Stable amorphous calcium magnesium phosphate particulate composition

Abstract

The present invention relates to a particulate composition comprising XRD amorphous calcium magnesium phosphate particles and a method of producing such a composition. The XRD amorphous calcium magnesium phosphate particles are spheroidal particles having a hollow core. The paste containing particles can be used in a dental product, such as a toothpaste, to treat dentinal hypersensitivity by mineralization and occlusion of exposed dentinal tubules.

Description

TECHNICAL FIELD

[0001] The present invention relates to spherically shaped and hollow calcium magnesium phosphate particles, compositions comprising the particles, and methods of making the particles and compositions. The particles and compositions comprising the particles can be used, for example, in toothpaste and treat hypersensitive teeth by increasing mineralization, in particular by increasing mineralization deep into dentin tubules. BACKGROUND

[0002] Dentin hypersensitivity is a widespread clinically relevant problem that manifests as sharp and sudden pain in response to external thermal, mechanical, osmotic or evaporative stimuli. Hypersensitivity can occur if the protective layer of dentin is lost due to loss of enamel, or if the cementum is exposed due to gum recession, thus opening the dentin tubules to the oral environment. Loss of enamel can be the result of abrasion, erosion or chipping. Gum recession becomes more frequent with age, but can also occur in younger individuals due to, for example, over-brushing, periodontal pocket reduction surgery, overuse of dental floss or secondary reactions to periodontal disease.

[0003] Amorphous calcium phosphate (ACP) is a metastable phase that lacks long-range crystalline order and is therefore more soluble than crystalline calcium phosphates such as hydroxyapatite (HA) and tricalcium phosphate (TCP). The higher solubility of ACP makes it more bioactive because bioavailable calcium and phosphate ions are more readily released into the local environment. ACP has been shown to act as a precursor to apatite in teeth and thus forms an important part of natural mineralization. This makes the development of synthetic ACP for biomedical applications an interesting field of research, but few successful approaches have been reported due to its inherent metastability and subsequent limitations in handling and product formulation. As a result, many commercially available products rely on ACP that is precipitated in situ, for example by providing calcium and phosphate salts in a dual-barrel type delivery just prior to application to the tooth surface.

[0004] In order to use synthetic ACP in biomedical applications, it needs to be stabilized or formulated such that it does not prematurely crystallize and lose part of its bioactivity. Stabilization of ACP can be achieved, for example, by Mg substitution or the use of milk-derived casein phosphopeptide (CPP).

[0005] WO 2014 / 148997 Al (WO’997) discloses crystalline calcium phosphate particles substantially free of strontium for treating exposed dentin tubules. However, these particles are less soluble and therefore not readily available as a source of calcium and phosphate ions.

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

[0007] There is a need for ACP particles that remain stable in their amorphous state during storage, and compositions comprising the ACP particles, wherein the particles are stable. Another need in this field is stable ACP particles with controlled morphology and free of potential allergens, which particles can also be produced on a large scale. Summary of the Invention

[0008] The present invention addresses the problems of the prior art by providing a composition for stabilizing ACP particles and a scalable, controlled, continuous manufacturing process for forming such particles and compositions. Stabilizing the particles directly with a paste-forming compound during the manufacturing process increases the stability and shelf life of the particles and facilitates the formulation of product formulations containing the particles. It also reduces the risk of particle aggregation, which can lead to uneven particle formulations and reduce the ability of the particles to penetrate dentinal tubules. Furthermore, by directly forming the composition rather than drying, grinding, and sieving to form a fine powder, any safety concerns associated with airborne particles during 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 more easily penetrate the dentinal tubules, exhibit an appropriate affinity for dentin, and allow for a higher release of ions due to the amorphous state of the particles. This promotes more effective treatment of the exposed dentinal tubules by increasing their mineralization. In addition, the use of particles according to the present invention to mineralize the dentinal tubules provides a surface that is more resistant to wear and acid corrosion. The present invention can be easily applied to the treatment site by forming a product formulation containing the particles, such as a toothpaste, desensitizing gel, varnish or sealant. The method for preparing the particles according to the present invention makes it easy to prepare the particles and compositions in a controlled manner, with reproducible results at different production 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, the particles having a hollow core and a shell, wherein the particles are XRD amorphous, and wherein the shell of the particle comprises 15 wt% to 30 wt% calcium, 50 wt% to 70 wt% phosphate, 5 wt% to 11 wt% magnesium and 1 wt% to 20 wt% bound water, and wherein the Ca / P molar ratio is in the range of 0.70 to 1.20, and wherein the (Ca+Mg) / P molar ratio is in the range of 1.00 to 1.70, and wherein the particles have an average particle size in the range of 100 nm to 500 nm, and wherein the amount of particles in the composition is 25 wt% to 50 wt%.

