 1 L, the molar concentration of the carboxylate of the polycarboxy compound is considered to be N mol/L.

In certain embodiments, the molar concentration (mol/L) of soluble calcium: the molar concentration (mol/L) of carboxylate in the polycarboxy compound ranges from about 0.0099 to about 0.169, about 0.00542 to about 0.169, from about 0.0121 to about 0.169, from about 0.0247 to about 0.169, from about 0.0378 to about 0.169, from about 0.0114 to about 0.169, from about 0.0555 to about 0.169, from about 0.0619 to about 0.169, from about 0.0662 to about 0.169, from about 0.0676 to about 0.169, From about 0.0704 to about 0.169, from about 0.0715 to about 0.169, from about 0.0745 to about 0.169, from about 0.0747 to about 0.169, from about 0.0784 to about 0.169, from about 0.0902 to about 0.169, from about 0.0941 to about 0.169, from about 0.101 to about 0.169, from about 0.106. - about 0.169, from about 0.113 to about 0.169, from about 0.0099 to about 0.00542, from about 0.00199 to about 0.0121, from about 0.00199 to about 0.0247, from about 0.00199 to about 0.0378, from about 0.00199 to about 0.0414, from about 0.00199 to about 0.0555, from about 0.00199 to about 0.0619, from about 0.0099 to about 0.0662, from about 0.0099 to about 0.0676, from about 0.0099 to about 0.0704, from about 0.0099 to about 0.0715, from about 0.0099 to about 0.0745, from about 0.0099 to about 0.0747, from about 0.0099 to about 0.0784, from about 0.0099 to about 0.0902, From about 0.0099 to about 0.0941, from about 0.0099 to about 0.101, from about 0.0099 to about 0.106, from about 0.0099 to about 0.113. In certain embodiments, the molar concentration of soluble calcium (mol/L): the molar concentration (mol/L) of carboxylate in the polycarboxy compound ranges from about 0.00403 to about 0.334, about 0.00667 to about 0.334, from about 0.0219 to about 0.334, from about 0.0293 to about 0.334, from about 0.0396 to about 0.334, from about 0.0597 to about 0.334, from about 0.0835 to about 0.334, from about 0.178 to about 0.334, from about 0.271 to about 0.334, from about 0.00228 to about 0.216, From about 0.00403 to about 0.361, from about 0.00667 to about 0.361, from about 0.0219 to about 0.361, from about 0.0293 to about 0.361, from about 0.0396 to about 0.361, from about 0.0597 to about 0.361, from about 0.0835 to about 0.361, from about 0.178 to about 0.361, from about 0.271 - about 0.361. In certain embodiments, the polycarboxy compound is a citrate compound, Molar concentration of soluble calcium (mol/L): The ratio of the molar concentration (mol/L) of the carboxylate in the citrate compound also satisfies any of the above ratio ranges.

In certain embodiments, the molar concentration of soluble calcium (mol/L): the molar concentration of carboxylate in the citrate (mol/L) ranges from about 0.00178 to about 0.271, from about 0.00178 to about 0.178, about 0.00178 to about 0.0835, from about 0.00178 to about 0.0396, from about 0.00178 to about 0.0219, from about 0.00178 to about 0.00667. In certain embodiments, the molar concentration of the soluble calcium (mol/L): the molar concentration of the carboxylate in the citrate (mol/L) ranges from about 0.0396 to about 0.178, from about 0.0396 to about 0.0835. , about 0.0835 - about 0.178.

In certain embodiments, the weight percent (w/w) of the polycarboxylate in the polycarboxy compound in the oral care composition ranges from about 0.001% to about 30%, for example, from about 0.01% to about 30%, by weight. 0.01% to about 25%, from about 0.01% to about 20%, from about 0.01% to about 15%, from about 0.01% to about 10%, from about 0.05% to about 16%, from about 0.05% to about 12%, from about 0.05% - about 8%, from about 0.05% to about 4%, from about 0.05% to about 2.73%, from about 0.05% to about 2.68%, from about 0.05% to about 2.64%, from about 0.05% to about 2.25%, from about 0.05% to about 2%, from about 0.05% to about 1.2%, from about 0.05% to about 1%, from about 0.05% to about 0.742%, from about 0.05% to about 0.65%, from about 0.05% to about 0.6%, from about 0.05% to about 0.571% From about 0.05% to about 0.5%, from about 0.05% to about 0.418%, from about 0.05% to about 0.414%, from about 0.05% to about 0.369%, from about 0.05% to about 0.363%, from about 0.05% to about 0.355%, about 0.05% to about 0.351%, from about 0.05% to about 0.33%, from about 0.05% to about 0.319%, from about 0.05% to about 0.245%, from about 0.05% to about 0.2%, from about 0.05% to about 0.15%, from about 0.05% - about 0.138%, from about 0.05% to about 0.113%, from about 0.05% to about 0.1%, from about 0.1% to about 12%, from about 0.2% to about 12%, from about 0.3% to about 12%, from about 0.4% to about 12%, from about 0.5% to about 12%, from about 0.6% to about 12%, from about 0.7% to about 12%, from about 0.8% to about 12%, from about 0.9% to about 12%, from about 1% to about 12% About 1.1% - about 12% and the like. Polycarboxylate The amount of the oral care composition can be determined by methods well known in the art. For example, high performance liquid chromatography, spectrophotometry (for example, see, Zhu Junli, spectrophotometric method for quantitative determination of citric acid and its salt content, Analytical Laboratories, 2012, 2) can be measured. In certain embodiments, the weight percent of the polycarboxylate is determined by ultraviolet spectrophotometry by determining the absorbance or luminescence intensity of the polycarboxylate at a particular wavelength or range of wavelengths, and characterizing the polycarboxylate The method of quantitative analysis. The method generally comprises the steps of separately taking different concentrations of the polycarboxylate standard solution, adjusting the instrument zero point with a blank liquid, and determining the specific absorption wavelength of the polycarboxylate on the ultraviolet spectrophotometer (for example, the specific absorption wavelength of the citrate is 490nm) absorbance, draw a standard curve; accurately weigh a certain amount of oral care composition (such as toothpaste or gel or mouthwash) and dissolve in water, centrifuge to remove the supernatant, the supernatant is properly diluted and filtered The sample to be tested is obtained, its absorbance is measured, and the equivalent polycarboxylate content is derived from the standard curve.

In certain embodiments, the polycarboxy compound is a citrate compound. The weight percentage of citrate in the oral care composition can be determined using high performance liquid chromatography. The method generally comprises the steps of accurately weighing a certain amount of oral care composition (such as toothpaste or gel or mouthwash) and dissolving in water, taking the supernatant after centrifugation, and performing appropriate dilution filtration on the supernatant. High performance liquid chromatography analysis, compared with the standard curve of the citric acid standard solution, the concentration of citrate in the sample is obtained, and the weight percentage of citrate can be reversed according to the dilution ratio. In certain embodiments, the weight percent (w/w) of citrate in the citrate compound in the oral care composition also satisfies the weight percent of the polycarboxylate in the oral care composition in the polycarboxy compound (w /w) Range of any of the above ranges.

The polycarboxy compound and hydroxyapatite can be mixed over a wide range of ratios. Without being bound by theory, it is considered that in the mixture of the hydroxyapatite and the polycarboxy compound of the present application, the polycarboxy compound is mainly distributed on the surface of the hydroxyapatite, thereby producing the effect of surface modification, and making the said The mixture differs from the hydroxyapatite itself in several ways. In certain embodiments, in the oral care composition, the molar concentration (mol/L) of the carboxylate in the polycarboxy compound: the molar concentration (mol/L) of the hydroxyapatite molecule ranges from From about 1.238 to about 99.041, for example, from about 1.238 to about 71.676, from about 1.238 to about 63.712, from about 1.238 to about 55.748, from about 1.238 to about 47.784, from about 1.238 to about 39.820, from about 1.238 to about 31.856, from about 1.238 to about 23.892, From about 1.238 to about 15.928, from about 1.238 to about 7.964, from about 15.928 to about 79.640, from about 23.892 to about 79.640, from about 31.856 to about 79.640, from about 39.820 to about 79.640, from about 47.784 to about 79.640, from about 55.748 to about 79.640, about 63.712. It is approximately 79.640, approximately 71.676 to approximately 79.640. In certain embodiments, the polycarboxy compound is a citrate compound. In certain embodiments, the molar concentration of the carboxylate in the citrate compound (mol/L): the molar concentration of the hydroxyapatite molecule (mol/L) also satisfies the carboxylate in the polycarboxy compound Molar concentration (mol/L): Any of the above ratio ranges of the molar concentration (mol/L) of the hydroxyapatite molecule. The chemical formula of the hydroxyapatite molecule is: Ca10(PO4)6(OH)2, and its molecular weight is 1004. Therefore, the molar concentration of the hydroxyapatite molecule can be divided by its molecular weight by the quality of the hydroxyapatite ( That is, 1004), which is divided by the volume of the test solution.

