Stabilized amorphous calcium magnesium phosphate particle composition

Abstract

The present invention relates to a particle composition comprising XRD amorphous calcium magnesium phosphate particles and a method for producing the same. The XRD amorphous calcium magnesium phosphate particles are spherical particles with a hollow core. A paste containing the particles can be used in dental products such as toothpaste to treat dentin hypersensitivity by mineralizing and sealing exposed dentinal tubules.

Description

Technical Field

[0001] The present invention relates to spherical and hollow calcium magnesium phosphate particles, compositions containing such particles, and methods for preparing such particles and compositions. Such particles and compositions containing the same can be used, for example, for toothpastes, and can be used for the treatment of hypersensitive teeth, particularly by increasing the calcification in the deep part of the dentinal tubules.

Background Art

[0002] Dentin hypersensitivity is a widespread clinically relevant problem, characterized by sharp, sudden pain that occurs as a reaction to external thermal, mechanical, osmotic or evaporative stimuli. Hypersensitivity can occur when the protective covering of dentin is lost due to enamel loss, or when cementum is exposed due to gingival recession and the dentinal tubules are opened to the oral environment. Enamel loss can occur as a result of abrasion, erosion or abfraction. Gingival recession occurs frequently with aging, but can also occur in younger individuals, for example, due to aggressive toothbrushing, pocket reduction surgery, excessive interdental cleaning, or secondary reactions to periodontal disease.

[0003] Amorphous calcium phosphate (ACP) is a metastable phase without long-range crystalline order and thus is more soluble than crystalline calcium phosphates such as hydroxyapatite (HA) and tricalcium phosphate (TCP). Because of its high solubility, ACP more readily releases biologically available calcium and phosphate ions into the local environment, making it more bioactive. ACP has been shown to act as a precursor to tooth apatite and play an important role in natural calcification. As a result, the development of synthetic ACP for biomedical applications has become an interesting research field, but few successful processes have been reported due to its inherent metastability and subsequent limitations in handling and product formulation. Therefore, many commercial products rely on in-situ precipitated ACP, such as supplying calcium salts and phosphates in a dual-barrel manner immediately before application to the tooth surface.

[0004] To utilize synthetic ACP for biomedical applications, it is necessary to stabilize or formulate it early so that it does not crystallize prematurely and lose some of its bioactive properties. Stabilization of ACP can be achieved, for example, by Mg substitution or by the use of casein phosphopeptides (CPP) derived from milk.

[0005] WO2014 / 148997A1 (WO’997) discloses crystalline calcium phosphate particles essentially free of strontium for use in the treatment of exposed dental tubules. However, those particles have low solubility and thus will not act as a source of calcium and phosphate ions very readily.

[0006] CN107619031A discloses a method for preparing calcium phosphate and magnesium phosphate spherical particles, including using lake water or seawater as a source of calcium and magnesium ions.

[0007] There is a need for ACP particles that remain stable in the amorphous state during storage, and compositions containing such stable ACP particles. Another need in this field is for stabilized ACP particles that have a controlled morphology, are free of potential allergens, and can also be manufactured on a large scale. Summary of the Invention

[0008] The present invention aims to solve the problems of the prior art by providing a composition for stabilizing ACP particles, as well as a scalable and controlled continuous manufacturing process for forming such particles and compositions. By directly stabilizing the particles in the manufacturing process using a paste-forming compound, the stability and storage of the particles can be improved, and the formulation of particle-containing products can be facilitated. Also, the risk of particle aggregation can be reduced (failure to do so may cause non-uniformity of the particle formulation and may reduce the ability of the particles to penetrate the dentinal tubules). Further, by directly forming the composition instead of drying, grinding and sieving to form a fine powder, concerns about the safety of airborne particles due to product handling are minimized.

[0009] The average diameter of the dentinal tubules is about 2 μm, and the present invention provides particles of an appropriate size that can more easily penetrate the dentinal tubules, exhibit appropriate affinity with dentin, and enable higher ion release as a result of the amorphous state of the particles. Thereby, the calcification of the dentinal tubules is promoted, and the exposed dentinal tubules can be treated more efficiently. Furthermore, by using the particles according to the present invention for calcifying the dentinal tubules, a surface that is more resistant to abrasion and acid etching can be provided. The present invention can be easily applied to the treatment site by forming a particle-containing product formulation, such as a toothpaste, a desensitizing gel, a varnish or a sealant. The method according to the present invention for preparing the particles facilitates the preparation of the particles and the composition in a controlled manner having reproducible results at various manufacturing output scales, and the method can be carried out in a continuous manner.

[0010] In a first aspect, the present invention relates to a composition comprising a paste-forming compound and XRD amorphous calcium magnesium phosphate spherical particles having a hollow core and a shell, wherein the particles are XRD amorphous, the shell of the particles contains 15-30 wt% calcium, 50-70 wt% phosphate, 5-11 wt% magnesium, and 1-20 wt% bound water, the Ca / P molar ratio is in the range of 0.70-1.20, the (Ca+Mg) / P molar ratio is in the range of 1.00-1.70, the particles have an average particle size in the range of 100-500 nm, and the amount of particles in the composition is 25-50 wt%.

[0011] In a second aspect, the present invention relates to a method for preparing a composition, the method comprising a. providing a first aqueous solution having a pH of 6-10 and a first temperature, the first aqueous solution containing dihydrogen phosphate ions and / or hydrogen phosphate ions and preferably one or more counterions selected from sodium and / or potassium, b. providing a second aqueous solution having a second temperature, the second aqueous solution containing calcium ions and magnesium ions and preferably one or more counterions selected from chloride, sodium and / or potassium, the amount of calcium being in molar excess of magnesium, c. heating the first aqueous solution, the second aqueous solution, or both the first and second aqueous solutions to the first and second elevated temperatures, respectively, d. contacting the first and second aqueous solutions with each other to give a third aqueous solution having a third temperature, the amount of phosphate in the third aqueous solution being in molar excess of the total amount of calcium and magnesium, e. enabling the formation of particles, f. collecting the formed particles, g. optionally, washing the separated particles using a suitable solvent, h. Optionally, a step of dehydrating the washed particles at a fifth temperature until a slurry containing 70 to 95% by weight, preferably 75 to 85% by weight of free water is obtained; i. A step of mixing the spherical particles with a paste-forming compound, wherein the amount of particles in the composition is 25 to 50% by weight; j. A step of dehydrating the mixture of the spherical particles and the paste-forming compound at a seventh temperature; k. Optionally, a step of homogenizing the mixture of the spherical particles and the paste-forming compound to obtain a composition.

[0012] In a third aspect, the present invention relates to the use of the composition according to the present invention as a component in toothpaste, desensitizing gel, bleaching paste, dental varnish, dental prophylactic paste, pit and fissure sealant, dental filling material, capping material, mouthwash, interdental cleaner, chewing gum, implant, bone graft material, bone void filler.

[0013] In a fourth aspect, the present invention relates to a toothpaste, desensitizing gel, bleaching paste, sealant, dental varnish or dental prophylactic paste containing the composition according to the present invention, wherein the amount of particles is 0.5 to 15% by weight.

[0014] In a fifth aspect, the present invention relates to a bleaching paste containing the composition according to the present invention and carbamide peroxide, wherein the amount of particles is 3 to 10% by weight and the amount of carbamide peroxide is 10 to 20% by weight.

[0015] All embodiments disclosed herein relate to all aspects of the present invention, and all embodiments can be combined unless otherwise specified.

Brief Description of the Drawings

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Mode for Carrying Out the Invention

[0017] In the present application, the term "average particle size" corresponds to the average particle size of individual particles and fused particles forming small clusters. The average particle size is determined using dynamic light scattering (DLS).

[0018] In the present application, the term "stable" refers to being stable with respect to physical properties such as chemical composition, and / or particle morphology, and / or crystallinity, and / or average particle size, and / or particle surface area, and / or viscosity regarding the composition. For this reason, a stable particle or a stable composition may mean that the composition or the particles remain essentially the same during storage for a long period of 12 months or more.

[0019] In the present application, the term "X-ray diffraction (XRD) amorphous" refers to a material or particle lacking long-range crystalline order. The crystallinity or XRD amorphous state of the particles is determined by powder X-ray diffraction scanning 2θ from 7 to 60° with a step size of about 0.02° using Cu-Kα (λ = 1.5406 Å). Crystalline materials reflect X-rays according to the arrangement of their crystal planes, generating a pattern of distinguishable sharp peaks, while XRD amorphous materials generate only a single broad diffused peak. For this reason, in the present application, when the generated pattern lacks distinguishable sharp peaks and is characterized only by a broad diffused peak, the particles are classified as XRD amorphous.