[0011] In a second aspect, the present invention relates to a method for preparing a composition, comprising the steps of:

[0012] a. providing a first aqueous solution having a pH of 6 to 10 and a first temperature, wherein the first solution contains dihydrogen phosphate ions and / or hydrogen phosphate ions and preferably one or more counter ions selected from sodium and / or potassium;

[0013] b. providing a second aqueous solution having a second temperature, wherein the second solution contains calcium ions and magnesium ions and one or more counter ions preferably selected from chloride, sodium and / or potassium; and wherein the amount of calcium is in molar excess over magnesium;

[0014] c. heating the first aqueous solution, the second aqueous solution, or both the first aqueous solution and the second aqueous solution to a first high temperature and a second high temperature, respectively;

[0015] d. contacting the first aqueous solution and the second aqueous solution with each other to obtain a third aqueous solution having a third temperature, wherein the amount of phosphate in the third aqueous solution is in molar excess over the total amount of calcium and magnesium;

[0016] e. forming particles;

[0017] f. collecting the formed particles;

[0018] g. Optionally, washing the separated particles with a suitable solvent;

[0019] h. Optionally, dehydrating the washed particles at a fifth temperature until a slurry comprising 70% to 95% by weight, preferably 75% to 85% by weight, of free water is obtained;

[0020] i. The spherical particles are mixed with a paste-forming compound, wherein the amount of the particles in the composition is 25% to 50% by weight;

[0021] j at a seventh temperature so that the mixture of spherical particles and paste compound dehydration; and

[0022] k. Optionally, homogenizing the mixture of the spherical particles and the paste-forming compound to obtain a composition.

[0023] In a third aspect, the present invention relates to the use of a composition according to the invention as an ingredient in a toothpaste, a desensitizing gel, a bleaching paste, a dental varnish, a dental prophy paste, a pit and fissure sealant, a tooth filling material, a capping material, a mouth wash, an interdental cleaning device, a chewing gum, an implant, a bone graft material, a bone void filling material.

[0024] In a fourth aspect, the present invention relates to a toothpaste, desensitizing gel, bleaching paste, sealant, dental varnish or dentifrice comprising a composition according to the invention, wherein the amount of particles is from 0.5% to 15% by weight.

[0025] In a fifth aspect, the present invention relates to a bleaching paste comprising a composition according to the invention and carbamide peroxide, wherein the amount of particles is from 3% to 10% by weight and the amount of carbamide peroxide is from 10% to 20% by weight.

[0026] All embodiments disclosed herein relate to all aspects of the invention and, unless stated otherwise, all embodiments are combinable. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 .SEM image of calcium magnesium phosphate particles.

[0028] Figure 2 XRD pattern of calcium magnesium phosphate particles. These particles are XRD amorphous.

[0029] Figure 3 .DLS particle size distribution of calcium magnesium phosphate particles.

[0030] Figure 4 . Schematic diagram of steps 1 and 2 of the method according to the present invention.

[0031] Figure 5 . Schematic diagram of steps 3 and 4 of the method according to the present invention.

[0032] FIG. 6 . a) Schematic representation of steps 5 and 6 of the method according to the invention, and b) flow chart of the method according to the invention.

[0033] Figure 7 . The pH buffering capacity of the calcium magnesium phosphate particles according to the present invention.

[0034] Figure 8 . pH buffering capacity of a desensitizing gel containing calcium magnesium phosphate particles according to the present invention.

[0035] Figure 9 Ion release profile of Ca, Mg and P of the calcium magnesium phosphate particles according to the present application. a) release within the first 6 hours, b) sustained release followed by a decrease of the ion concentration indicating precipitation from solution.

[0036] Figure 10 Occlusion of dentinal tubules using the spherically and hollow calcium phosphate particles according to WO 2014 / 148997 A1.

[0037] Figure 11 Occlusion of dentinal tubules with the spherically and hollow calcium magnesium particles according to the present application.

[0038] Figure 12 Occlusion and mineralization of dentinal tubules after two weeks of daily treatment with a desensitizing gel containing the spherically and hollow calcium magnesium phosphate particles according to the present application.

[0039] Figure 13 SEM images of occluded and mineralized dentin surfaces and cross sections of dentinal tubules after four times and four days of daily treatment with a fluoride containing toothpaste and a desensitizing gel containing the spherically and hollow calcium magnesium phosphate particles according to the present application.

[0040] Figure 14 SEM images and XRD patterns revealing the degradation and crystallization of the calcium magnesium phosphate particles according to the present application in tap water.

[0041] Figure 15 SEM images and XRD patterns revealing the degradation and crystallization of the calcium magnesium phosphate particles according to the present application after 7, 14 and 28 days in artificial saliva.