The oral care compositions described herein can be in any form known in the art suitable for oral care, such as, but not limited to, toothpaste, gel, mouthwash, dental floss, paste used to clean the oral surface. , dentifrice, tooth gel, teeth, powder, tablet, or liquid preparation Stickers, mouth sprays, tooth powders, foams, chewing gums, lipsticks, sponges, mouthwashes, chewing gums, or denture products.

In certain embodiments, the oral care composition is a toothpaste wherein the weight percentage of hydroxyapatite is from 0.5% to 10%, the weight percentage of polycarboxylate is from 0.0874% to 6.995%, and the carboxyl group in the polycarboxy compound The molar concentration of the acid radical (mol/L): the molar concentration of the hydroxyapatite molecule (mol/L) ranges from 1.238 to 54.155, and the concentration of soluble calcium ranges from 7.34 to 800 ppm.

In certain embodiments, the oral care composition is a mouthwash wherein the weight percentage of hydroxyapatite is from 0.5% to 5%, and the weight percentage of polycarboxylate is from 0.0874% to 6.795%, and in the polycarboxy compound Molar concentration of carboxylate (mol/L): The molar concentration (mol/L) of the hydroxyapatite molecule ranges from 1.238 to 54.155, and the soluble calcium concentration ranges from 7.34 to 800 ppm.

In certain embodiments, the oral care composition is a gel wherein the weight percentage of hydroxyapatite is from 0.5% to 10%, and the weight percentage of polycarboxylate is from 0.0874% to 6.795%, and in the polycarboxy compound Molar concentration of carboxylate (mol/L): The molar concentration (mol/L) of the hydroxyapatite molecule ranges from 1.238 to 54.155, and the soluble calcium concentration ranges from 7.34 to 800 ppm.

"Oralally acceptable carrier" means a carrier which can be used as an ingredient in an oral care composition, is suitable for use in the physiological environment of the oral cavity, and does not cause excessive side effects on the oral cavity. The carrier may comprise a suitable cosmetic and/or therapeutic active. Preferably, the orally acceptable carrier is compatible with the hydroxyapatite, polycarboxyl compound, soluble calcium provided herein, and does not unduly interfere with the blocking activity of the hydroxyapatite on the dentinal tubules.

A wide variety of orally acceptable carriers known in the art can be used, such as, but not limited to, thickeners, abrasives, surfactants, flavoring agents.

A "thickener" is a substance that increases the viscosity of a solution or liquid/solid mixture, but does not substantially alter its properties. The purpose of adding a thickener is to provide the skeleton, flow and stability of the product. Exemplary thickeners include, but are not limited to, one or more of the following: hydroxyethyl cellulose, carboxymethyl cellulose and salts thereof (eg, sodium carboxymethylcellulose), carrageenan, carboxyl Vinyl polymer, xanthan gum, carrageenan, gelatin, amylopectin, sodium alginate, and the like. In certain embodiments, the thickening agent comprises one or more of xanthan gum, carrageenan or sodium carboxymethylcellulose.

"Abrasion agent" is the main component of the cleaning action in toothpaste. When selecting the friction agent, the hardness, size, shape and content of the friction agent should be fully considered to ensure effective cleaning without abrading the teeth. Exemplary abrasives include, but are not limited to, calcium carbonate, calcium hydrogen phosphate, calcium pyrophosphate, tricalcium phosphate, ceria, aluminum citrate, aluminum hydroxide, aluminum oxide, zeolite, titanium oxide, zirconium ruthenate, and the like. In certain embodiments, the abrasive comprises cerium oxide.

"Surfactant" is the purpose of emulsifying perfume and foaming in toothpaste, and to some extent can assist the full and complete dispersion of the hydroxyapatite-polycarboxy compound complex. Exemplary surfactants include, but are not limited to, anionic surfactants such as sodium dodecyl sulfate; amphoteric surfactants such as betaines; amino acid surfactants such as sodium lauryl sarcosinate and nonionic surfactants Agents such as polyoxyethylene and polyoxypropylene copolymers, polyethylene glycol, and the like.

"Flavor" refers to a substance used to improve the sensory properties of an oral care composition. Exemplary flavoring agents include, but are not limited to, sodium saccharin, flavoring oils such as spearmint oil, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage oil, eucalyptus oil, cinnamon oil, lemon oil, and orange skin Oil, methyl salicylate and eugenol. In certain embodiments, the flavoring agent comprises methyl salicylate and/or eugenol.

In certain embodiments, the oral care composition further comprises one or more active ingredients. "Active ingredient" means an ingredient that is capable of treating or ameliorating an oral condition or disease. In certain embodiments, the active ingredient comprises an anti-caries agent, an anti-allergic agent, an antibacterial agent.

"Anti-caries agent" refers to a substance which inhibits caries, for example, a substance which can enhance the anti-caries ability of teeth by reducing the solubility of hydroxyapatite in enamel, or a substance which controls plaque and inhibits the growth of bacteria. Exemplary anti-caries agents include, but are not limited to, fluoride ion sources such as sodium fluoride, potassium fluoride, calcium fluoride, magnesium fluoride, stannous fluoride, ammonium fluoride, sodium monofluorophosphate, monofluorophosphate Potassium, fluoroantimonate, etc.; phosphorus-containing reagents such as calcium phosphate, sodium trimetaphosphate, magnesium glycerophosphate, phytate, calcium lactate, sodium caseinate, etc., and arginine and its derivatives . In certain embodiments, the anti-caries agent comprises a source of fluoride ions.

"Antisensitizer" refers to a substance that prevents or treats dentin hypersensitivity by inhibiting nerve impulses or by being able to seal or reduce the permeability of dentinal tubules. Exemplary anti-allergic agents include, but are not limited to, potassium ion sources such as dipotassium glycyrrhizinate, potassium fluoride, potassium nitrate, potassium chloride, and the like. In certain embodiments, the anti-sensitizer comprises a source of potassium ions.

"Antibacterial agent" means a chemical substance that is capable of maintaining the growth or reproduction of certain microorganisms in an oral care composition below a necessary level for a certain period of time. Exemplary antibacterial agents include, but are not limited to, zinc oxide, stannous chloride, tetrahydrocurcumin, cetylpyridinium chloride, triclosan, and the like.

The oral care compositions provided herein can be prepared by mixing a polycarboxy compound, hydroxyapatite, soluble calcium with the orally acceptable carrier. Polycarboxylate The hydroxyapatite, soluble calcium and orally acceptable carrier can be formulated in the above amounts and ratios and mixed in an appropriate order and in an appropriate manner.

Composition of polycarboxy compound, hydroxyapatite, and soluble calcium

The application also provides a composition comprising hydroxyapatite, a polycarboxy compound, and soluble calcium. The hydroxyapatite may be a nano hydroxyapatite, and the polycarboxy compound may be any of the polycarboxylate compounds described herein (e.g., citrate compounds).

In certain embodiments, the composition can be dispersed in water to form an aqueous mixture as described herein. When the composition is dispersed in water or a matrix to form a homogeneous mixture, the molar concentration of the soluble calcium (mol/L): the molar concentration of the carboxylate in the polycarboxy compound (mol/L) may range It is a range of any ratio of the molar concentration (mol/L) of soluble calcium in the oral care composition to the molar concentration (mol/L) of the carboxylate in the polycarboxy compound as described herein. In certain embodiments, the molar concentration of carboxylate (mol/L) of the carboxylate in the polycarboxy compound after the composition is dispersed in water or a matrix to form a homogeneous mixture: Mohs of hydroxyapatite molecules The ratio of the concentration (mol/L) may be the molar concentration (mol/L) of the carboxylate in the polycarboxy compound in the oral care composition as described herein: the molar concentration of the hydroxyapatite molecule (mol/L) Any range of ratios.

Aqueous mixture of polycarboxy compound, hydroxyapatite and soluble calcium

The present invention also provides an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium. By "aqueous mixture" is meant that the solvent in the mixture is mostly composed of water, for example at least 50%, 70%, 80%, 90%, 95% or 100% consists of water. In certain embodiments, the solvent of the aqueous mixture is water, or an aqueous solution of a buffer salt. In certain embodiments, the aqueous mixture consists essentially of hydroxyapatite, a polycarboxy compound, soluble calcium, Water, and buffer salts.

In the aqueous mixture, the molar concentration of the soluble calcium (mol/L): the ratio of the molar concentration (mol/L) of the carboxylate in the polycarboxy compound may be in the oral care combination as described herein before. The ratio of the molar concentration (mol/L) of soluble calcium to the molar concentration (mol/L) of carboxylate in the polycarboxy compound.