[0020] In the present application, the term "bound water" corresponds to the water of hydration associated with amorphous calcium magnesium phosphate particles. This bound water is part of the chemical formula of the particles, i.e., the particles have the chemical formula Ca w Mg x H y (PO 4 ) z ·nH 2 O. The term "free water" indicates residual or excess water that is not part of the chemical formula of the particles. Free water may be, for example, part of the composition according to the present invention, or alternatively, water used in the process of forming ACP particles and / or the composition.

[0021] The object of the present invention is to provide particles, compositions, and particulate-containing product formulations that promote rapid and efficient calcification of dental tubules. The purpose of the particles is not only to mechanically block or fill the gaps in the dental tubules, but also to calcify the tubules. For this reason, without being bound by theory, it is believed that the particles need to be in an amorphous state when delivered to the treatment site in order to rapidly and efficiently release calcium ions and phosphate ions, resulting in local supersaturation and subsequent precipitation of hydroxyapatite-like minerals. Thus, the object includes providing particles that are stable during storage, particularly with respect to crystallinity. The inventors have shown that the present invention provides a much faster sealing of dental tubules compared to the more crystalline calcium phosphate particles of WO2014 / 148997A1 (Example 20).

[0022] The particles of the present invention are spherical particles having a hollow core and a shell, as shown in FIG. 1. The shell is preferably porous in order to more rapidly release ions from the particle itself and substances carried within the hollow core of the particle. The diameter of the pores is preferably on the order of 1 to 30 nm. Since the particles are XRD amorphous, as shown in FIG. 2, they dissolve more easily and release ions, which is involved in the remineralization of dental tubules. In a preferred embodiment, the particles are essentially long-range amorphous, but may have a degree of crystallinity that is short-range (nano) crystalline, for example, resolvable by high-resolution transmission electron microscopy (HRTEM). Without being bound by theory, spherical particles having an average particle size in the range of 100 to 500 nm are considered to penetrate more deeply and easily into dental tubules than, for example, larger spherical particles or particles in the shape of rods or flakes. Furthermore, the X-ray amorphous characteristics of the particles are believed to be the result of magnesium substitution, bound water, and the method of formation of the present particles.

[0023] Calcium, phosphate, and magnesium are the main components of the particles or the shell of the particles. The shell of the particles contains 15 - 30 wt% calcium, 50 - 70 wt% phosphate, 5 - 11 wt% magnesium, and 1 - 20 wt% bound water, with the Ca / P molar ratio in the range of 0.70 - 1.20 and the (Ca + Mg) / P molar ratio in the range of 1.00 - 1.70. Magnesium replaces calcium in the calcium phosphate crystal structure. For the particles to form a good composition or formulation and to penetrate into the dentinal tubules with a diameter of about 2 μm, the particles have an average particle size in the range of 100 - 500 nm.

[0024] The particles are preferably not too small such that they have too high buoyancy and dissolve too fast, nor too large such that they cannot penetrate deeply into the dentinal tubules, and preferably have a narrow size distribution (see Figure 3). An advantage of the present invention is that the particles of the composition do not aggregate into larger clusters. In a preferred embodiment, the average particle size is 150 - 450 nm, more preferably 250 - 350 nm. The content or composition of the particles or the shell of the particles can vary. For example, the amount of bound water or the degree of hydration depends on the drying process when preparing the particles or the composition. In a preferred embodiment, the amount of bound water is 12 - 16 wt%. By having bound water in the particles, the ability of the particles to crystallize is suppressed, and instead the particles are thought to remain amorphous.

[0025] Preferably, the calcium content in the particles is 18 wt% or more, or 20 wt% or more, but preferably 25 wt% or less, more preferably 23 wt% or less, and even more preferably 22 wt% or less. Preferably, the phosphate (PO 4)The content is 55% by weight or more, more preferably 58% by weight or more, but preferably 65% by weight or less, more preferably 62% by weight or less. Preferably, the magnesium content in the particles is 6% by weight or more, or preferably 7% by weight or more, but preferably 9% by weight or less, more preferably 8% by weight or less. For the particles to be XRD amorphous, the degree of magnesium substitution of calcium needs to be sufficiently high, preferably at least 20 mol%, more preferably 25 - 50 mol%, even more preferably 30 - 35 mol%.

[0026] Since the recalcification process depends partly on the presence of ions such as calcium, magnesium, and phosphate, the ratio of these ions in the particles is important. Preferably, the Ca / P molar ratio is 0.8 or more, more preferably 0.9 or more, preferably 1.1 or less, more preferably 1.0 or less. Preferably, the (Ca + Mg) / P molar ratio is 1.2 or more, more preferably 1.3 or more, preferably 1.5 or less, more preferably 1.4 or less.

[0027] In a preferred embodiment, the content of the shell of the particles contains 21 - 24% by weight of calcium, preferably 22 - 23% by weight, 56 - 60% by weight of phosphate, preferably 58 - 59% by weight, 5 - 8% by weight of magnesium, preferably 6 - 7% by weight, and 12 - 16% by weight of bound water, preferably 13 - 15% by weight. The Ca / P ratio is 0.8 - 1.1, preferably 0.9 - 1.0, and the (Ca + Mg) / P ratio is 1.2 - 1.5, preferably 1.3 - 1.4.

[0028] In another preferred embodiment, the content of the shell of the particles contains 20 - 26% by weight of calcium, 52 - 64% by weight of phosphate, 5 - 9% by weight of magnesium, and 12 - 16% by weight of bound water, the Ca / P ratio is 0.80 - 1.00, and the (Ca + Mg) / P ratio is 1.15 - 1.45.

[0029] The particles of the present invention can further contain other ions such as sodium, potassium, silicon, zinc, and fluoride. Preferably, the content of the above ions is 0.1 to 3% by weight, preferably less than 2% by weight, more preferably less than 1% by weight. In one embodiment, the particles contain one or more of sodium, potassium, and fluoride. The particles preferably do not contain or are essentially free of strontium.

[0030] The average surface area determined by the Brunauer-Emmett-Teller (BET) method using nitrogen gas is preferably 10 to 40 m 2 / g, more preferably 15 to 35 m 2 / g, still more preferably 20 to 30 m 2 / g. When the surface area is large, the dissolution of the particles is accelerated, but it is desirable that the particles do not dissolve before application and before entering the dentinal tubules.

[0031] The inventors have shown that the particles of the present invention cause an increase in pH during dissolution in an aqueous medium and promote the nucleation and growth of hydroxyapatite mineral on the dentin surface and inside the exposed dentinal tubules (see Example 18). This is advantageous because the particles dissolve in saliva or dentin fluid during use, thereby presumably promoting the nucleation and growth of hydroxyapatite mineral.

[0032] For the particles to be remineralization efficient, they need to be stable, especially in their XRD amorphous state. It is preferred that the particles remain XRD amorphous during storage for at least 24 months, i.e., have a storage life of at least 24 months. In this way, it is possible to manufacture the particles at one site and deliver them for product formulation at another site without degrading the remineralization properties. Another advantage of particles remaining XRD amorphous is that they can be stored for a certain period before use, thus eliminating the need to use them directly during manufacture.

[0033] Even if the amount of free water is reduced, the particles are thought to maintain an XRD amorphous state. This can be achieved, for example, by formulating the particles with a paste-forming compound that is essentially free of water, such as a paste-forming compound of less than 10% by weight, to form a composition. The present invention provides a process for forming such a composition having homogeneously dispersed particles, a limited amount of free water, and stable properties. Such a process for forming the above composition can also be advantageous from the viewpoint of preparing a final product, such as toothpaste, to which the composition can be added. For this reason, it is advantageous that the composition has good fluidity and / or viscosity and can be easily mixed with other components to prepare, for example, toothpaste.

[0034] The particles of the present invention are preferably used or formulated in a composition in the form of a slurry or suspension. In addition to the particles, this composition preferably contains a paste-forming compound selected from among glycerol, triglyceride, polyethylene glycol, propylene glycol, polypropylene glycol, polyvinyl alcohol, mineral oil or liquid paraffin, or a combination thereof. In a preferred embodiment, the paste-forming compound is glycerol. The composition can also contain free water, preferably 10% by weight or less, more preferably 8% by weight or less, and even more preferably 5% by weight or less of the total content of the composition, but preferably 1% by weight or more, more preferably 2% by weight or more, and even more preferably 3% by weight or more of free water.