[0042] Figure 16 SEM images and XRD patterns of the particles after 18 months of storage of a composition according to the present application containing 40 wt% calcium magnesium phosphate particles, 55 wt% glycerol and 5 wt% free water.

[0043] Figure 17 SEM images and XRD patterns of the particles after 12 months of accelerated storage of a composition according to the present application containing 40 wt% calcium magnesium phosphate particles, 55 wt% glycerol and 5 wt% free water.

[0044] Figure 18 SEM images of the calcium magnesium phosphate particles in a desensitizer gel according to the present application after 18 months of ambient storage.

[0045] Figure 19 SEM images of the calcium magnesium phosphate particles in a desensitizer gel according to the present application after 12 months of accelerated storage.

[0046] Figure 20 SEM images of calcium magnesium phosphate particles according to the present invention after storage for 20 weeks in a composition containing 5% to 50% excess free water.

[0047] Figure 21 XRD pattern of the calcium magnesium phosphate particles according to the present invention after storage for up to 20 weeks in a composition containing 5% to 50% excess free water.

[0048] Figure 22 SEM images and XRD patterns of the calcium magnesium phosphate particles according to the present invention after storage as dry fine powder in a closed container under ambient conditions (20°C to 25°C) for 11 months. DETAILED DESCRIPTION

[0049] 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).

[0050] In this application, the term 'stable' means stable in terms of chemical composition, and / or particle morphology, and / or crystallinity, and / or average particle size, and / or particle surface area, and / or physical properties (for compositions, such as viscosity). Thus, a stable particle or composition may mean that the composition or particle remains substantially the same during storage for an extended period of time (e.g., 12 months or considerably longer).

[0051] In this application, the term "X-ray diffraction (XRD) amorphous" refers to a material or particle that lacks long-range crystalline order. The crystallinity or XRD amorphous state of the particle is determined using Cu-Kα Determined by powder X-ray diffraction, scanning 2θ from 7° to 60° with a step size of approximately 0.02°. Crystalline materials reflect X-rays according to the alignment of their crystal planes and produce a recognizable, sharp peak pattern, whereas amorphous materials by XRD produce only a single, broad, diffuse peak. For the purposes of this application, particles will be classified as XRD amorphous if the resulting pattern lacks a recognizable, sharp peak and is characterized solely by a broad, diffuse peak.

[0052] In this application, the term "bound water" corresponds to the water of hydration associated with the amorphous calcium magnesium phosphate particles. The 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 (PO4) z nH2O. The term "free water" refers to any residual or excess water that is not part of the particle formula. Free water can, for example, be part of the composition according to the present invention or water used in the process of forming the ACP particles and / or composition.

[0053] The present invention aims to provide particles, compositions and product formulations that promote the rapid and effective mineralization of dentinal tubules. The purpose of the particles is not only to mechanically block or fill the space of dentinal tubules, but also to mineralize the tubules. 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 quickly and effectively release calcium ions and phosphate ions, thereby producing local supersaturation and subsequent hydroxyapatite-like mineral precipitation. Therefore, this purpose includes providing particles that are stable (especially in terms of crystallinity) during storage. The inventors have demonstrated (Example 20) that, compared with the more crystalline calcium phosphate particles according to WO2014 / 148997A1, the present invention makes the occlusion of dentinal tubules faster.

[0054] See also Figure 1 The particles of the present invention are spherical particles having a hollow core and a shell. The shell is preferably porous to facilitate faster release of ions from the particle itself or release of substances loaded in the hollow core of the particle. The pore diameter is preferably about 1 nm to 30 nm. Since the particles are amorphous by XRD, see Figure 2 , they more readily dissolve and release ions that subsequently participate in the remineralization of the dentinal tubules. In a preferred embodiment, the crystallinity of the particles is substantially long-range amorphous, but may be short-range (nano) crystalline if resolved using, for example, high resolution transmission electron microscopy (HRTEM). Without being bound by theory, spherical particles having an average particle size in the range of 100 nm to 500 nm are believed to more readily penetrate deeply into the dental tubules than, for example, larger spherical particles or rod-shaped or plate-shaped particles. It is further believed that the X-ray amorphous character of the particles is a result of magnesium substitution, bound water, and the method by which the particles are formed.

[0055] Calcium, phosphate, and magnesium are the primary components of the particles or their shells, with the particle shell comprising 15% to 30% calcium, 50% to 70% phosphate, 5% to 11% magnesium, and 1% to 20% bound water by weight, wherein the Ca / P molar ratio is in the range of 0.70 to 1.20, and wherein the (Ca+Mg) / P molar ratio is in the range of 1.00 to 1.70. Magnesium replaces calcium in the calcium phosphate crystal structure. To ensure that the particles form a good composition or formulation and to allow the particles to penetrate into dentinal tubules having a diameter of approximately 2 μm, the average particle size of the particles is in the range of 100 nm to 500 nm.