In the aqueous mixed solution, the molar concentration (mol/L) of the carboxylate in the polycarboxy compound: the molar concentration (mol/L) of the hydroxyapatite molecule may be in the range described above in the present application. Molar concentration (mol/L) of carboxylate in the polycarboxy compound in the oral care composition: any ratio range of the molar concentration (mol/L) of the hydroxyapatite molecule.

In the aqueous mixed solution, the concentration of the hydroxyapatite, the polycarboxy compound, and the soluble calcium may be appropriately adjusted as needed, provided that the concentration is suitable for the aqueous mixed solution and/or can be prepared. The oral care composition of the present application is sufficient. In the preparation of an oral care composition, the aqueous mixture may be combined with other ingredients, such as an orally acceptable carrier, which may dilute the amount of each component of the aqueous mixture. Thus, depending on the degree of dilution possible during the preparation of the oral care composition, the concentration of each component in the aqueous mixture may also vary, for example, in certain embodiments, may be higher than in the oral cavity of the present application. The concentration of the corresponding component in the care composition is, for example, 1.5 times, 2 times, 2.5 times, 3 times, 5 times, 8 times, 10 times, 20 times, etc., of the concentration of the components in the oral care composition.

The weight percentage (w/w) of hydroxyapatite in the aqueous mixture, or when the aqueous mixture is diluted 1.5 times, 2 times, 2.5 times, 3 times, 5 times, 8 times, 10 times, or 20 The weight percentage of the hydroxyapatite in the diluted aqueous mixture may be the present application. The aforementioned hydroxyapatite is in any range of weight percent (w/w) in the oral care composition.

The weight percentage (w/w) of the polycarboxylate in the aqueous mixture, or when the aqueous mixture is diluted 1.5 times, 2 times, 2.5 times, 3 times, 5 times, 8 times, 10 times, or 20 times The weight percent of the post-polycarboxylate in the diluted aqueous mixture can be any of the weight percent (w/w) of the polycarboxylates previously described herein in the oral care composition.

The soluble calcium concentration (ppm) in the aqueous mixture, or soluble when the aqueous mixture is diluted 1.5 times, 2 times, 2.5 times, 3 times, 5 times, 8 times, 10 times, or 20 times The concentration of calcium in the diluted aqueous mixture can be within any of the soluble calcium concentrations (ppm) in the oral care compositions previously described herein.

In certain embodiments, the hydroxyapatite particles having a particle size greater than about 100 nm in the aqueous mixture are no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, Or no more than about 10%.

Without being bound by theory, it is believed that the dispersibility of hydroxyapatite in aqueous solution can be improved after mixing hydroxyapatite with polycarboxyl compound and soluble calcium, for example, it can be expressed as the same concentration of hydroxyapatite in the same concentration. The addition of a polycarboxy compound and soluble calcium to the aqueous solution can prolong the time during which the hydroxyapatite forms a precipitate and delamination, such as from 2 hours to 12 hours or longer. Or appear to increase the absolute value of the zeta potential of the aqueous solution of hydroxyapatite. The dispersibility of the aqueous hydroxyapatite solution can be characterized by means well known in the art, such as dynamic light scattering, particle size distribution, and the like.

The improvement of the dispersibility of hydroxyapatite can bring about many beneficial effects. In certain embodiments, the improvement in dispersibility can increase the occlusion effect of hydroxyapatite on the tubules. For example, the commercially available hydroxyapatite as shown in Figure 2 has poor dispersibility when using this commercially available hydroxyapatite. When the stone is subjected to dentinal tubule sealing experiments, it is almost impossible for hydroxyapatite to block the dentinal tubules, as shown in Fig. 7(b). When the commercially available hydroxyapatite was mixed with a polycarboxy compound and soluble calcium, the dispersibility and the tube sealing effect were significantly improved, as shown in Fig. 8(b). In addition, improvements in dispersibility also contribute to the preparation of oral care compositions.

Accordingly, the present application also provides a method of increasing the dispersibility of hydroxyapatite in a solution comprising mixing hydroxyapatite with a polycarboxy compound and soluble calcium. In certain embodiments, the method further comprises dispersing the mixed hydroxyapatite with a polycarboxy compound and soluble calcium in a solution or matrix.

In certain embodiments, the hydroxyapatite in the aqueous mixture of the present application is capable of entering the dentinal tubules. In certain embodiments, the hydroxyapatite is capable of entering dentin tubules of at least about 5 microns, at least about 10 microns, at least about 15 microns, at least about 20 microns, at least about 25 microns, at least about 30 microns, at least about 35 microns, at least about 40 microns, at least about 50 microns, at least about 55 microns, at least about 60 microns, at least about 65 microns, at least about 70 microns, at least about 75 microns, at least about 80 microns, and the like.

In certain embodiments, an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium has a negative zeta potential.

Without being bound by theory, it is believed that polycarboxylates and soluble calcium can alter the electrical properties of the surface of the hydroxyapatite, accumulating a negatively charged carboxyl group on the surface of the hydroxyapatite. In certain embodiments, the aqueous mixture comprising hydroxyapatite, polycarboxyl compound, and soluble calcium may have a zeta potential ranging from about -38 to about -20 mV. It is well known in the art that instrumental measurements typically have some measurement error. Measurement errors within the above ranges are understood and accepted by those skilled in the art. In certain embodiments, comprising hydroxyapatite, a polycarboxy compound, and soluble calcium The zeta potential of the aqueous mixture can range from -38 to -20 mV. In contrast, when there is no polycarboxy compound, hydroxyapatite and soluble calcium have a positive charge on the surface at an appropriate pH, and the aqueous solution also exhibits a positive zeta potential, for example, at certain concentrations. About 30mV.

The Zeta potential, also known as the zeta potential or zeta potential (ζ-potential or ζ-potential), refers to the potential of the shear plane and is an important indicator of the stability of the colloidal dispersion. The Zeta potential can be measured by techniques and/or equipment well known in the art, such as electrophoresis, electroosmosis, flow potential, and ultrasonic. In certain embodiments, the zeta potential can be determined by a flow potentiometry, for example, using a suitable potentiometer (such as a Malvern Zetasizer Nano ZS potentiometer) to determine the potential of the mixture. By determining the zeta potential, the dispersibility and surface modification of the hydroxyapatite can be determined to help assess the ability of the hydroxyapatite to enter the dentinal tubules in the aqueous mixture.

In certain embodiments, the aqueous mixture has a pH of from about 7 to about 14. Preferably, the pH of the aqueous mixture is within the physiologically acceptable range of the oral cavity, i.e., when applied to the oral cavity, does not cause excessive irritation or injury to the tissues of the oral cavity (e.g., teeth, muscles, mucous membranes, etc.). In certain embodiments, the aqueous mixture has a pH of from about 7 to about 10, from about 7 to about 9, or from about 7 to about 8. The pH of the aqueous mixture can be adjusted by means well known in the art. For example, the aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium can be formulated using a suitable buffer, and/or the pH adjusted to the desired range with a suitable acid or hydrazine.

In certain embodiments, the mixture further comprises metal ions. In certain embodiments, the metal ion is capable of interacting with a carboxyl group in a polycarboxy compound, such as a metal salt or complex with a carboxyl group, and the like. Exemplary metal ions are, for example, copper ions, zinc ions, silver ions, or any combination thereof. In certain embodiments, metal ions have a benefit to oral health. At the office. For example, copper ions have the effect of preventing plaque and whitening; zinc ions can inhibit the formation of plaque and calculus, thereby preventing the adhesion and deposition of various pigments such as smoke spots and tea spots on the tooth surface, and achieving the effect of removing stains. Silver ion has superior antibacterial ability and broad spectrum antibacterial properties.

An aqueous mixture comprising hydroxyapatite, a polycarboxy compound and soluble calcium as described herein can be prepared by a suitable method. In certain embodiments, the method comprises mixing a polycarboxy compound with dispersed hydroxyapatite, soluble calcium in an aqueous solution.

"Dispersed hydroxyapatite" means hydroxyapatite dispersed in a solvent. Preferably, the hydroxyapatite is dispersed in water or an aqueous solution, and the aqueous solution may contain a necessary solute such as, but not limited to, a pH adjusting buffer salt or the like. The dispersed hydroxyapatite may have a suitable dispersion density to facilitate better formation of the complex with the polycarboxy compound.

The polycarboxy compound, the dispersed hydroxyapatite, and the soluble calcium can be mixed using any suitable mixing method. In certain embodiments, the polycarboxy compound, soluble calcium, and agitation may be added to the dispersed hydroxyapatite.

In certain embodiments, the polycarboxy compound is selected from the group consisting of citrate compounds, such as potassium citrate, sodium citrate, and the like, polyaspartate, such as sodium polyaspartate, polyaspartate Potassium acid or the like, iminodisuccinate, such as potassium iminodisuccinate, sodium iminodisuccinate, etc., 2-phosphonobutane-1,2,4-tricarboxylate, for example 2-phosphonobutane-1,2,4-tricarboxylic acid tetrasodium, etc., polyacrylates, such as sodium polyacrylate, potassium polyacrylate, and the like. A salt which does not cause side effects to the oral cavity is preferred. In certain embodiments, a solid of a polycarboxy compound can be added to the dispersed hydroxyapatite. The solid of the polycarboxy compound may be a solid form of a polycarboxy compound powder, crystal or the like which is suitable for dispersion.