[0035] Glycerol is a preferred paste-forming compound because it is widely used and generally accepted as a component in pharmaceuticals, cosmetics, and personal care products. It dissolves readily in water, has a high boiling point, and can be selectively retained in the composition during evaporation of excess free water by choosing an appropriate drying temperature in the processes described in the present invention. Furthermore, glycerol is hygroscopic, which is thought to assist in the extraction of free water seen in the vicinity of the particles, thus enhancing the stability of the particles. The affinity of glycerol for water also allows some free water to remain in the composition without significantly impairing its shelf life, thereby facilitating the preparation of a high-particle-content composition with still-preferred viscosity and making the preparation process easier and more economical by having less free water that needs to be removed.

[0036] Amorphous calcium phosphate is a metastable phase that tends to crystallize into more stable forms of calcium phosphate, such as octacalcium phosphate or hydroxyapatite. The amorphous calcium phosphate particles according to the present invention are stabilized by magnesium substitution, but may crystallize over time under ambient conditions depending on temperature and humidity. Compositions having the particles and paste-forming compounds according to the present invention can enable long-term stabilization of the particles.

[0037] The composition or particulate-containing product formulation of the present invention preferably has a very limited amount of free water, such as less than 10% by weight. Some free water associated with glycerol may remain in the composition even after drying. An excess amount of free water can form smaller particles that have a higher tendency to crystallize after the particles are decomposed. This process of particle decomposition and crystallization is essential for the bioactive properties of the particles that result in the calcification and occlusion of dentinal tubules, and thus needs to be preferably preserved until it reaches the treatment site or when it comes into contact with saliva and dentinal fluid in the oral cavity and on the dentin surface. However, a completely water-free composition is also not preferred because it is too concentrated for proper functioning in, for example, toothpaste. By having a small amount of free water in the composition or particulate-containing product formulation, such as less than 10% by weight but more than 1% by weight, the composition can have good fluidity while maintaining the stability of the particles, i.e., maintaining XRD amorphous for 18 months or more. In one embodiment, the amount of free water in the composition is 10% by weight or less of the total content of the composition or formulation, more preferably 8% by weight or less of free water, even more preferably 5% by weight or less of free water, but preferably 1% by weight or more, more preferably 2% by weight or more, even more preferably 3% by weight or more.

[0038] The composition or particulate-containing product formulation can further comprise additives such as fluoride, potassium, hydrogen peroxide or carbamide peroxide, xylitol, xanthan gum, flavor such as menthol, polymer thickeners or preservatives. Fluoride is preferred for strengthening teeth. Potassium is a preferred nerve depolarizer. Hydrogen peroxide and carbamide peroxide are preferred tooth bleaching agents.

[0039] In the composition, the particles are preferably present in an amount or concentration of 1 to 50% by weight. The amount is preferably adjusted such that the viscosity, homogeneity, and handleability of the composition are sufficient and the particles are well dispersed and do not aggregate. The particle concentration in the composition preferably needs to be increased to maximize the value per unit volume, but should not be so high that the viscosity increases to a level that hinders normal handling or homogenization. In a preferred embodiment, the amount of particles in the composition is 25 to 50% by weight. In another preferred embodiment, the amount is 35 to 45% by weight, more preferably about 40% by weight. The amount or concentration of the paste-forming compound is preferably at least 50% by weight, more preferably at least 55% by weight. In a preferred embodiment, the concentration of the paste-forming compound is 55 to 65% by weight, preferably about 60% by weight. In a preferred embodiment, the composition comprises 35 to 45% by weight, preferably about 40% by weight of particles, 50 to 60% by weight, preferably about 55% by weight of glycerol, and 3 to 8% by weight, preferably about 5% by weight of free water.

[0040] The method of forming the composition by mixing and drying the paste-forming compound, the presence of magnesium, and the particles is important for the long-term stability and shelf life of the particles. The inventors have demonstrated that the particles in the composition of the present invention are stable over a long period of time under both ambient and accelerated conditions (see Examples 24 and 25). Ambient conditions refer to room temperature (20 to 25°C), and accelerated conditions refer to 40°C.

[0041] This composition can be used to prepare particulate-containing product formulations such as dental or oral care products. Dental or oral care products such as toothpastes, desensitizing gels, bleaching pastes or gels, dental varnishes, prophylactic pastes or sealants preferably contain from 0.5 to 15% by weight of the particles according to the invention, together with some paste-forming compounds and additives. The concentration of the paste-forming compounds varies between different particulate-containing product formulations in order to provide particulate-containing product formulations with good handling properties such as viscosity, homogeneity and spreadability for different applications. In a preferred embodiment for the desensitizing gel, the concentration of the particles is from 5 to 9% by weight, more preferably from 6 to 8% by weight, even more preferably about 7.5% by weight. The concentration of the paste-forming compounds is preferably from 50 to 90% by weight, more preferably from 60 to 85% by weight, even more preferably from 70 to 80% by weight in order to provide a product with good handling properties such as viscosity, homogeneity and spreadability.

[0042] The long-term stability of the particulate-containing product formulation is important to ensure sufficient product shelf life. For example, it may be important that the appearance of the particles and the consistency of the composition are essentially maintained and that the particles remain XRD amorphous during storage. The inventors have demonstrated that the desensitizing gel containing the particles and additives according to the invention is stable over a long period of time both under ambient conditions and under accelerated conditions (see Examples 26, 27). The desensitizing gel preferably contains from 5 to 9% by weight of particles. In a preferred embodiment, the desensitizing gel contains 6% by weight or more, or 7% by weight or more, but preferably 8% by weight or less, or about 7.5% by weight of particles.

[0043] Toothpastes preferably contain from 0.5 to 6% by weight of particles. In a preferred embodiment, the toothpaste contains 0.5% by weight or more, or 1% by weight or more of particles, but preferably 5% by weight or less, or 4% by weight or less, or 3% by weight or less.

[0044] The varnish, preventive paste or sealant preferably contains 5 to 15% by weight of particles. In a preferred embodiment, the varnish, preventive paste or sealant contains 6% by weight or more, or 8% by weight or more, or 10% by weight or more of particles, but preferably 13% by weight or less, or 11% by weight or less.

[0045] Next, refer to FIGS. 4 and 5 showing the overall method for preparing the spherical and hollow particles according to the present invention. Here, step 1 schematically shows points a - b in the method according to the claims, step 2 shows point c, step 3 shows points d - e, and step 4 shows point f.

[0046] In the first step, a first aqueous solution having a pH of 6 - 10, preferably a pH of 7 - 10, more preferably a pH of 7 - 8 is provided, and this solution has a first temperature. The first aqueous solution contains dihydrogen phosphate ions and / or hydrogen phosphate ions, counter ions, and optionally additional ions. The counter ions are preferably sodium ions and / or potassium ions. The additional ions can be selected from sodium, potassium, chloride, silicon, zinc and fluoride, or combinations thereof. The H 2 PO 4 :HPO 4 molar ratio is preferably in the range of 0 - 100:75 - 600, more preferably in the range of 1 - 2:4 - 6. In a preferred embodiment, the concentration of dihydrogen phosphate is 0 - 100 mM, more preferably 20 - 80 mM. Hydrogen phosphate preferably has a concentration in the first aqueous solution of 30 - 300 mM, more preferably 80 - 250 mM. The total concentration of phosphate in the first aqueous solution is preferably 60 - 800 mM.

[0047] A second aqueous solution having a second temperature is also provided, and this second aqueous solution contains calcium and magnesium ions, counterions, and optionally additional ions. The counterions are preferably chloride ions, sodium ions and / or potassium ions. The additional ions can be selected from sodium, potassium, chloride, silicon, zinc and fluoride, or combinations thereof. The concentration of calcium in the second aqueous solution is preferably 10 to 200 mM, and the concentration of magnesium is preferably 5 to 120 mM. In a preferred embodiment, the calcium concentration is 20 to 100 mM, more preferably 30 to 70 mM. In another preferred embodiment, the magnesium content is 10 to 60 mM, more preferably 12 to 40 mM. Calcium is preferably in molar excess over magnesium in the second aqueous solution. The molar ratio of calcium to magnesium is preferably 4:1 to 1.05:1, more preferably 2:1 to 4:3, or more preferably about 5:3.