[0056] Preferably, the particles are not so small as to exhibit too much positive buoyancy and dissolve too quickly, or so large as to not penetrate deeply into the dentinal tubules, and have a narrow size distribution, see Figure 3. An advantage of the present invention is that the particles of the composition do not agglomerate into larger clusters. In a preferred embodiment, the average particle size is from 150 nm to 450 nm, more preferably from 250 nm to 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 from 12 wt% to 16 wt%. It is believed that by having bound water in the particles, the ability of the particles to crystallize is inhibited, and instead the particles remain amorphous.

[0057] The calcium content in the particles is preferably 18 wt% or more, or 20 wt% or more, but preferably 25 wt% or less, or more preferably 23 wt% or less, and more preferably 22 wt% or less. The phosphate (PO4) content in the particles is preferably 55 wt% or more, or more preferably 58 wt% or more, but preferably 65 wt% or less, and more preferably 62 wt% or less. The magnesium content in the particles is preferably 6 wt% or more, or preferably 7 wt% or more, but preferably 9 wt% or less, and more preferably 8 wt% or less. For XRD amorphous particles, the degree of magnesium substitution of calcium should be sufficiently high and is preferably at least 20 mol%, more preferably 25 mol% to 50 mol%, and more preferably 30 mol% to 35 mol%.

[0058] Because the remineralization process relies in part on the presence of ions such as calcium, magnesium, and phosphate, the ratio of these ions in the particles is important. The Ca / P molar ratio is preferably 0.8 or higher, more preferably 0.9 or higher, preferably 1.1 or lower, and more preferably 1.0 or lower. The (Ca+Mg) / P molar ratio is preferably 1.2 or higher, more preferably 1.3 or higher, preferably 1.5 or lower, and more preferably 1.4 or lower.

[0059] In a preferred embodiment, the shell of the particles contains 21 to 24% by weight, preferably 22 to 23% by weight, of calcium, 56 to 60% by weight, preferably 58 to 59% by weight, of phosphate, 5 to 8% by weight, preferably 6 to 7% by weight, of magnesium, and 12 to 16% by weight, preferably 13 to 15% by weight, of bound water. The Ca / P ratio is 0.8 to 1.1, preferably 0.9 to 1.0, and the (Ca+Mg) / P ratio is 1.2 to 1.5, preferably 1.3 to 1.4.

[0060] In another preferred embodiment, the shell of the particles has a content of 20-26 wt% calcium, 52-64 wt% phosphate, 5-9 wt% magnesium and 12-16 wt% bound water, wherein the Ca / P ratio is 0.80-1.00 and the (Ca+Mg) / P ratio is 1.15-1.45.

[0061] The particles of the present invention may further contain other ions, such as sodium, potassium, silicon, zinc, and fluorine. These ions are preferably present in an amount of 0.1% to 3% by weight, preferably less than 2% by weight, and more preferably less than 1% by weight. In one embodiment, the particles include one or more of sodium, potassium, and fluorine. The particles are preferably free or substantially free of strontium.

[0062] The average surface area, determined by the Brunauer–Emmett–Teller (BET) method using nitrogen, is preferably 10 m 2 / g~40m 2 / g, more preferably 15m 2 / g~35m 2 / g, more preferably 20m 2 / g~30m 2 / g. A larger surface area allows the particles to dissolve faster, but the particles should not dissolve before use and before entering the dentinal tubules.

[0063] The inventors have demonstrated that the particles of the present invention, when dissolved in an aqueous medium, cause an increase in pH, which facilitates the nucleation and growth of hydroxyapatite mineral on the dentin surface and within exposed dentinal tubules, see Example 18. This is advantageous because during use, the particles dissolve in saliva or dentin fluid, thus potentially promoting the nucleation and growth of hydroxyapatite mineral.

[0064] For the particles to be effective for remineralization, they must be stable, particularly in their XRD amorphous state. Preferably, the particles remain XRD amorphous for at least 24 months during storage, meaning they have a shelf life of at least 24 months. This allows the particles to be manufactured at one location and shipped to another for product formulation without degrading their remineralization performance. Another advantage of particles that remain XRD amorphous is that they can be stored on the shelf for a period of time before use, thus eliminating the need for immediate use at the time of manufacture.

[0065] It is believed that if the amount of free water is reduced, the particles remain in their XRD amorphous state. This can be achieved, for example, by formulating the particles with a paste-forming compound that is substantially free of water (such as <10% by weight) to form a composition. The present invention provides a method for forming such a composition comprising uniformly dispersed particles, a limited amount of free water, and having stable properties. This method of forming the composition is also advantageous in preparing a finished product (e.g., a toothpaste to which the composition can be added). Therefore, advantageously, the composition has good fluidity and / or viscosity and can be easily mixed with other ingredients to prepare, for example, a toothpaste.