In certain embodiments, the soluble calcium is present in the form of calcium ions. In a certain In some embodiments, the soluble calcium-containing compound is dispersed in a solvent, preferably dispersed in water or an aqueous solution to form soluble calcium. The solid of the soluble calcium-containing compound may be a solid form of a calcium-containing compound powder, crystals or the like suitable for dispersion and dissolution. In certain embodiments, a soluble calcium-containing compound can be added to the dispersion of hydroxyapatite to form a mixture with the polycarboxy compound. In certain embodiments, the soluble calcium is derived from unreacted calcium ions during the preparation of the hydroxyapatite while not being removed by methods well known in the art, such as centrifugation, and the unreacted calcium ions are derived from the preparation. A soluble source of calcium for hydroxyapatite, such as calcium chloride, calcium nitrate, and the like. In certain embodiments, the soluble calcium is derived from calcium ions dissociated by hydroxyapatite under chelating or acidic conditions or bound calcium bound to a chelating agent, such as EDTA, etc., such as Citric acid, etc.

In certain embodiments, a solution containing a soluble calcium, polycarboxy compound can be added to the dispersed hydroxyapatite. The concentration of the solution containing the soluble calcium and polycarboxy compound and the content of the dispersed hydroxyapatite may be selected such that the aqueous mixture obtained after mixing has the desired concentration and content. These are routine experimental procedures well known to those skilled in the art.

use

In another aspect, the invention provides a method of filling a dentinal tubule comprising contacting the dentin with an oral care composition provided herein to allow the hydroxyapatite to enter a dentinal tubule.

The hydroxyapatite in the oral care compositions provided herein can enter the dentinal tubules. Preferably, the hydroxyapatite is capable of entering at least about 5 microns, at least about 10 microns, at least about 15 microns, at least about 20 microns, at least about 30 microns, at least about 40 microns, into the dentinal tubules, At least about 50 microns, at least about 60 microns, at least about 70 microns.

The depth of hydroxyapatite into the dentinal tubules can be determined by appropriate experimental methods. For example, the oral care composition can be used to contact a dental sample, such as a dental sample of an animal, after a certain period of time (eg, 10-120 minutes), the dental sample is taken, a parallel section of the dentinal tubule is prepared, and hydroxyphosphorus is observed and measured under electron microscope. The depth of entry of the gray stone. The hydroxyapatite entering the dentinal tubule plays an important role in the occlusion of the dentinal tubule, which not only can block the opening of the dentinal tubule, but also can maintain the state of dentinal tubule sealing for a long time, which is helpful to achieve Better and more durable anti-tooth sensitivity.

The oral care composition can be any suitable oral care composition provided herein, such as, but not limited to, toothpaste, mouthwash, gel, dental floss, paste used to clean the oral surface, powder, tablets, or A dentifrice such as a liquid preparation, a tooth gel, a tooth paste, an oral spray, a tooth powder, a foam, a chewing gum, a lipstick, a sponge, a mouthwash, a chewing gum, or a denture product. By performing oral care, particularly dental care, with the oral care compositions provided herein, hydroxyapatite can be effectively promoted into dentinal tubules. In certain embodiments, the oral care composition is a toothpaste, the method comprising brushing the toothpaste to allow the hydroxyapatite to enter a dentinal tubule. In certain embodiments, the oral care composition is a gel, the method comprising brushing with the gel, or contacting the tooth with the gel to allow the hydroxyapatite to enter a dentinal tubule . In certain embodiments, the oral care composition is a mouthwash, the method comprising contacting the teeth with the mouthwash to allow the hydroxyapatite to enter the dentin tubules.

In certain embodiments, the aqueous mixture comprising hydroxyapatite, polycarboxyl compound, and soluble calcium provided herein can be used to prepare a mouth that relieves or prevents tooth sensitivity. Care composition. Tooth sensitivity is a common oral discomfort. The main reason is that the fluid flow in the dentinal tubules changes, stimulating the end of the pulp nerve, generating impulses and transmitting pain. Mainly manifested as irritating pain, causing soreness when brushing teeth, eating hard things, sour, sweet, cold, hot, etc., especially sensitive to cold stimulation. The hydroxyapatite provided by the present application can deeply penetrate into the dentinal tubules and deeply block the dentinal tubules, thereby reducing the stimulation of the dentin and/or the dental nerve by the external environment, and alleviating or preventing the sensitivity of the teeth.

In certain embodiments, an aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium provided herein can be used to prepare an oral care composition for filling dentinal tubules in a tooth. As indicated by the present application, hydroxyapatite is capable of filling dentinal tubules and is capable of entering a certain depth.

Dental material

In another aspect, the invention provides a dental material having dentinal tubules characterized in that the dentin tubules are filled with hydroxyapatite. In certain embodiments, wherein the dental material is a tooth.

Upon treatment or treatment of the teeth with the oral care composition, the hydroxyapatite is capable of deep filling the dentinal tubules to form a dental material such as a tooth filled with hydroxyapatite in the dentinal tubules.

In certain embodiments, the hydroxyapatite has a filling depth in the dental tubule of at least about 5 microns, at least about 10 microns, at least about 15 microns, at least about 20 microns, at least about 30 microns, at least about 40 microns, at least about 50 microns, at least about 60 microns, or at least about 70 microns. In certain embodiments, the dental tubules have a diameter of between about 1 and 4 microns.

In the present application, when "about" is used to modify the value, the index value floats up and down. Within the range of ±10%, ±5%, ±4%, or ±3%.

Specific embodiment

Example 1: Preparation of an aqueous mixture of nano hydroxyapatite, citrate and soluble calcium

raw material

Raw material 1: Nano hydroxyapatite (Nano HAP) is a commercial product (purchased from Fluidinova, Portugal), which is about 15% aqueous solution of Nano HAP containing about 1053 ppm of soluble calcium. The soluble calcium is derived from the preparation of nano hydroxyapatite. The complete soluble calcium source calcium chloride is not reacted at the same time, and is not removed by means well known to those skilled in the art.

Raw material 2: Nano hydroxyapatite (Nano HAP) is a commercial product (purchased from Shanghai Zilin Biotechnology Co., Ltd.), which is a dry powder of Nano HAP, which is configured as a 15% aqueous solution of Nano HAP, and its soluble calcium is about 4 ppm. Since the solubility of Nano HAP is very small, the soluble calcium produced by dissolving in water is basically negligible.

The topography and size of the two Nano HAPs are shown in Fig. 1 and Fig. 2, and Fig. 1 shows a short rod shape of 20 nm to 50 nm long, and Fig. 2 shows a needle shape of 20 nm to 50 nm.

Potassium citrate is a food grade raw material.

Other materials and reagents used in the preparation may be obtained commercially by purchase or by a person skilled in the art after simple configuration according to known techniques.

1.2 Experimental instruments

Zeta potentiometer (Malvern Zetasizer Nano ZS); scanning electron microscope (HITACHI S-4800).

1.3 Experimental steps and results analysis

1.3.1 Use of raw materials 1

Raw material 1 was used as a source of Nano HAP and soluble calcium. Raw material 1 was diluted with deionized water and mixed well. Then, different doses of potassium citrate were added according to the different ratios in Table 1 below, and then uniformly mixed to obtain a suspension 1 -I~1-VIII.

According to the ratios in Table 1, the Nano HAP in each group was separately dispersed in water, and then potassium citrate was added to the solution to be dispersed to obtain a suspension 1-I~1-VIII. The zeta potential of suspension 1-I~1-VIII was tested by Zeta potential meter to characterize the effect of different doses of potassium citrate on the surface electrical properties of Nano HAP. The zeta potential measurement results of the suspension 1-I~1-VIII are shown in Fig. 3.

It can be seen from Fig. 3 that the surface of the raw material Nano HAP and soluble calcium has a strong positive charge, and the zeta potential of the aqueous suspension is +34.3 mV. Different doses of potassium citrate were added to form a nano-hydroxyapatite-citrate complex. Different amounts of citrate caused a strong negative charge on the surface of Nano HAP, and the zeta potential of the aqueous suspension was -30 mV to - Near 38mV. This It is indicated that the negatively charged citrate adsorbed on the surface of Nano HAP to convert the charge on the surface of Nano HAP from a strong positive charge to a stronger negative charge.

From the results of the above characterization methods, it was found that in the suspension 1-I~1-VIII, citrate was successfully adsorbed on the surface of Nano HAP, and the surface modification of Nano HAP was carried out.