[0048] In a preferred embodiment, the amount of phosphate in the first aqueous solution is in molar excess relative to the total amount of calcium and magnesium in the second aqueous solution. In a preferred embodiment, the molar ratio of phosphate to calcium and magnesium (PO 4 :(Ca + Mg)) is 1.5:1 or more, preferably 2:1 or more. In another preferred embodiment, the molar ratio is 2:1 to 6:1, or more preferably 2.2:1 to 5:1.

[0049] The first aqueous solution and the second aqueous solution each preferably have a first temperature and a second temperature of 10 to 35 °C, more preferably 20 to 30 °C, and more preferably 20 to 25 °C. The water of the first aqueous solution and the second aqueous solution may be tap water, or preferably purified water, more preferably deionized water, distilled water, double-distilled water or ultrapure water. Although the present invention is described as using two aqueous solutions, the first aqueous solution and the second aqueous solution, those skilled in the art will understand that in practice the first aqueous solution and the second aqueous solution may each be two or more aqueous solutions or sub-solutions.

[0050] Thereafter, at least one of the two aqueous solutions, the first and / or the second aqueous solution, is heated to the first and second temperature increase temperatures, respectively. In one embodiment, both the first aqueous solution and the second aqueous solution are heated to the first and second temperature increase temperatures, respectively. In FIG. 4 (right side), both aqueous solutions are heated using a heat exchanger, but any suitable heating device can be used. This heating step is not bound by theory but is thought to be important for the formation of nanobubbles (long-lasting gas-containing cavities) in the electrolyte solution. When the two solutions are brought into contact, ions of the two solutions precipitate thereon to form the hollow structure of the particles of the present invention. By heating at least one of the two solutions, an individual temperature increase of preferably at least 40° C., more preferably at least 50° C. occurs. In other words, there is a first / second temperature difference between the first / second temperature and the first / second temperature increase temperature, respectively. In a preferred embodiment, the first temperature difference is 40 to 80° C., preferably 50 to 70° C. In another preferred embodiment, the second temperature difference is 40 to 80° C., preferably 50 to 70° C. And the first and second temperature increase temperatures are each preferably at least 60° C., more preferably 70 to 90° C.

[0051] Thereafter, the two solutions, at least one of which is heated, are brought into contact with each other to form a third aqueous solution having a third temperature (FIG. 5, step 3). This can be done by adding one solution to the other, preferably adding the second solution to the first solution, but preferably the two solutions are brought into contact continuously, preferably in a continuously flowing form. Contacting in a continuously flowing form facilitates more efficient production, allows easy scaling up of the output of the particles formed, and provides better control of the process. In one embodiment, the two solutions (the first aqueous solution and the second aqueous solution) are brought into contact in a manifold or a three-way manifold, preferably a Y-shaped manifold (Y cross-section), as schematically shown in FIG. 5 (left side). When the two solutions are brought into contact with each other, precipitation occurs almost instantaneously (in less than 10 seconds), and this precipitation is continued for an appropriate period depending on both practical constraints and the targeted fine-tuning for the desired properties, but typically it is 1 to 600 seconds. The continuous flow process of mixing the two solutions can continue provided that the starting solutions are replenished, thereby enabling continuous recovery of the particles formed. The amount of phosphate is in molar excess with respect to the total amount of calcium and magnesium when the first solution and the second solution are brought into contact (PO 4 >(Ca + Mg)). Without being bound by theory, the excess phosphate with respect to the total amount of calcium and magnesium in the third aqueous solution increases the buffering capacity and that limits the formation of the crystalline calcium phosphate phase (see Example 12). In a preferred embodiment, the molar ratio of phosphate to calcium and magnesium in the third aqueous solution (PO 4 :(Ca + Mg)) is 1.5:1 or more, preferably 2:1 or more. In another preferred embodiment, the molar ratio is 2:1 to 6:1, more preferably 2.2:1 to 5:1. In a preferred embodiment, in the third aqueous solution, calcium is in molar excess with respect to magnesium. The molar ratio of calcium to magnesium is preferably 4:1 to 1.05:1, more preferably 2:1 to 4:3, or more preferably about 5:3.

[0052] In a preferred embodiment, the third temperature is 70 to 95°C, more preferably 80 to 85°C. This is because the mass yield of the reaction is higher, and the degree of crystallization increases at temperatures exceeding 100°C (see Example 16). When bringing the first aqueous solution into contact with the second aqueous solution, the volume ratio of the first aqueous solution to the second aqueous solution is preferably 2:1 to 1:2, preferably 1.10:1 to 1:1.10, preferably 1:05:1 to 1:1.05, and more preferably 1:1.

[0053] A suspension of the precipitated particles and the aqueous solution is formed, and then the precipitated particles are separated and / or recovered using any suitable technique. Preferably, the separation and / or collection is carried out using suitable filtration techniques, centrifugation and / or sedimentation and decantation. Preferably, the separated and / or collected particles are then washed using any suitable solvent such as water or alcohol. The washing is preferably carried out using purified water, more preferably deionized water, distilled water, double-distilled water or ultrapure water. The washing can preferably be carried out at a fourth temperature of 50 to 90 °C, more preferably 70 to 80 °C. The washing step can be repeated to ensure that the particles are clean and free of unwanted ionic residues. The separated and / or collected and washed particles can then be dehydrated or partially dehydrated, preferably by centrifugation, more preferably under high temperature and / or reduced pressure. In a preferred embodiment, the dehydration / partial dehydration or drying is carried out at a fifth temperature of at least 50 °C, preferably 50 to 150 °C, more preferably 60 to 110 °C, more preferably 60 to 80 °C, or about 80 °C. The dehydration or partial dehydration is preferably carried out until a slurry containing 70 to 90% by weight, more preferably 75 to 85% by weight of free water is obtained. At this stage, the particles are still sufficiently suspended and uniformly dispersed in the slurry, but the slurry can be easily mixed with the paste-forming compound to form a wet composition essentially free of aggregates. Further dehydration of the slurry at this stage or complete drying of the particles results in the formation of larger particle aggregates, in which case it becomes increasingly difficult to mix with the paste-forming compound and suspend uniformly to obtain a smooth and freely flowing composition. The inventors have found that it is essentially impossible to obtain an equally homogeneous, smooth and freely flowing composition when mixing dry or nearly dry separated particles with a paste-forming compound, even when using micronized and sieved powders. Also, avoiding drying and grinding to form fine powders for dispersion in the paste-forming compound or product formulation reduces the health and safety risks associated with powder handling.

[0054] Drying the particles without the presence of the paste-forming compound can unintentionally increase the crystallinity, promote the formation of hard particles that require high energy for dispersion, and potentially expose the integrity of the particles to risk. The stability of the particles according to the present invention is limited when stored as a fine powder under ambient conditions (see Example 30), which further emphasizes the importance of forming the composition using the paste-forming compound already at the manufacturing stage.

[0055] In one embodiment, despite the cited drawbacks, if desired, the formed, separated, and optionally washed and / or dehydrated particles are further dried at a sixth temperature, preferably 50 to 150 °C, more preferably 60 to 110 °C, to form a powder.

[0056] Referring now to Figure 6a, the preparation of the composition of the present invention is schematically shown. The preparation of the composition of the present invention is carried out by preparing the particles according to the present invention and mixing the particles with a paste-forming compound. Mixing the particles with the paste-forming compound is preferably carried out after the particles have been partially dehydrated, i.e., while the particles are still suspended and preferably homogeneously dispersed in a slurry. The slurry before mixing with the paste-forming compound preferably contains 10 to 30% by weight of particles and 70 to 90% by weight of water, more preferably 15 to 25% by weight of particles and 75 to 85% by weight of water. The paste-forming compound is preferably selected from glycerol, triglyceride, polyethylene glycol, propylene glycol, polypropylene glycol, polyvinyl alcohol, mineral oil, or liquid paraffin. In a preferred embodiment, the paste-forming compound is glycerol. In a preferred embodiment, the paste-forming compound is essentially free of water, for example, the water content is less than 10% by weight.