[0066] The particles of the present invention are preferably used in or formulated in a composition, wherein the composition is preferably in the form of a slurry or suspension. In addition to the particles, the composition also includes a paste-forming compound, which is preferably selected from glycerol, triglycerides, 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 may also include free water, preferably 10% or less of free water by weight of the total composition, or more preferably 8% or less of free water, or even more preferably 5% or less of free water, but preferably 1% or more, more preferably 2% or more, and even more preferably 3% or more of free water by weight.

[0067] Glycerol is a preferred paste-forming compound because it is widely used and recognized as an acceptable ingredient in pharmaceuticals, cosmetics, and personal care products. Glycerol is readily soluble in water and has a high boiling point. In the method described herein, by selecting an appropriate drying temperature, it can be selectively retained in the composition while evaporating excess free water. In addition, glycerol is hygroscopic, which is believed to help extract the free water found near the particles, thereby improving the stability of the particles. The affinity of water for glycerol further allows some free water to remain in the composition without significantly compromising shelf life, thereby helping to prepare a composition with a high particle content, which still has good viscosity because there is less free water to remove, and makes the preparation process easier and more economical.

[0068] 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 still crystallize over time under ambient conditions, depending on temperature and humidity. The composition according to the present invention comprising particles and a paste-forming compound enables long-term stability of the particles.

[0069] The composition or granule-containing product formulation of the present application preferably has a very limited amount, such as <10 wt.%, of free water. Some of the free water is bound to the glycerol and can remain in the composition even after drying. Excess free water can degrade the granules, which can then form smaller granules with a higher tendency to crystallize. This process of granule degradation and crystallization is essential for the bioactivity of the granules (to induce mineralization and occlusion of dentin tubules) and should therefore preferably be preserved until they reach the treatment site or until they come into contact with saliva and dentinal fluid in the oral cavity and on the dentin surface. However, a composition that is completely free of water is also undesirable because it would be too thick to function properly in a toothpaste or the like. By keeping a small amount, such as <10 wt.% and >1 wt.%, of free water in the composition or granule-containing product formulation, the composition has good flow properties while still maintaining the stability of the granules, i.e., they remain XRD amorphous for 18 months or more. In one embodiment, the amount of free water in the composition is 10 wt.% or less of the total content of the composition or formulation, or more preferably contains 8 wt.% or less of free water, or even more preferably 5 wt.% or less of free water, and preferably 1 wt.% or more, more preferably 2 wt.% or more, even more preferably 3 wt.% or more of free water.

[0070] The composition or granule-containing product formulation can further preferably contain additives, such as fluoride, potassium, hydrogen peroxide or urea peroxide, xylitol, xanthan gum, flavorants (e.g., menthol), polymeric thickening agents, or preservatives. Fluoride is preferred because it strengthens the teeth. Potassium is a preferred nerve depolarizer. Hydrogen peroxide and urea peroxide are preferred tooth bleaching agents.

[0071] In the composition, the granules are preferably present in an amount or concentration of 1 wt.% to 50 wt.%. This amount should be adjusted so that the viscosity, uniformity, and handleability of the composition are sufficient to ensure that the granules are adequately dispersed and do not agglomerate. The concentration of granules in the composition should preferably be high enough to maximize the value per unit volume, but not so high that the viscosity increases to a level that impedes normal handling or homogenization. In a preferred embodiment, the amount of granules in the composition is 25 wt.% to 50 wt.%. In another preferred embodiment, the amount is 35 wt.% to 45 wt.%, more preferably about 40 wt.%. The amount or concentration of the pasting compound is preferably at least 50 wt.%, more preferably at least 55 wt.%. In a preferred embodiment, the concentration of the pasting compound is 55 wt.% to 65 wt.%, preferably about 60 wt.%. In a preferred embodiment, the composition includes 35 wt.% to 45 wt.%, preferably about 40 wt.% of the granules, 50 wt.% to 60 wt.%, preferably about 55 wt.% of the glycerol, and 3 wt.% to 8 wt.%, preferably about 5 wt.% of the free water.

[0072] The presence of the paste-forming compound, magnesium, and the method of mixing the particles and the paste-forming compound and drying to form the composition are important for the long-term stability and shelf life of the particles. The inventors have demonstrated that the particles in the compositions 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°C to 25°C), and accelerated conditions refer to 40°C.