1.3.2 Use of raw materials 2

Raw material 2 was used as the source of Nano HAP, diluted with deionized water, and the raw material CaCl2.2H2O was added to obtain soluble calcium. The zeta potential change is shown in Table 2 below. The addition of soluble calcium changes the electrical properties of the Nano HAP surface. Before the addition of soluble calcium, the surface of Nano HAP has a weak negative charge. After adding a small amount of soluble calcium ions, the surface electrical properties of Nano HAP change, from negative to positive. Calcium ions are the constituent ions of Nano HAP, which have an important influence on the surface structure and surface electrical properties of Nano HAP.

After adding soluble calcium, potassium citrate of different ratios was added according to Table 3. The surface charge was changed to become a negative charge, and the absolute value of the zeta potential was increased, as shown in Fig. 4. This also shows that the dispersibility of nano-hydroxyapatite is greatly improved.

Example 2: Nano-hydroxyapatite plugging and entry into dentinal tubules

2.1 Preparation method of dentinal tubule exposure model

(A) Preparation method perpendicular to the dentinal tubule observation surface model A

Take the cow's teeth, cut a 2mm thick disc perpendicular to the long axis of the cattle tooth at the junction of the root and the crown, and wipe the edge of the disc with a polishing machine to obtain a rectangular observation area of 2mm x 6mm. Then, the observation area was polished with 600 mesh, 1200 mesh, and 2000 mesh sandpaper to obtain a smooth and smooth observation surface. After the polishing was completed, the etching was carried out for 5 minutes with 6 wt% citric acid, and the dentinal tubules were exposed, and then washed with an ultrasonic cleaner for 3 times for 15 minutes to obtain a model A perpendicular to the dentinal tubule observation surface. The model perpendicular to the dentinal tubule observation surface model A observed under SEM is as shown in Fig. 5, and the open dentinal tubules can be clearly seen.

(B) Preparation method parallel to the dentinal tube observation surface model B

The model A of the vertical dentinal tubule was obtained according to the method in (A), and the model was treated with the sample to be tested, and after the treatment was completed, it was dried in an oven at 40 ° C for 24 hours. The model is then thrown away parallel to the dentinal tubules with a scalpel, and the resulting paraboloid parallel to the dentinal tubule is prepared parallel to the dentinal tubule observation surface model B. Small parallel to dentin observed under SEM As shown in Fig. 6, the tube observation surface model B shows that the dentinal tubule has a smooth wall and no sediment, and a fibrous substance can be seen.

2.2 Experimental process

2.2.1 Nano-hydroxyapatite sealing dentinal tubule opening experiment

2.2.1.1 Raw materials

Raw material 1: Nano hydroxyapatite (Nano HAP) is a commercial product (purchased from Fluidinova, Portugal), which is about 15% aqueous solution of Nano HAP containing about 1053 ppm of soluble calcium. The soluble calcium is derived from the preparation of nano hydroxyapatite. The complete soluble calcium source calcium chloride is not reacted at the same time, and is not removed by means well known to those skilled in the art.

Raw material 2: Nano hydroxyapatite (Nano HAP) is a commercial product (purchased from Shanghai Zilin Biotechnology Co., Ltd.), which is a dry powder of Nano HAP, which is configured as a 15% aqueous solution of Nano HAP, and its soluble calcium is about 4 ppm. Since the solubility of Nano HAP is very small, the soluble calcium produced by its dissolution in water is almost negligible.

The topography and size of the two Nano HAPs are shown in Fig. 1 and Fig. 2, and Fig. 1 shows a short rod shape of 20 nm to 50 nm long, and Fig. 2 shows a needle shape of 20 nm to 50 nm.

Potassium citrate is a food grade raw material.

2.2.1.2 Experimental steps

Two different raw materials were prepared with deionized water to prepare a suspension with a Nano HAP content of 2.25%. The model A was treated for 2 min, then the model A was rinsed and dried, and the plugging of the surface of the model A was observed under SEM. Figure 7 shows.

The two Nano HAPs were separately mixed with potassium citrate and soluble calcium according to the ratio of Table 4, wherein the 1'-I group used the raw material 1, and the soluble calcium was derived from the unreacted raw material when the raw material was prepared. Soluble calcium source. The 2'-II group used the raw material 2, the soluble calcium source was derived from the added CaCl2.2H2O, and the model A was treated with the 1'-I and 2'-II suspensions respectively for 2 min, then the model A was rinsed and dried, and the model was observed under SEM. The sealing of the A surface is shown in Figure 8.

The blocking effect of the raw material 1 Nano HAP without potassium citrate on the surface of dentinal tubules is shown in Figure 7(a). The raw material 2 Nano HAP without potassium citrate and soluble calcium is applied to the surface of dentinal tubules. The sealing effect is shown in Figure 7(b). The raw material 1 Nano HAP can form a plug on the open surface of the dentinal tubule (see Figure 7(a)), while the less dispersible raw material 2 Nano HAP has a lower blocking rate of the dentinal tubule (see section 7(b). ))), indicating that the force between Nano HAP and dentin is poor.

The blocking effect of two Nano HAPs treated with potassium citrate and soluble calcium on the surface of dentinal tubules is shown in Figures 8(a) through 8(b). Although there are significant differences in the sealing effect between the two Nano HAP materials, after treatment with potassium citrate and soluble calcium, both Nano HAPs form a plug on the surface of the dentinal tubules, as shown in Figure 8(a). Figure 8(b) shows. In particular, for the poorly dispersible raw material 2 (as shown in Fig. 2), the blocking rate of the dentinal tubules after treatment with citrate and soluble calcium is remarkably improved. The raw material 1 (as shown in Fig. 1), which originally had a certain plugging effect, had different deposit morphology on the surface of the dentin before and after treatment with citrate and soluble calcium. Nano treated with citrate and soluble calcium The HAP plugging layer appears to be more robust (eg Figure 8(a) shows that the introduction of citrate and soluble calcium enhances the interaction between Nano HAP and dentin.

2.2.2 Nano-hydroxyapatite into the dentinal tubule internal experiment

The suspensions 1"-I, 1"-II, 1"-III, 1"-IV were arranged according to the different ratios in Table 5, wherein the Nano HAP used was the Nano HAP raw material shown in Fig. 1, that is, the raw material 1. 10 ml of each suspension was taken, and 2 dentin models A were placed in each suspension, respectively, soaked in each suspension for 40 min, and shaken on a shaker to ensure uniform suspension. After the soaking was completed, the dentin model A observation surface was washed with 100 ml of deionized water for 30 seconds and dried at 40 °C. Model B was obtained by following one of the two models A of each suspension according to the method B in 2.1. Models A and B obtained by treating the suspensions 1"-I, 1"-II, 1"-III, and 1"-IV, respectively, were observed under SEM, and the results are shown in Figures 9-12.

Using raw material 2, add different concentrations of soluble calcium to the raw material to see if it can enter the dentinal tubules. The results are shown in Table 6.

Table 6 Suspensions of different ratios of Nano HAP, potassium citrate, and soluble calcium

2.3 Experimental results and analysis

In the absence of Nano HAP, the dentinal tubules in Model A are all open (as shown in Figure 5), and the dentinal tubule wall in Model B is smooth, without any deposits, visible fibers Shaped matter (as shown in Figure 6).

After treatment with a non-citrate-treated Nano HAP suspension (ie, suspension 1"-I), a layer of non-citrate-modified Nano HAP was deposited on the surface of model A (eg, Figure 9(a) and Figure 9 ( b) as shown in the figure), and in model B, it can be seen that Nano HAP is only deposited on the surface of dentin and does not enter the dentinal tubules, that is, the depth of the dentinal tubules is 0 micrometers, and the tube wall of the dentinal tubules is smooth. Visible fibrous substances (as shown in Figures 9(c) and 9(d)).

When treated with a suspension of Nano HAP containing citrate and soluble calcium (ie suspension 1"-II, 1"-III or 1"-IV), the opening of the dentinal tubule on the surface of model A is completely blocked (eg 10(a), 10(b), 11(a), 11(b), 12(a), 12(b), and in model B It can be seen that the Nano HAP enters the inside of the dentinal tubules to a depth of Less than 5 microns, even up to 100 microns (as shown in Figure 10(c), Figure 10(d), Figure 11(c), Figure 11(d), Figure 12(c), Figure 12(d) shows). When treated with a suspension of Nano HAP containing potassium citrate but a very low soluble calcium content (ie suspension 2"-I), there is Nano HAP deposition on the surface of model A (as shown in Figure 13(a)). In model B, it can be seen that Nano HAP is only deposited on the surface of dentin and does not enter the dentinal tubule. The tube wall of the dentinal tubule is smooth and visible fibrous material (as shown in Figure 13(b)).