[0057] The composition of the obtained particles, free water, and paste-forming compound is preferably dehydrated to remove as much free water as possible and form a long-term stable and homogeneous composition. In one embodiment, the amount of free water is less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight of water. The presence of a small amount of water in the composition may help to form a smooth and homogeneous composition with an appropriate viscosity. In a preferred embodiment, the amount of free water in the composition is 0.1% by weight or more, or 0.5% by weight or more, or 1% by weight or more, but preferably 8% by weight or less, or 5% by weight or less. The dehydration of the mixture of the obtained spherical and hollow particles and the paste-forming compound is preferably carried out at a seventh temperature and / or under reduced pressure, and the seventh temperature is preferably in the range of 50 to 150 °C, more preferably 60 to 90 °C. Also, the reduced pressure is preferably 500 mbar or less. This mixture is preferably homogenized by mechanical means during and / or after dehydration to form a smooth composition. The obtained mixture can be homogenized using a mechanical homogenization device, such as a rotor-stator type homogenizer, for 1 to 30 minutes. The preparation of the composition is schematically summarized in Figure 6b. As shown, the process includes at least the following three steps. 10:1 A step of partially dehydrating the ACP particles prepared as described above until the particles form a slurry containing 10 to 30% by weight of particles and 70 to 90% by weight of water; 10:2 A step of mixing the particle-containing slurry until it becomes a homogeneous mixture with the paste-forming compound; and 10:3 A step of dehydrating the composition formed in step 10:2 at either the seventh temperature and / or under reduced pressure until the amount of water is 8% by weight or less, or 5% by weight or less, or 2% by weight or less.

[0058] The hygroscopicity of glycerol can impart effective storage capacity to the amorphous calcium magnesium phosphate particles according to the present invention. Advantageously, in a composition containing glycerol, even if it contains excessive free water, the ACP particles may remain XRD amorphous during storage (see Example 28).

[0059] Tooth bleaching or whitening is a common method in modern cosmetic dentistry, typically using hydrogen peroxide or carbamide peroxide to remove stains and enhance the appearance and whiteness of teeth. Currently, various markets allow the application of peroxides of various strengths to whitening products, but a typical formulation for over-the-counter products contains 16% carbamide peroxide corresponding to 5 - 6% hydrogen peroxide. A common side effect of tooth whitening is tooth hypersensitivity, and the treatment may soften the enamel and reduce the strength of the teeth. Therefore, it is a concern to provide effective whitening products and treatment methods that can also reduce tooth hypersensitivity and increase the hardness of the enamel by calcification. Thus, it can be an advantage that the composition according to the present invention does not adversely affect the bleaching process of tooth whitening products, as shown in Example 29.

Examples

[0060] Example 1 According to Step 1 of Figure 4, a first aqueous solution was prepared at a concentration of 125 mM NaCl, 160 mM Na 2 HPO 4 , and 30 mM KH 2 PO 4 (pH 7.4), and a second aqueous solution was prepared at a concentration of 125 mM NaCl, 25 mM CaCl 2 , and 15 mM MgCl 2They were prepared at the concentration of . These two aqueous solutions were separately heated from room temperature to 85 °C via a plate heat exchanger according to Step 2 of Figure 4, and then flow-mixed at a volume ratio of 1:1 according to Step 3 of Figure 5 to form a precipitate at 85 °C. This precipitate was recovered by filtration using a fine-mesh filter cloth according to Step 4 of Figure 5, then washed with deionized water at 70 °C, and then partially dehydrated using a vacuum. A slurry containing about 20 wt% of precipitated particles and 80 wt% of water was mixed with glycerol according to Step 5 of Figure 6 to form a homogeneous mixture with a dry weight ratio of particles to glycerol of 2:3. Then, according to Step 6 of Figure 6, this mixture was dried in a forced convection oven at 80 °C to remove moisture and homogenized by mechanical means to form a smooth and viscous composition. The dry content of the composition was 98 wt%.

[0061] The formed particles were spherical and composed of a porous shell and a hollow interior. The diameter of individual spheres was in the range of 100 - 300 nm, while the formations of clusters and fused spheres were in the range of 200 - 500 nm. Representative scanning electron microscope (SEM) images of those particles are shown in Figure 1.

[0062] As a result of XRD analysis, it was found that those particles were amorphous. There were no characteristic peaks, and only a broad increase in intensity was observed near 2 theta = 30°, which suggests the presence of amorphous calcium phosphate (see Figure 2).

[0063] Elemental analysis of the particles was performed by inductively coupled plasma optical emission spectrometry (ICP-OES). The verified content is shown in Table 1. Assuming that all P exists as PO 4 the calculated values of PO 4 are also shown in the table together with the Ca / P molar ratio and the (Ca + Mg) / P molar ratio. The sum of the measured values of Ca and Mg and the calculated values of PO 4 is 86 wt%, which is the estimated amount of bound H 2 O. Based on the data of this example, the equilibrium chemical formula of the particles is proposed as follows. Ca 2.7Mg 1.3 H(PO 4 ) 3 *4H 2 O TIFF0007689745000001.tif44170

[0064] The particle size distribution was measured by DLS after suspending the formed particles in ethanol and dispersing the aggregated particles by ultrasonic waves. The Z-average particle size was 370 nm, and the numerical distribution was as shown in Figure 3.

[0065] Also, the surface area of the material measured by the BET method using nitrogen gas was 24 m 2 / g.

[0066] Example 2 The first aqueous solution was prepared at a concentration of 500 mM NaCl, 640 mM Na 2 HPO 4 , and 119 mM KH 2 PO 4 (pH 7.4). The second aqueous solution was prepared at a concentration of 500 mM NaCl, 100 mM CaCl 2 , and 60 mM MgCl 2 . After heating these two solutions separately to 85°C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0067] Example 3 The first aqueous solution was prepared with 100 mM NaCl, 128 mM Na 2 HPO 4 , and 24 mM KH 2 PO 4 (pH 7.4). The second aqueous solution was prepared with 100 mM NaCl, 20 mM CaCl 2 , and 12 mM MgCl 2It was prepared. After heating these two solutions separately to 70 °C, they were mixed in a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0068] Example 4 The first aqueous solution was prepared with 100 mM NaCl, 128 mM Na 2 HPO 4 , and 24 mM KH 2 PO 4 (pH 7.4). The second aqueous solution was prepared with 100 mM NaCl, 20 mM CaCl 2 , and 12 mM MgCl 2 . After heating these two solutions separately to 80 °C, they were mixed in a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0069] Example 5 The first aqueous solution was prepared with 100 mM NaCl, 128 mM Na 2 HPO 4 , and 24 mM KH 2 PO 4 (pH 7.4). The second aqueous solution was prepared with 100 mM NaCl, 20 mM CaCl 2 , and 12 mM MgCl 2 . After heating these two solutions separately to 90 °C, they were mixed in a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0070] Example 6 The first aqueous solution was prepared with 160 mM Na 2 HPO 4, and 30 mM of KH 2 PO 4 prepared in (pH 7.4). The second aqueous solution was prepared with 50 mM of CaCl 2 , and 30 mM of MgCl 2 . After heating these two solutions separately to 85 °C, they were mixed in a 1:1 volume ratio to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0071] Example 7 The first aqueous solution was prepared with 100 mM of NaCl and 150 mM of KH 2 PO 4 in (pH 4.7). The second aqueous solution was prepared with 100 mM of NaCl, 20 mM of CaCl 2 , and 12 mM of MgCl 2 . After heating these two solutions separately to 85 °C, they were mixed in a 1:1 volume ratio to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The precipitated particles were rounded but not spherical. The particles had a rough surface and did not appear hollow. XRD analysis demonstrated that the particles were crystalline whitlockite, a magnesium-substituted type of tricalcium phosphate (TCP).

[0072] Example 8 The first aqueous solution was prepared with 100 mM of NaCl, 75 mM of Na 2 HPO 4 , and 75 mM of KH 2 PO 4 in (pH 6.4). The second aqueous solution was prepared with 100 mM of NaCl, 20 mM of CaCl 2 , and 12 mM of MgCl 2It was prepared. After heating these two solutions separately to 85°C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0073] Example 9 The first aqueous solution was prepared with 100 mM NaCl, 145 mM Na 2 HPO 4 , and 4.8 mM KH 2 PO 4 (pH 8.1). The second aqueous solution was prepared with 100 mM NaCl, 20 mM CaCl 2 , and 12 mM MgCl 2 . After heating these two solutions separately to 85°C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0074] Example 10 The first aqueous solution was prepared with 75 mM Na 2 HPO 4 (pH 9.3). The second aqueous solution was prepared with 20 mM CaCl 2 , and 12 mM MgCl 2 . After heating these two aqueous solutions separately to 85°C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was recovered by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0075] Example 11 The first aqueous solution was prepared with 190 mM Na 2 HPO 4 (pH 9.4). The second aqueous solution was prepared with 50 mM CaCl 2 , and 30 mM MgCl2 It was prepared with 2 . After heating these two aqueous solutions separately to 85 °C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2.