[0073] The composition can be used to prepare product formulations containing particles, such as tooth or oral care products. Tooth or oral care products such as toothpaste, desensitizing gel, bleaching paste or gel, tooth varnish, toothpaste or sealant preferably contain 0.5% to 15% by weight of the particles of the present invention, as well as some paste-forming compounds and additives. The concentration of the paste-forming compound varies in different product formulations containing particles, so as to provide product formulations containing particles for different applications with good handling properties, such as viscosity, uniformity and spreadability. In a preferred embodiment for desensitizing gel, the concentration of the particles is 5% to 9% by weight, more preferably 6% to 8% by weight, and more preferably about 7.5% by weight. The concentration of the paste-forming compound is preferably 50% to 90% by weight, more preferably 60% to 85% by weight, and more preferably 70% to 80% by weight, so as to provide the product with good handling properties, such as viscosity, uniformity and spreadability.

[0074] The long-term stability of product formulations containing particles is important for ensuring adequate product shelf life. For example, during storage, it is important that the particle appearance and composition consistency are substantially maintained and that the particles remain XRD amorphous. Referring to Examples 26 and 27, the inventors have demonstrated that desensitizing gels containing the particles and additives of the present invention are stable under both ambient and accelerated conditions for extended periods of time. The desensitizing gel preferably contains 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, and preferably 8% by weight or less or about 7.5% by weight of particles.

[0075] The toothpaste preferably contains 0.5 to 6 wt% of particles. In a preferred embodiment, the toothpaste contains 0.5 wt% or more, or 1 wt% or more of particles, but preferably 5 wt% or less, or 4 wt% or less, or 3 wt% or less.

[0076] The varnish, toothpaste or sealant preferably contains 5% to 15% by weight of particles. In a preferred embodiment, the varnish, toothpaste 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.

[0077] Now see Figure 4 to Figure 5wherein a general method for preparing the spheroidal and hollow particles of the present application is disclosed, wherein step 1 schematically represents points a to b in the claimed method, step 2 represents point c, step 3 represents points d to e, and step 4 represents point f.

[0078] In a first step, a first aqueous solution is provided having a pH of 6 to 10, preferably 7 to 10, more preferably 7 to 8, and wherein the solution has a first temperature. The first aqueous solution comprises 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 the group consisting of sodium, potassium, chloride, silicon, zinc, and fluorine, or combinations thereof. The molar ratio of H2PO4:HPO4in the first aqueous solution is preferably in the range of 0-100:75-600, more preferably 1-2:4-6. In a preferred embodiment, the concentration of dihydrogen phosphate is 0 to 100 mM, or more preferably 20 mM to 80 mM. The concentration of hydrogen phosphate in the first aqueous solution is preferably 30 mM to 300 mM, more preferably 80 mM to 250 mM. The total concentration of phosphate in the first aqueous solution is preferably 60 mM to 800 mM.

[0079] A second aqueous solution having a second temperature is also provided, which comprises calcium ions and magnesium ions, counter ions, and optionally additional ions. The counter ions are preferably chloride ions, sodium ions, and / or potassium ions. The additional ions can be selected from the group consisting of sodium, potassium, chloride, silicon, zinc, and fluorine, or combinations thereof. The concentration of calcium in the second aqueous solution is preferably 10 mM to 200 mM, and the concentration of magnesium is preferably 5 mM to 120 mM. In a preferred embodiment, the calcium concentration is 20 mM to 100 mM, more preferably 30 mM to 70 mM. In another preferred embodiment, the magnesium content is 10 mM to 60 mM, more preferably 12 mM to 40 mM. In the second aqueous solution, calcium is preferably in molar excess 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.

[0080] In a preferred embodiment, the amount of phosphate in the first aqueous solution is in molar excess to the total amount of calcium and magnesium in the second aqueous solution. In a preferred embodiment, the molar ratio of phosphate to calcium ions and magnesium ions (PO4:(Ca+Mg)) is 1.5:1 or higher, preferably 2:1 or higher. In another preferred embodiment, the molar ratio is 2:1 to 6:1, or more preferably 2.2:1 to 5:1.

[0081] The first aqueous solution and the second aqueous solution have a first temperature and a second temperature, respectively, and the first temperature and the second temperature are preferably each 10°C to 35°C, more preferably 20°C to 30°C, and more preferably 20°C to 25°C. The water in the first aqueous solution and the second aqueous solution can 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, namely the first aqueous solution and the second aqueous solution, it should be understood by those skilled in the art that the first aqueous solution and the second aqueous solution can actually each be two or more aqueous solutions or sub-solutions.