Dentinal tubules on the surface of model A after treatment with a Nano HAP suspension containing citrate and a relatively high soluble calcium content (ie suspension 2"-II, 2"-III, 2"-IV or 2"-V) The opening of the model is completely blocked (scanning electron microscopy (SEM) image of the dentinal tubule on the surface of the model A treated with the suspension 2"-II as shown in Fig. 14(a) and Fig. 14(b). The SEM image of the dentinal tubules on the surface of the model A treated with the suspension 2"-III, 2"-IV looks the same as that of the suspension 2"-II treatment, therefore, only the suspension 2"-II is provided here. The SEM image of the dentinal tubules on the surface of the treated model A is for illustrative purposes, while in model B it can be seen that the Nano HAP enters the interior of the dentinal tubules to a depth of at least 5 microns (as in Figure 15(a), Figure 15(b), Figure 15(c), and Figure 15(d)).

Since the sealing layer deposited on the surface of the dentin is gradually brushed off during the daily brushing process, it does not exert a long-lasting anti-allergy effect, and the plugging substance entering the dentinal tubule will have a long-lasting anti-allergy. effect. This experiment proves that the hydroxyapatite treated by citrate and soluble calcium has enhanced binding ability to dentinal tubules, and can enter the dentinal tubules to a depth of at least 5 micrometers or even 100 micrometers, which has a long-lasting resistance. Sensitive effect.

Example 3: Application of nano hydroxyapatite, citrate and soluble calcium in toothpaste and mouthwash formula

3.1 nano hydroxyapatite, citrate and soluble calcium in toothpaste formulations application

Raw material 1:15% Nano HAP solution containing 1053 ppm of unreacted soluble calcium. The raw material was commercialized and purchased from Fluidinova, Portugal.

Raw material 2: Nano HAP dry powder, formulated into a 15% aqueous solution of Nano HAP, containing about 4 ppm of soluble calcium, which was obtained by decomposition of Nano HAP. The raw materials are commercial finished products, which were purchased from Shanghai Zilin Biotechnology Company.

Raw material 3: 15% Nano HAP solution, the synthesis process is the same as raw material 1, but after repeated centrifugation to remove most of the unreacted soluble calcium, the soluble calcium in the raw material is about 43ppm. The raw material is commercialized and purchased from Fluidinova, Portugal.

3.1.1 Toothpaste containing 4.5wt% nano-hydroxyapatite, citrate and soluble calcium

The composition of Formulations 1, 2, 3, and 4 is shown in Table 7. Formulations 1, 3, and 4 used Raw Material 1, in which Formulation 3 and Formulation 4 were added to trisodium phosphate dodecahydrate to adjust the concentration of calcium ions. As a calcium adsorbent, trisodium phosphate dodecahydrate can be combined with a part of soluble calcium in the formula to form a calcium phosphate precipitate, thereby adjusting the content of soluble calcium in the formula. Formulation 2 used material 2 and added soluble calcium.

Preparation Process

The aqueous suspension of Nano HAP is prepared, and the content of soluble calcium is adjusted, and soluble calcium can be added if necessary. The preparation ratio can be determined freely according to the water content of the formula and the amount of NanoHAP added. In this example, a 15% aqueous solution of Nano HAP is prepared.

The suspension of step 1 was ultrasonically mixed with the humectant sorbitol. Add potassium citrate, continue ultrasonic mixing, add trisodium phosphate dodecahydrate and mix well.

Titanium dioxide and sodium saccharin were added to the suspension of step 2, and the mixture was stirred well.

Mix polyethylene glycol and glycerin, add xanthan gum, and mix well.

The mixture prepared by the step 4 was added to the mixture prepared in the step 3, and heated to obtain a mixed glue.

The abrasive ceria was added to the glue prepared in the step 5, and the mixture was evacuated.

Deionized water and surfactant were added and stirred under vacuum.

Finally add the essence, stir and vacuum.

The paste prepared according to the above process is as shown in Fig. 16, and the surface of the paste is fine and smooth.

The results of the test for soluble calcium and citrate in the formulations tested for soluble calcium and citrate as described in the present application are shown in Table 8 below.

3.1.2 Toothpaste containing 2.25 wt% nano hydroxyapatite, citrate and soluble calcium.

The composition of Formulations 5, 6, 7, 8, and 9 is shown in Table 9. Formulations 5, 8, and 9 used Raw Material 1, and the soluble calcium was derived from soluble calcium which was not completely reacted at the time of preparation of the raw material. Formulations 8 and 9 were added with trisodium phosphate trihydrate to adjust the concentration of calcium ions. As a calcium adsorbent, trisodium phosphate dodecahydrate can be combined with a part of soluble calcium in the formula to form a calcium phosphate precipitate, which can adjust the solubility in the formula. The content of calcium. Formulations 6, 7 use starting material 3 and add soluble calcium.

The preparation process is the same as the preparation process of 3.1.1.

Tested for the method of testing soluble calcium and citrate as described in this application The soluble calcium and citrate results in the formulation are shown in Table 10 below.

3.1.3 Toothpaste containing 1.8 wt% nano hydroxyapatite, citrate and soluble calcium.

Using the raw material 1, the soluble calcium is derived from the unreacted soluble calcium at the time of preparation of the raw material.

Formulation 10 is shown in Table 11 below.

The preparation process is the same as the preparation process of 3.1.1. The resulting paste is also smooth and delicate.

The results of the test for soluble calcium and citrate in the formulations according to the method for testing soluble calcium and citrate described in the present application are shown in Table 12 below.

3.1.4 Toothpaste containing 1 wt% of nano hydroxyapatite, citrate and soluble calcium.

Using the raw material 1, the soluble calcium is derived from the unreacted soluble calcium of the raw material.

Formulation 11 is shown in Table 13 below.

The preparation process is the same as the preparation process of 3.1.1. The resulting paste is also smooth and delicate.

The results of the test for soluble calcium and citrate in the formulations according to the method for testing soluble calcium and citrate described in the present application are shown in Table 14 below.

Table 14. Teeth containing 1wt% nano-hydroxyapatite, citrate and soluble calcium

3.1.5 efficacy test

(1) Using the paste prepared by the process described in 3.1.1-3.1.4, model A was used for brushing test. Model A was brushed for 2 min, rinsed, dried, and observed under a scanning electron microscope.

(2) The paste prepared by the process described in 3.1.1-3.1.4 and deionized water are prepared into a toothpaste slurry at a ratio of 1:3, and the model B is immersed in the toothpaste slurry for 40 minutes, then rinsed, dried, and scanned. Observed under an electron microscope.

Efficacy tests were performed using Model A and Model B, and the results are shown in Table 15 below.

It can be seen that the toothpaste formula containing nano-hydroxyapatite, citrate and soluble calcium can effectively block dentinal tubules and can enter the dentinal tubules for long-lasting anti-allergic effect, containing different concentrations of soluble calcium. The depth of the nano-hydroxyapatite into the dentinal tubules is different in the formulation.

3.2 Application of nano-hydroxyapatite, citrate and soluble calcium in mouthwash formula

3.2.1 Mouthwash containing 4.5% by weight of nano-hydroxyapatite, citrate and soluble calcium

Using the raw material 3, different proportions of soluble calcium were added.

Formulation 12 is shown in Table 16 below.

Preparation Process

Adding xanthan gum to glycerin and stirring for 10 min; Prepare an aqueous suspension of Nano HAP, add soluble calcium. If the purchased raw material contains proper amount of soluble calcium, this step is omitted. The preparation ratio can be determined according to the water content of the formula and the amount of Nano HAP. The 15% Nano HAP aqueous solution is prepared in this example. .

To the nano-hydroxyapatite suspension prepared in step 2, sorbitol and deionized water were added to ultrasonically and uniformly mixed, and potassium citrate was added, and ultrasonic mixing was continued.

Sodium saccharin was added and stirred well to obtain a suspension of nano hydroxyapatite.

The mixture prepared in the step 1 was added to the suspension of the nano hydroxyapatite prepared in the step 4, and heated to form a gel.

Add surfactant and stir for 10 min.

Add the essence and continue stirring for 30 minutes.

The results of the test for soluble calcium and citrate in the formulations tested for soluble calcium and citrate as described in the present application are shown in Table 17 below.

3.2.2 Mouthwash formulation containing 2.25 wt% nano hydroxyapatite, citrate and soluble calcium

Using the raw material 3, different proportions of soluble calcium were added.

The formulation is shown in Table 18 below.

The preparation process is the same as the preparation process of 3.4.1.

The results for the test of soluble calcium and citrate in the formulations according to the method for testing soluble calcium and citrate described in the present application are shown in Table 19 below.

3.2.3 A mouthwash formulation containing 1.5 wt% of nano hydroxyapatite, citrate and soluble calcium.

Use raw material 3 and add different proportions of soluble calcium

Formulation 17 is shown in Table 20 below.

The preparation process is the same as the 3.2.1 preparation process.