[0076] Example 12 The first aqueous solution was prepared with 60 mM of Na 2 HPO 4 (pH 9.3). The second aqueous solution was prepared with 50 mM of CaCl 2 , and 30 mM of MgCl 2 . After heating these two aqueous solutions separately to 85 °C, they were mixed at a volume ratio of 1:1 to form a precipitate. This precipitate was collected by filtration, washed, and then analyzed by SEM and XRD. The recovered particles were neither spherical nor hollow but were composed of irregular and seemingly dense particles with a rough surface. As a result of the XRD analysis of the material, it was confirmed that the crystal phase was whitlockite. This result is consistent with the type of particles formed at the low pH shown in Example 7. The difference from this example is that although the initial pH of the phosphate solution is high, HPO 4 2- is not in excess with respect to the contents of Ca 2+ and Mg 2+ , and as a result, the following reaction occurs. 3 - xCa 2+ + xMg 2+ + 2HPO 4 2- → Ca 3-x Mg x (PO 4 ) 2 + 2H +

[0077] Without excess HPO 4 2- , the system loses its buffering capacity, and the H + of the product lowers the pH and promotes the formation of crystalline particles of TCP with a higher Ca / P ratio than the particles formed and characterized in Example 1.

[0078] Example 13 The first aqueous solution was prepared with 220 mM of Na 2 HPO 4 (pH 9.4). The second aqueous solution was prepared with 60 mM of CaCl 2 , and 36 mM of MgCl 2 . After heating these two aqueous solutions separately to 85°C, they were mixed in a 1:1 volume ratio to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in Figure 1 and were XRD amorphous similar to the pattern shown in Figure 2. The pH of the filtrate was 7.0, indicating that HPO 4 2- was in sufficient excess to maintain a neutral pH.

[0079] In this example, particles with twice the mass of those in Example 1 could be obtained. TIFF0007689745000002.tif130170

[0080] Example 14 The first aqueous solution was prepared with 0.5 mM of KCl, 200 mM of NaCl, 16 mM of Na 2 HPO 4 , and 3 mM of KH 2 PO 4 . The second aqueous solution was prepared with 0.5 mM of KCl, 200 mM of NaCl, 2.5 mM of CaCl 2 , and 1.5 mM of MgCl 2 .

[0081] In the first experiment, these two aqueous solutions were heated separately to 45°C. Next, the first solution (phosphate) was mixed in equal amounts with the second solution (calcium and magnesium), i.e., in a different way from Steps 2 and 3 in Figures 4 and 5, to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were a mixture of spherical particles and microcrystals and were brushite (CaHPO 4 *2H 2was identified as (O).

[0082] In the second experiment, two solutions were separately heated to 65°C. Next, the first solution (phosphate) was mixed with the second solution (calcium and magnesium) in equal amounts to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in FIG. 1 and were XRD amorphous similar to the pattern shown in FIG. 2.

[0083] In the third experiment, two solutions were separately heated to 85°C. Next, the first solution (phosphate) was mixed with the second solution (calcium and magnesium) in equal amounts to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The formed particles were similar in shape, size, and appearance to the particles shown in FIG. 1 and were XRD amorphous similar to the pattern shown in FIG. 2. The mass yield of the reaction improved at 85°C compared to the experiment at 65°C.

[0084] This series of experiments indicates that there is a favorable temperature window for the precipitation reaction to be stable and effective from the viewpoints of consistency in shape, size, and appearance and mass yield.

[0085] Example 15 The first aqueous solution was prepared with 0.5 mM KCl, 200 mM NaCl, 16 mM Na 2 HPO 4 , and 3 mM KH 2 PO 4 (pH 7.4). The second aqueous solution was prepared with 0.5 mM KCl, 200 mM NaCl, 2.5 mM CaCl 2 , and 0.75 mM MgCl 2 . These two aqueous solutions were separately heated to 85°C. Then, the first solution (phosphate) was mixed with the second solution (calcium and magnesium) in equal amounts to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. No spherical particles were present, but the formation of a poorly crystalline phase identified as whitlockite by XRD was observed.

[0086] In the second experiment, 0.5 mM KCl, 200 mM NaCl, 16 mM Na 2 HPO 4 , and 3 mM KH 2 PO 4 were used to prepare the first aqueous solution. The second aqueous solution was prepared with 0.5 mM KCl, 200 mM NaCl, and 2.5 mM CaCl 2 . These two solutions were separately heated to 85 °C. Next, the first solution (phosphate) was mixed in equal amounts with the second solution (calcium) to form a precipitate. This precipitate was collected by filtration, washed, and analyzed by SEM and XRD. No spherical particles were present, but flaky crystals identified as tricalcium phosphate (TCP) by XRD were formed.

[0087] These experiments showed that magnesium acts as a stabilizer for the amorphous phase and that a sufficient degree of magnesium substitution is required to retain the amorphous phase.

[0088] Example 16 Using a microwave synthesizer, an alternative heating method and an expansion of the process temperature range were evaluated. In the experiment, a single solution was prepared with 0.5 mM KCl, 200 mM NaCl, 16 mM Na 2 HPO 4 , 3 mM KH 2 PO 4 , 2.5 mM CaCl 2 , and 1.5 mM MgCl 2 . In various experiments, the solution was placed in a sealed glass vial and rapidly heated (in less than 2 minutes) from room temperature (23 °C) to 50, 70, 90, 100, 120, or 140 °C using microwave-assisted heating. Analysis of the resulting precipitate by SEM confirmed that spherical and hollow particles comparable to the particles shown in Figure 1 were formed in all cases. At temperatures above 100 °C, the surface of the particles became slightly rougher and signs of crystallization were observed.

[0089] This experiment shows that particles can be synthesized using another heating means and that particles can be synthesized within a wide temperature window depending on the heating means.

[0090] Example 17 A composition containing 40 wt% of spherical and hollow calcium magnesium phosphate particles according to the present invention and 60 wt% of glycerol was mixed with deionized water to evaluate the pH buffering capacity. In the experiment, 0.5 g of the composition was added to 500 mL of water to make a concentration of 0.1 wt%. The pH of the solution was monitored for the first 30 minutes of dissolution of the composition. The results are shown in Figure 7. By adding the composition, the pH of the solution rapidly increased from about 7.5 to 9.5 within 5 minutes and then stabilized.

[0091] Such rapid release of ions is an important feature for certain dental materials and products. The local increase in pH promotes the nucleation and growth of hydroxyapatite and is beneficial for the remineralization of enamel and dentin.

[0092] Example 18 A desensitizing gel containing 7.5 wt% of spherical and hollow calcium magnesium phosphate particles according to the present invention was mixed with aqueous solutions at pH 4 and pH 7.9 at a concentration of 0.1 wt%. The pH of the starting solutions was adjusted using 0.1 M HCl and 0.1 M NaOH, respectively. The pH of the solution was monitored for the first 30 minutes during which the gel dissolved. The results are shown in Figure 8. The gel was demonstrated to increase the pH in both cases, from pH 4.0 to 8.6 and from pH 7.9 to 9.3. When a similar test was performed with a corresponding gel in which calcium magnesium phosphate was replaced with inert glass particles, the pH did not change, indicating that the particles caused the effect.

[0093] This desensitizing gel is intended as a treatment option for dentin hypersensitivity by remineralizing exposed dentinal tubules. The increase in pH by the particles is thought to promote the nucleation and growth of hydroxyapatite mineral on the dentin surface and inside the exposed dentinal tubules.

[0094] Example 19 The spherical and hollow calcium magnesium phosphate particles according to the present invention were dispersed in 0.05 M Tris HCl buffer (pH 7.4) at a concentration of 10 mg / mL and stored at 37°C for up to 8 weeks. The particles were filtered, and the filtrate was analyzed by ICP-OES to monitor the release of calcium ions, magnesium ions, and phosphate ions from the particles. The filtrate was diluted before analysis. The results are shown in Fig. 9, and the release was characterized by an initial burst followed by a decrease in ion concentration, with Ca being the most prominent. The initial burst release of ions promoted a rapid calcification process, and the subsequent decrease in calcium content in the filtrate suggested that calcium phosphate reprecipitated from the solution but had a higher Ca / P ratio than in the case of the original particles, i.e., a calcium phosphate close to hydroxyapatite.