[0082] Then, at least one of the two aqueous solutions, i.e., the first aqueous solution and / or the second aqueous solution, is heated to a first high temperature and a second high temperature, respectively. In one embodiment, the first aqueous solution and the second aqueous solution are heated to a first high temperature and a second high temperature, respectively. Figure 4 In the right-hand side, both solutions are heated using a heat exchanger, but any suitable heating device may be used. Without being bound by theory, it is believed that the heating step is important for the formation of nanobubbles (persistent, gas-containing cavities) in the electrolyte solution. When the two solutions come into contact, ions from both solutions precipitate on the nanobubbles and form the hollow structure of the particles of the present invention. Heating at least one of the two solutions should increase the temperature of each solution by preferably at least 40°C, more preferably at least 50°C. In other words, the first temperature / second temperature and the first elevated temperature / second elevated temperature are a first temperature difference and a second temperature difference, respectively. In a preferred embodiment, the first temperature difference is between 40°C and 80°C, preferably between 50°C and 70°C. In another preferred embodiment, the second temperature difference is between 40°C and 80°C, preferably between 50°C and 70°C. The first elevated temperature and the second elevated temperature are each preferably at least 60°C, more preferably between 70°C and 90°C.

[0083] The two solutions, at least one of which has been heated, are then brought into contact with each other to produce a third aqueous solution having a third temperature ( Figure 5 , step 3). This can be done by adding one of the solutions to the other solution, preferably the second solution to the first solution, but preferably the two solutions are contacted in a continuous manner, and preferably in a continuous flow. By contacting them in a continuous flow, more efficient production is promoted, making it easier to scale up the output of the particles formed and providing better control of the process. In one embodiment, the two solutions (the first aqueous solution and the second aqueous solution) are contacted in a manifold or a three-way manifold, preferably in a Y-shaped manifold (Y-shaped cross section), such as Figure 5(Left hand side) Schematically shown. When the two solutions come into contact with each other, precipitation occurs more or less immediately (<10 seconds), and the precipitation is continued for a suitable period of time, which depends on practical limitations and targeted fine-tuning of the desired properties, but is typically 1 second to 600 seconds. If the starting solution is supplemented, the continuous flow process in which the two solutions are mixed can be continued, allowing the particles formed to be continuously recovered. When the first solution and the second solution come into contact, the amount of phosphate radical is in molar excess over the total amount of calcium and magnesium (PO4>(Ca+Mg)). Without being bound by theory, in the third aqueous solution, the total amount of phosphate radical in excess of calcium and magnesium will increase the buffering capacity, which in turn limits the formation of crystalline calcium phosphate phases, see Example 12. In a preferred embodiment, in the third aqueous solution, the molar ratio of phosphate radical to calcium and magnesium (PO4:(Ca+Mg)) is 1.5:1 or higher, preferably 2:1 or higher. In another preferred embodiment, the molar ratio is 2:1 to 6:1, or more preferably 2.2:1 to 5:1. In a preferred embodiment, in the third aqueous solution, calcium is in molar excess over 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.

[0084] In a preferred embodiment, the third temperature is 70° C. to 95° C., more preferably 80° C. to 85° C., because the mass yield of the reaction is higher and the degree of crystallization increases at a temperature greater than 100° C., see Example 16. When the first aqueous solution and the second aqueous solution are contacted, the volume ratio between the first aqueous solution and the second aqueous solution is preferably 2:1 to 1:2, preferably 1.10:1 to 1:1.10, or preferably 1.05:1 to 1:1.05, or more preferably 1:1.

[0085] A suspension of precipitated particles and an aqueous solution is formed, and the precipitated particles are then separated and / or collected using any suitable technique. Preferably, separation and / or collection is accomplished using suitable filtration techniques, centrifugation and / or sedimentation and decantation. The separated and / or collected particles are then preferably washed using any suitable solvent, such as water or an alcohol. Preferably, the washing is performed using purified water, more preferably deionized water, distilled water, double-distilled water, or ultrapure water. The washing may preferably be performed at a fourth temperature of 50°C to 90°C, more preferably 70°C to 80°C. To ensure that the particles are clean and free of undesirable ionic residues, the washing step may be repeated. The separated and / or collected and washed particles may then be dehydrated or partially dehydrated, preferably by centrifugation or more preferably at elevated temperature and / or reduced pressure. In a preferred embodiment, the dehydration / partial dehydration or drying is performed at a fifth temperature of at least 50°C, preferably 50°C to 150°C, more preferably 60°C to 110°C, more preferably 60°C to 80°C or about 80°C. 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 well suspended and uniformly dispersed in the slurry, and the slurry can be easily mixed with the paste-forming compound to form a wet composition that is substantially free of any agglomerates. Further dehydration of the slurry or complete drying of the particles at this stage would result in the formation of larger particle agglomerates, which are increasingly difficult to mix and uniformly suspend in the paste-forming compound to obtain a smooth and free-flowing composition. The inventors have found that when dry or substantially dry separated particles are mixed with the paste-forming compound, it is essentially impossible to obtain a similarly uniform, smooth and free-flowing composition even when finely ground and sieved powders are used. Avoiding drying and grinding to form a fine powder for dispersion in the paste-forming compound or product formulation also reduces the health and safety risks associated with powder handling.