Tested for the method of testing soluble calcium and citrate as described in this application The soluble calcium and citrate results in the formulation are shown in Table 21 below.

3.2.4 Mouthwash formula containing 0.75 wt% nano hydroxyapatite, citrate and soluble calcium

Using the raw material 3, different proportions of soluble calcium were added.

Formulation 18 is shown in Table 22 below.

The preparation process is the same as the 3.2.1 preparation process.

The results for the test of soluble calcium and citrate in the formulations according to the method for testing soluble calcium and citrate described in this application are shown in Table 23 below.

3.2.5 efficacy test

(1) Mouthwash prepared by the process described in 3.2.1-3.2.4, model A was used for the soaking experiment, and model A was soaked in mouthwash for 10 min, then rinsed, dried, and observed under a scanning electron microscope.

(2) Model B was immersed in mouthwash for 40 min, then rinsed, dried, and observed under a scanning electron microscope.

Efficacy tests were performed using Model A and Model B, and the results are shown in Table 24 below.

Example 4: Clinical Trial of Oral Care Compositions

A 2-week, double-blind, parallel, randomized, controlled clinical trial study was completed at the Clinical Laboratory Center to further confirm the effectiveness of the present invention in the actual application process. Forty subjects were selected according to the following inclusion criteria and randomly assigned to the test group and the control group, with 20 subjects in each group. Subjects were healthy adult males and females who met inclusion and exclusion criteria.

4.1 Test design

This clinical trial used a random, double-blind, parallel design.

Baseline visits were performed on subjects, assessed for eligibility based on inclusion/exclusion criteria, oral soft tissue (OST) examination, and tooth sensitivity (tap evaluation (Yeaple probe) and steam evaluation (Schiff sensitivity score and visual analogy) Ruler (VAS).

The subjects of the test group used the toothpaste of Formulation 1 of the Example 3.1.1 of the present invention (test toothpaste), and the subjects of the control group used the control toothpaste, which was a placebo formulation, and replaced the formulation of Example 3.1 with water of the same quality. Nano HAP.

Subjects brushed their teeth twice a day with the toothpaste and toothbrush provided by the test, each time the toothpaste packed the entire toothbrush head and brushed for 1 minute. After 7 days of use, subjects completed oral soft tissue (OST) examination, cold air blowing sensitivity assessment, and touch sensitivity assessment.

4.2 Evaluation method of efficacy

The efficacy evaluation was based on the sensitivity evaluation of cold air blowing and the sensitivity evaluation method of touch pressure. Considering the mechanism of nano-hydroxyapatite treatment of dentin sensitivity, this test uses cold air blowing sensitivity evaluation as the main evaluation index, and touch sensitivity evaluation as the secondary evaluation index.

4.2.1 Sensitivity evaluation of cold air blowing

The air gun using the dental unit is sprayed for 1 second at a distance of 1 cm from the sensitive teeth. The air compressor pressure is 60 p.si (±5 p.si), the air temperature is 19-21 ° C, and the finger is placed when blowing. Adjacent teeth to avoid affecting the accuracy of the results. Using the Schiff cold air sensitivity index, the scores were as follows: 0 = teeth and subjects did not respond to air stimuli; 1 = teeth and subjects responded to air stimuli, but did not request discontinuation of stimulation; 2 = teeth and subjects respond to air stimuli, request to stop stimulation or remove stimuli; 3 = teeth and subjects respond to air stimuli, stimuli cause pain, request to stop.

The lower the Schiff cold air sensitivity index score, the lower the sensitivity level of dentin.

4.2.2 Touch sensitivity evaluation

Use a calibrated Yeaple electronic pressure sensitive probe. The instrument can quantitatively measure the pressure (grams) applied to the tooth surface. When testing for sensitivity, the probe contacts the dentin exposed to the buccal surface of the selected tooth and is placed at the enamel dentin junction. The initial setting of 10 grams of probing power, followed by an increase of 10 grams of force each time until the subject showed an uncomfortable feeling, the maximum probing power was 80 grams. The higher the value of the probing power, the lower the sensitivity level of dentin.

4.3 Test results and analysis

One-way analysis of variance (ANOVA) and t-test were performed on the data obtained in this study using SPSS statistical software. The two-sided test was used and the test level α was 0.05.

4.3.1 Cold air blowing sensitive results

The baseline of the subjects enrolled in the study and the cold air blown sensitivity assessment scores after 1 week of treatment are shown in Table 25. As can be seen from Table 25, the average of the air-stimulation sensitivity scores of the subjects in the test group after using the test toothpaste for one week was 0.6, and that of the control group was 1.75. Compared with baseline, the reduction was 54.1% and 23.9%, respectively, and there were significant differences in the group (P<0.05). After 1 week of use, the sensitivity of the test group to the control group was reduced by 44.3%, with a significant difference (P < 0.05).

4.4.2 Touch Sensitive Results

See Table 26 for the baseline of the subjects in this study and the ones after 1 week of treatment. As can be seen from Table 26, the average value of the touch sensitive score after using the test toothpaste for one week was 25.75 g, and that of the control group was 19.25 g. Compared with baseline, the difference was 134% and 71%, respectively, and there were significant differences in the group (P<0.05). After one week of use, the test group increased by 33.76% compared with the control group, with a significant difference (P<0.05).

⁴ The t-test of the baseline corrected mean (two-sample equal variance hypothesis) compares the significant differences.

4.4.3 Analysis of sensitive evaluation results

From the above-mentioned cold air blowing sensitivity evaluation and touch sensitivity evaluation results, the sensitivity level of the dentin of the test group was significantly lower than that of the control group after one week of brushing with the test toothpaste (p<0.05), indicating that the sensitivity level of the test group was significantly lower than that of the control group (p<0.05). Test toothpaste has superior desensitization efficacy.

Example 5: Study on the entry of hydroxy hydroxyapatite into dentinal tubules by citrate and soluble calcium

It can be seen from the foregoing examples that the simultaneous addition of citrate and soluble calcium can promote the entry of nano-hydroxyapatite into the dentinal tubules, thereby enhancing the effect of sealing the dentinal tubules. In order to investigate whether citrate alone, soluble calcium alone, or citrate and soluble calcium together promote nano-hydroxyapatite into dentinal tubules, the inventors conducted the following experiment.

5.1 The role of citrate

Feedstock 1: Approximately 15% aqueous solution of Nano HAP from Portugal, wherein the nano-hydroxyapatite was 15% by weight and the soluble calcium concentration was about 1053 ppm.

NanoXIM was diluted 6.67 times with deionized water, ie, the weight percentage of nano-hydroxyapatite was 2.25%, and the soluble calcium concentration was 157.87 ppm. Whether the nano-hydroxyapatite enters the dentinal tubules when the presence of citrate is added. The results are shown in Table 27.

As can be seen from Table 27, when only soluble calcium is present and citrate is absent, the nano-hydroxyapatite cannot enter the dentinal tubules.

5.1.1 Effect of different citrate ratios

Using the raw material 1, adding different amounts of potassium citrate, to see if the nano-hydroxyapatite can enter the dentinal tubules, the results are shown in Table 28.

It can be seen that citrate acts in a wide range of ratios, but citrate If the amount is too much or the amount of citrate is too small to enter the dentinal tubule, it is considered that the proportional relationship between citrate and soluble calcium plays a certain range.

5.2 The role of soluble calcium

Raw material 1:15% Nano HAP solution containing 1053 ppm of unreacted soluble calcium. The raw material was commercialized and purchased from Fluidinova, Portugal.

Raw material 2: Nano HAP dry powder was prepared into a 15% aqueous solution of Nano HAP, and its soluble calcium was measured to be about 4 ppm, which was decomposed by Nano HAP and negligible. The raw materials were purchased from Shanghai Zilin Biotechnology Company.

Raw material 3: 15% Nano HAP solution, the synthesis process is the same as raw material 1, but after repeated centrifugation to remove most of the unreacted soluble calcium, the soluble calcium in the raw material is about 43ppm. The raw material is commercialized and purchased from Fluidinova, Portugal.

The three raw materials were all formulated into a paste having a weight percentage of nano-hydroxyapatite of 15% and different soluble calcium concentrations. The weight percentage and soluble calcium concentration of nano-hydroxyapatite in each paste are shown in Table 29 (soluble calcium is a test value).

Dilute the three aqueous solutions prepared above and add potassium citrate with the same weight percentage to see if it can enter the dentinal tubules. The results are shown in Table 30.

Table 30. Cases of nano-hydroxyapatite entering dentinal tubules after addition of potassium citrate with the same weight percentage

As can be seen from Table 30, the weight percentages of nano-hydroxyapatite and potassium citrate in each paste were the same, and the soluble calcium concentrations were different. With the increase of soluble calcium concentration, nano-hydroxyapatite is more likely to enter the dentinal tubules. When the soluble calcium concentration is very low, for example 4 ppm, the nano-hydroxyapatite cannot enter the dentinal tubules even if citrate is present at the same time. This suggests that soluble calcium is essential for nano-hydroxyapatite to enter the dentinal tubules.