[0095] Example 20 To evaluate the dentin sealing and remineralization properties, a gel containing 5 wt% of the spherical and hollow calcium magnesium phosphate particles according to the present invention was prepared. Also, a similar gel containing 5 wt% of hollow calcium phosphate particles according to the prior invention (WO2014 / 148997A1) was prepared and tested in parallel for comparison of the results.

[0096] For the test, a 1-mm-thick dentin sample was cut out from an extracted human permanent molar and etched with phosphoric acid to expose the tubules. The exposed dentin surface was brushed with a soft-bristled toothbrush up to 7 days, twice a day, to apply the gel. During brushing, the dentin samples were stored in artificial saliva at 37 °C. After the final application of the gel, the samples were dried and prepared for SEM evaluation. The appearances of the dentin surfaces after treatment with the gel for 4 days and 7 days are shown in FIGS. 10 and 11. The particles according to the present invention were able to provide faster and more complete occlusion of the tubules than the particles prepared according to WO2014 / 148997. This is due to the smaller average diameter of the spherical particles, which allows them to penetrate the tubules more easily, and to the amorphous nature of the particles of the present invention, which enables more rapid dissolution and release of bioactive ions that mineralize the surface.

[0097] Example 21 A desensitizing gel containing 7.5 wt% of the spherical and hollow calcium magnesium phosphate particles according to the present invention was evaluated for dentin occlusion and remineralization properties. For the test, a 1-mm-thick dentin sample was cut out from an extracted human permanent molar and etched with phosphoric acid to expose the dentinal tubules. This dentin sample was brushed with the gel twice a day for 1 minute on each side for a total of 14 days. After each brushing sequence, the samples were rinsed with deionized water and stored in artificial saliva at 37 °C until the next brushing sequence. After the treatment was completed, the samples were vacuum dried and evaluated by SEM.

[0098] The treatment results are shown in FIG. 12. It can be seen that the exposed dentinal tubules are completely occluded. Observing the cross section, it can be seen that mineralization is occurring in the deep part (>60 μm) inside the tubules. The degree of occlusion achieved by this treatment is expected to completely eliminate the movement of the fluid inside the tubules, thereby providing an effective analgesic effect on sensitive teeth.

[0099] Example 22 The dentin sealing property and remineralization characteristics were evaluated when a desensitizing gel containing 7.5 wt% spherical and hollow calcium magnesium phosphate particles according to the present invention was applied in combination with a fluoride-containing dentifrice. For the test, 1-mm-thick dentin samples were cut out from extracted human permanent molars and etched with phosphoric acid to expose the tubules. These dentin samples were first brushed with a standard fluoride-containing dentifrice and then with the desensitizing gel. This operation was repeated 4 times a day for 4 days. The dentin samples were stored in artificial saliva at 37°C during brushing. After the treatment, the samples were vacuum dried and evaluated by SEM.

[0100] The treatment results are shown in Fig. 13. It can be seen that the exposed tubules are completely sealed with a dense calcified layer. Also, according to the cross-sectional evaluation of the dentin samples, it was demonstrated that the minerals deposited in the tubules consisted of high aspect ratio fine crystals and that many tubules were completely sealed more than 20 μm away from the dentin surface.

[0101] Example 23 Spherical and hollow calcium magnesium phosphate particles according to the present invention were stored in tap water and artificial saliva at 37°C for up to 28 days. The purpose was to evaluate the characteristics of particle decomposition and crystallization in different media within this time frame.

[0102] The particle samples were evaluated by SEM after 7 days, 14 days, and 28 days and were collected for XRD evaluation after 28 days.

[0103] Fig. 14 shows the results for tap water. It can be seen that the particles retained their characteristic form for up to 2 weeks. After 4 weeks, the particles decomposed and partially crystallized into hydroxyapatite. In artificial saliva, the particles decomposed within 1 week and began to recrystallize (see Fig. 15). After 2 weeks, the spherical particles disappeared, and large flake-like crystals were formed after 4 weeks. This crystal phase was confirmed to be hydroxyapatite and whitlockite, which are minerals naturally present in human hard tissues.

[0104] Example 24 A composition containing 40 wt% spherical and hollow calcium magnesium phosphate particles, 55 wt% glycerol and 5 wt% free water according to the present invention was stored in a sealed state at room temperature (20 - 23°C) for up to 18 months, and then the properties of the composition and the particles were evaluated to determine stability.

[0105] As a result, it was found that the properties of the composition were maintained, and the main properties such as the particle morphology, crystallinity, particle size and chemical composition were maintained. For SEM and XRD data, see Figure 16. This result indicates that the composition having the particles and glycerol according to the present invention is stable and the shelf life of the composition is at least 18 months.

[0106] Example 25 Chemical reactions and phase transformations such as the decomposition and crystallization of amorphous calcium phosphate are accelerated at high temperatures. To evaluate the stability under accelerated conditions, a composition containing 40 wt% spherical and hollow calcium magnesium phosphate particles, 55 wt% glycerol and 5 wt% free water according to the present invention was stored in a sealed container at 40°C for up to 12 months. Then, the properties of the composition and the particles were evaluated to determine stability.

[0107] As a result, it was found that the characteristics of the composition were maintained, and the main properties such as the particle morphology, crystallinity, particle size and chemical composition were maintained. For SEM and XRD data, see Figure 17. When applying an acceleration factor 3 conservative for the storage conditions at 40°C, the result indicates that the composition having the particles and glycerol according to the present invention is stable and has a predicted shelf life of 36 months.

[0108] Example 26 The desensitizing gel containing the particles and additives according to the present invention was placed in an LDPE tube suitable for the product and stored for up to 18 months under ambient (20 - 23 °C) conditions. During that time, product characteristics such as the moisture content, viscosity, and appearance of the particles were evaluated. For the appearance of the particles in the gel after storage, refer to Figure 18. It was found that the evaluated product characteristics were maintained, and it was concluded that the product stability of the desensitizing gel was at least 18 months.

[0109] Example 27 The desensitizing gel containing the particles and additives according to the present invention was stored in an LDPE tube suitable for the product for up to 12 months under accelerated (40 °C, >90% rH) conditions, and then product characteristics such as the moisture content, viscosity, and appearance of the particles were evaluated. For the appearance of the particles after storage, refer to Figure 19. It was found that under the storage conditions with high relative humidity, the tube weight and the moisture content of the gel increased, but the appearance of the particles and the viscosity of the gel were basically maintained. Applying a conservative acceleration factor of 3 for the storage conditions, the test storage life of the desensitizing gel was 36 months.

[0110] Example 28 Even in a composition having excessive free water that normally promotes the crystallization of ACP, in order to demonstrate the stability of the composition containing the particles and glycerol produced according to the present invention, a composition having 40 wt% spherical and hollow calcium magnesium phosphate particles, 55 wt% glycerol, and 5 wt% free water according to the present invention was mixed with water to form a mixture having 5 - 50 wt% excessive free water. After storing those mixtures for up to 20 weeks under ambient (20 - 23 °C) conditions, the particles were analyzed by SEM and XRD to record significant changes in appearance and crystallinity (refer to the results in Figures 20 and 21). As a result, it was demonstrated that the particles remained spherical and amorphous in the mixtures containing 5 wt% and 10 wt% excessive water during the test period (20 weeks). In the mixtures containing 30 wt% and 50 wt% excessive free water, slight changes in the appearance of the particles were observed after 20 weeks of storage, but most of the particles still retained their characteristic spherical shape. An increase in crystallinity was first observed in the 50 wt% excessive free water sample after 8 weeks of storage.

[0111] Example 29 A prototype whitening gel containing 16% by weight of carbamide peroxide and 7.5% by weight of the spherical and hollow calcium magnesium phosphate particles according to the present invention was applied to enamel samples for 6 hours per day for 3 days and stored intermittently in artificial saliva at 37°C. A control whitening gel containing 16% by weight of carbamide peroxide but no particles was evaluated in parallel on enamel samples of the same tooth.