Experiments in 5.1 and 5.2 show that citrate and soluble calcium are important conditions for nano-hydroxyapatite to enter dentinal tubules. Neither alone can promote nano-hydroxyapatite into dentinal tubules. Only when citrate, soluble calcium and nano-hydroxyapatite interact, it will promote the entry of nano-hydroxyapatite into the dentinal tubules, and then block the dentinal tubules.

To investigate the relationship between soluble calcium concentration and nano-hydroxyapatite into dentinal tubules, the following experiment was carried out to determine the weight percentage of nano-hydroxyapatite and citrate, and to change the soluble calcium concentration, so as to find the nano-hydroxyl group. The preferred soluble calcium concentration of apatite into the dentinal tubules.

5.3 Relationship between soluble calcium concentration and nano-hydroxyapatite into dentinal tubules

Using raw material 3, add different concentrations of soluble calcium to the raw materials, and view the nanometer. Whether hydroxyapatite can enter the dentinal tubules, the results are shown in Table 31.

As can be seen from Table 31, nano-hydroxyapatite is more likely to enter the dentinal tubules as the concentration of soluble calcium increases. Among them, nano-hydroxyapatite is most likely to enter the dentinal tubule when the soluble calcium concentration is 87.88ppm-395.80ppm. When the soluble calcium concentration is too low (for example, less than 7.34 ppm) or too high (for example, higher than 739 ppm), the nano-hydroxyapatite cannot enter the dentinal tubules.

Example 6: Preparation of a suspension of nano hydroxyapatite, other polycarboxy compounds and soluble calcium

6.1 Experimental steps

Suspensions 3-I, 3-II, 3-III, 3-IV, 3-V were prepared according to the different ratios in Table 32 below. The Nano HAP used was Nano HAP, 2-phosphonic acid shown in Figure 1. The butane-1,2,4-tricarboxylic acid tetrasodium (PBTCA.Na4) requires the pH to be adjusted to 8.0 with NaOH. The model B obtained by treating the suspensions of 3-I, 3-II, 3-III, 3-IV, and 3-V, respectively, was observed under a scanning electron microscope.

6.2 Analysis of experimental results

The ratio of the weight percent of soluble calcium to the weight percent of polycarboxyl material (calculated) is shown in Table 33 below:

The results of using the Model B power test are shown in the following table:

While the invention has been described in terms of various aspects and embodiments, various modifications and changes may be made by those skilled in the art without departing from the spirit and scope of the invention. The various aspects and embodiments of the present disclosure are intended to be illustrative only, and are not intended to limit the scope of the application.

Claims (40)

An oral care composition comprising hydroxyapatite, a polycarboxy compound, soluble calcium, and an orally acceptable carrier. The oral care composition of claim 1, wherein the hydroxyapatite in the oral care composition is capable of entering a dentinal tubule. The oral care composition of claim 2, wherein the hydroxyapatite is capable of entering the dentinal tubules at least about 5 microns deep. The oral care composition of claim 1, wherein the polycarboxy compound is selected from the group consisting of citrate, polyaspartate, iminodisuccinate, 2-phosphonate Butane-1,2,4-tricarboxylate, polyacrylate. The oral care composition of any one of claims 1 to 4, wherein the soluble calcium concentration (ppm) ranges from about 7.34 ppm to about 800 ppm. The oral care composition according to any one of claims 1 to 4, wherein the molar concentration of the soluble calcium (mol/L): the molar concentration of the carboxylate in the polycarboxy compound (mol/L) The ratio ranges from about 0.00178 to about 0.361. The oral care composition of any one of claims 1 to 4 wherein: 1) the weight percentage (w/w) of hydroxyapatite in the composition ranges from about 0.01% to about 50%; 2) the weight percentage (w/w) of the polycarboxylate in the composition ranges from about 0.001% to about 30%, and 3) Molar concentration (mol/L) of carboxylate in the polycarboxy compound: The molar concentration (mol/L) of the hydroxyapatite molecule ranges from about 1.238 to about 99.041. The oral care composition of claim 7, wherein the hydroxyapatite has a weight percentage (w/w) ranging from about 0.1% to about 20%. The oral care composition of claim 7, wherein the polycarboxylate in the polycarboxy compound has a weight percent (w/w) in the oral care composition ranging from about 0.01% to about 12%. . The oral care composition of claim 9, wherein the polycarboxylate in the polycarboxy compound has a weight percent (w/w) in the oral care composition of from about 0.0874% to about 6.995%. The oral care composition of claim 1, wherein the orally acceptable carrier comprises one or more of a thickening agent, a rubbing agent, a surfactant, and a flavoring agent. The oral care composition of claim 1 further comprising one or more active ingredients. The oral care composition of claim 12, wherein the active ingredient comprises an anti-caries agent, an anti-allergic agent, and/or an antibacterial agent. The oral care composition of claim 13, wherein the anti-caries agent comprises a source of fluoride ions. The oral care composition of claim 13, wherein the anti-allergic agent comprises a source of potassium ions. The oral care composition of claim 1, which is a toothpaste, gel or mouthwash. A method of preparing an oral care composition according to any one of claims 1 to 16, which comprises mixing a polycarboxy compound, hydroxyapatite, soluble calcium with an orally acceptable carrier. An aqueous mixture comprising hydroxyapatite, a polycarboxy compound, and soluble calcium. The aqueous mixed solution according to claim 18, wherein the molar concentration of the soluble calcium (mol/L): the molar concentration (mol/L) of the carboxylate in the polycarboxy compound ranges from about 0.00178 - about 0.361. The aqueous mixed solution according to claim 18, wherein the molar concentration (mol/L) of the carboxylate in the polycarboxy compound: the molar concentration (mol/L) of the hydroxyapatite molecule ranges from about 1.238 to about 99.041. The aqueous mixture according to any one of claims 18 to 20, wherein in the aqueous mixture, the hydroxyapatite has a particle size ranging from about 10 nm to about 100 nm. The aqueous mixture of claim 18, wherein the aqueous mixture has a pH of from about 7 to about 14. The aqueous mixture according to claim 18, which further comprises a metal ion. The mixed solution of claim 23, wherein the metal ion is capable of interacting with a carboxyl group in the polycarboxy compound. The mixed solution of claim 24, wherein the metal ion comprises copper ions, zinc ions, silver ions or any combination thereof. A method of preparing an oral care composition according to any one of claims 1 to 16, which comprises mixing the aqueous mixture of claims 18 to 25 with an orally acceptable carrier. A method of filling a dentinal tubule comprising contacting the dentin with an oral care composition according to any one of claims 1-16 to allow the hydroxyapatite to enter a dentinal tubule. The method of claim 27, wherein the oral care composition is a toothpaste, the method comprising brushing the toothpaste to allow the hydroxyapatite to enter a dentinal tubule. The method of claim 27, wherein the oral care composition is a gel, the method comprising brushing with the gel, or contacting the tooth with the gel to allow the hydroxyphosphorus Graystone enters the dentin tubules. The method of claim 27, wherein the oral care composition is a mouthwash, the method comprising contacting the teeth with the mouthwash to allow the hydroxyapatite to enter the dentin tubules. A dental material having dentinal tubules, wherein the dentin tubules are filled with hydroxyapatite. The dental material of claim 31, wherein the dental material is a tooth. The dental material of any one of claims 31 to 32, wherein the hydroxyapatite has a filling depth in the dental tubule of at least about 5 microns, at least about 10 microns, at least about 20 microns, At least about 30 microns, at least about 40 microns, at least about 50 microns, at least about 60 microns, or at least about 70 microns. The dental material of claim 31, wherein the dental tubules have a diameter of from about 1 micron to about 4 microns. The use of an aqueous mixture comprising hydroxyapatite, a polycarboxy compound and soluble calcium according to any one of claims 18 to 25 in the preparation of an oral care composition for alleviating or preventing tooth sensitivity. Use of an aqueous mixture comprising hydroxyapatite, polycarboxyl compound and soluble calcium according to any one of claims 18-25, in the preparation of an oral care composition for filling dentinal tubules in teeth . A method for preparing an aqueous mixture comprising hydroxyapatite, a polycarboxy compound and soluble calcium according to any one of claims 18 to 25, which comprises a polycarboxy compound, hydroxyapatite and soluble calcium Mix in an aqueous solution. The method of claim 37, wherein the polycarboxy compound is selected from the group consisting of citrate, polyaspartate, iminodisuccinate, 2-phosphonobutane- 1,2,4-tricarboxylate, polyacrylate. A composition comprising hydroxyapatite, a polycarboxy compound, and soluble calcium. The composition according to claim 39, which is characterized in that, after being dispersed in water, an aqueous mixed liquid according to any one of claims 18 to 25 is formed.