[0112] The shade evaluation after treatment with different gels showed that the whitening effects were comparable, indicating that the particles according to the present invention do not have an adverse effect on the whitening process. The Vickers hardness evaluation (300 gf, 10 seconds) of the enamel samples before and after treatment showed that the hardness of the samples treated with the particle-containing whitening gel increased significantly, while the change in hardness of the samples treated with the control gel was not significant based on two-sided and paired t-tests at a significance level of 0.05 (see Table 3). The increase in hardness observed in the samples treated with the particle-containing whitening gel suggests that the particles induced the calcification of the surface enamel, thereby strengthening the teeth. TIFF0007689745000003.tif60128

[0113] Example 30 The amorphous calcium phosphate particles according to the present invention are stabilized by magnesium substitution, but under ambient conditions, they may still crystallize over time. Compositions having the particles and paste-forming compounds according to the present invention are formed in part to enable the long-term stability of the particles.

[0114] The particles according to the present invention were stored as dry fine powder in a sealed container for 11 months under ambient conditions to evaluate their stability. As a result, it was found that some of the particles retained their spherical shape but showed signs of decomposition and crystallization. Other particles were completely deformed. XRD evaluation confirmed that the crystallinity had increased, as shown in Figure 22.

[0115] The degradation / crystallization of the powder particles was significant compared to the stability of the particles in the glycerol-containing compositions (Examples 24, 25).

Claims

1. A composition comprising a paste-forming compound and X-ray diffraction (XRD) amorphous calcium magnesium phosphate spherical particles having a hollow core and a shell, wherein the paste-forming compound is selected from glycerol, triglyceride, polyethylene glycol, propylene glycol, polypropylene glycol, polyvinyl alcohol, mineral oil or liquid paraffin, the particles are XRD amorphous, the shell of the particles contains 15-30 wt% calcium, 50-70 wt% phosphate, 5-11 wt% magnesium, and 1-20 wt% bound water, the Ca / P molar ratio is in the range of 0.70-1.20, the (Ca+Mg) / P molar ratio is in the range of 1.00-1.70, the particles have an average particle size in the range of 100-500 nm, and the amount of particles in the composition is 25-50 wt%, characterized composition.

2. In the composition according to Claim 1, wherein the paste-forming compound is glycerol, characterized composition.

3. In the composition according to Claim 1 or 2, wherein the amount of particles in the composition is 35-45 wt%, characterized composition.

4. In the composition according to Claim 1 or 2, wherein the amount of particles in the composition is 40 wt%, characterized composition.

5. In the composition according to any one of Claims 1 to 4, wherein the spherical particles have a porous shell, characterized composition.

6. In the composition according to any one of Claims 1 to 5, wherein the average particle size of the spherical particles is 150-450 nm, characterized composition.

7. In the composition according to any one of Claims 1 to 5, wherein the average particle size of the spherical particles is 250-350 nm, characterized composition.

8. In the composition according to any one of Claims 1 to 7, wherein the spherical particles contain 12-16 wt% bound water, characterized composition.

9. In the composition according to any one of Claims 1 to 8, wherein the spherical particles contain 20-26 wt% calcium, 52-64 wt% phosphate, 5-9 wt% magnesium and 12-16 wt% bound water, and the Ca / P ratio is 0.80-1.00, the (Ca+Mg) / P ratio is 1.15-1.45, characterized composition.

10. In the composition according to any one of Claims 1 to 9, A composition, wherein the spherical particles further contain at least one ion selected from sodium, potassium, silicon, zinc, and fluoride.

11. In the composition according to any one of Claims 1 to 10, The spherical particles have an average surface area (BET) of 10 to 40 m ２ / g, and the composition is characterized by this.

12. In the composition according to any one of Claims 1 to 11, A composition, wherein the amount of the paste-forming compound is at least 50% by weight.

13. In the composition according to any one of Claims 1 to 12, A composition, which contains 10% by weight or less of free water.

14. In the composition according to any one of Claims 1 to 13, A composition, which contains 25 to 50% by weight of particles, at least 50% by weight of a paste-forming compound, and less than 10% by weight of free water.

15. In the composition according to any one of Claims 1 to 13, A composition, which contains 35 to 45% by weight of particles, at least 55% by weight of a paste-forming compound, and less than 8% by weight of free water.

16. A method for preparing the composition according to any one of Claims 1 to 15, comprising: a. providing a first aqueous solution having a pH of 6 to 10 and a first temperature, the first aqueous solution containing dihydrogen phosphate ions and / or hydrogen phosphate ions and one or more counterions; b. providing a second aqueous solution having a second temperature, the second aqueous solution containing calcium ions and magnesium ions and one or more counterions, the amount of calcium being in molar excess with respect to magnesium; c. heating the first aqueous solution, the second aqueous solution, or both the first and second aqueous solutions to first and second elevated temperatures, respectively; d. contacting the first and second aqueous solutions with each other to provide a third aqueous solution having a third temperature, the amount of phosphate in the third aqueous solution being in molar excess with respect to the total amount of calcium and magnesium; e. enabling the formation of particles; f. collecting the formed particles; g. washing the separated particles using a suitable solvent; h. dehydrating the washed particles at a fifth temperature until a slurry containing 70 to 95% by weight of free water is obtained. i. A step of mixing spherical particles with a paste-forming compound, wherein the amount of particles in the composition is 25 to 50% by weight; j. A step of dehydrating the mixture of spherical particles and the paste-forming compound at a seventh temperature; k. A method comprising a step of homogenizing the mixture of spherical particles and the paste-forming compound to obtain a composition.

17. In the method according to claim 16, The method, wherein the paste-forming compound is glycerol.

18. In the method according to claim 16 or 17, The method, wherein the third temperature is 70 to 95 °C.

19. In the method according to any one of claims 16 to 18, The method, wherein the temperature difference between the first temperature and the first temperature increase, and the temperature difference between the second temperature and the second temperature increase are at least 40 °C.

20. In the method according to any one of claims 16 to 19, The method, wherein the first aqueous solution and the second aqueous solution are brought into contact with each other at a volume ratio of 2:1 to 1:

2.

21. In the method according to any one of claims 16 to 19, The method, wherein the first aqueous solution and the second aqueous solution are brought into contact with each other at a volume ratio of 1.05:1 to 1:1.

05.

22. In the method according to any one of claims 16 to 21, The method, wherein the formed and separated particles are washed at a fourth temperature.

23. In the method according to any one of claims 16 to 22, The method, wherein the formed, separated and washed particles are partially dehydrated using centrifugation or reduced pressure and / or at a fifth temperature.

24. In the method according to any one of claims 16 to 23, The method, wherein the water in the first and second aqueous solutions is tap water.

25. In the method according to any one of claims 16 to 24, The method, wherein the solvent in the washing step g is purified water.

26. In the method according to any one of claims 16 to 25, The method, wherein the pH of the first aqueous solution is 7 to 10.

27. In the method according to any one of claims 16 to 26, H in the first aqueous solution ２ PO ４ :HPO ４ The method is characterized in that the molar ratio of is in the range of 0 to 100:75 to 600.

28. In the method according to any one of claims 16 to 27, The method, wherein the total concentration of phosphate in the first aqueous solution is 60 to 800 mM.

29. In the method according to any one of claims 16 to 28, the method characterized in that calcium in the second aqueous solution is in molar excess with respect to magnesium.

30. In the method according to any one of claims 16 to 29, A method characterized in that the amount of phosphate is in molar excess (PO ４ > (Ca + Mg)) with respect to the total amount of calcium and magnesium.

31. In the method according to any one of claims 16 to 30, the method characterized in that the particles are suspended in a slurry before being mixed with the paste-forming compound, and the slurry contains 10 to 30% by weight of particles and 70 to 90% by weight of water.

32. In the method according to any one of claims 16 to 31, the method characterized in that the particles that are formed, collected, washed and / or dehydrated are mixed with the paste-forming compound and dried at a seventh temperature and homogenized to form a smooth composition.

33. Use of the composition according to any one of claims 1 to 15 as a component in toothpaste, desensitizing gel, bleaching paste, dental varnish, dental prophylactic paste, pit and fissure sealant, dental filling material, capping material, mouthwash, interdental cleaning device, chewing gum, implant, bone graft material or bone void filler.

34. Toothpaste, desensitizing gel, bleaching paste, sealant, dental varnish or dental prophylactic paste, characterized by comprising the composition according to any one of claims 1 to 15 and having an amount of particles of 0.5 to 15% by weight.

35. A bleaching paste, characterized by comprising the composition according to any one of claims 1 to 15 and carbamide peroxide, having an amount of particles of 3 to 10% by weight and an amount of carbamide peroxide of 10 to 20% by weight.

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