[0086] Drying the particles in the absence of a pasting compound may also inadvertently increase crystallinity and promote the formation of harder particles that may require high energy to disperse, thereby compromising particle integrity. The stability of the particles of the present invention is limited when stored as a fine powder under ambient conditions, see Example 30, further emphasizing the importance of forming a composition with a pasting compound at the manufacturing stage.

[0087] In one embodiment, despite the above disadvantages, the formed, separated and optionally washed and / or dewatered particles are further dried to form a powder at a sixth temperature of preferably 50°C to 150°C, more preferably 60°C to 110°C, if necessary.

[0088] Turning now to Figure 6a, which schematically illustrates the preparation of a composition of the present invention. The preparation of the composition of the present invention is accomplished by preparing particles of the present invention and mixing the particles with a paste-forming compound. The mixing of the particles with the paste-forming compound is preferably performed after the particles are partially dehydrated, i.e., while the particles are still suspended and preferably evenly distributed in the slurry. Prior to mixing with the paste-forming compound, the slurry preferably comprises 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, triglycerides, 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 substantially free of water (such as <10% by weight of water).

[0089] The resulting composition of particles, free water and paste-forming compound is preferably dehydrated to remove as much free water as possible and form a stable and uniform composition with long-term stability. 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. Retaining a small amount of water in the composition can help form a smooth and uniform composition with suitable 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 resulting mixture of spherical and hollow particles and paste-forming compound is preferably dehydrated at a seventh temperature and / or reduced pressure, wherein the seventh temperature is preferably in the range of 50°C to 150°C, more preferably 60°C to 90°C. The reduced pressure is preferably 500 mbar or less. Preferably, during and / or after dehydration, the mixture is preferably homogenized by mechanical means to form a smooth composition. The resulting mixture can be homogenized, for example, using a mechanical homogenization device such as a rotor-stator homogenizer for 1 to 30 minutes. The preparation of the composition is schematically summarized in Figure 6b. As shown in the figure, the method includes at least three steps:

[0090] 10:1: partially dehydrating the ACP particles prepared as described above, dehydrating the particles until they form a slurry containing 10% to 30% by weight of particles and 70% to 90% by weight of water;

[0091] 10:2: Mixing the slurry containing the particles with the paste-forming compound until a homogeneous mixture is formed; and

[0092] 10:3: Dehydrating the composition formed in step 10:2 at a seventh temperature and / or under reduced pressure until the amount of water is 8 wt % or less, or 5 wt % or less, or 2 wt % or less.

[0093] The hygroscopicity of glycerol enables it to be an effective preservative for the amorphous calcium magnesium phosphate particles according to the present invention. Advantageously, for compositions comprising glycerol, the ACP particles can remain XRD amorphous during storage even in the presence of excess free water, see Example 28.

[0094] Tooth bleaching or whitening is a common practice in modern cosmetic dentistry, typically using hydrogen peroxide or carbamide peroxide to remove stains and enhance the appearance and whiteness of teeth. Different markets currently allow the use of different strengths of peroxide in whitening products, but a typical formulation of a takeaway product contains 16% carbamide peroxide, equivalent to 5% to 6% hydrogen peroxide. Common side effects of tooth whitening are increased tooth sensitivity, and tooth enamel may soften due to the treatment, resulting in reduced tooth strength. Therefore, it is of interest to provide effective whitening products and treatments that can also reduce tooth sensitivity and increase the hardness of tooth enamel through mineralization. Therefore, as shown in Example 29, the composition according to the present invention does not adversely affect the bleaching process of tooth whitening products, which may also be an advantage.

[0095] Example

[0096] Example 1

[0097] according to Figure 4 According to step 1 of the present invention, a first aqueous solution (pH 7.4) was prepared using concentrates of 125 mM NaCl, 160 mM Na2HPO4 and 30 mM KH2PO4, and a second aqueous solution was prepared using concentrates of 125 mM NaCl, 25 mM CaCl2 and 15 mM MgCl2. Figure 4 In step 2, the two solutions were heated from room temperature to 85°C by a plate heat exchanger, and then Figure 5 In step 3 of the method, flow mixing was performed at a volume ratio of 1:1 to form a precipitate at 85°C. Figure 5 According to step 4 in Figure 6 , the precipitate was collected by filtration using a fine mesh filter cloth, washed with deionized water at 70°C, and partially dehydrated using vacuum. According to step 5 in Figure 6 , the slurry containing approximately 20% by weight of the precipitated particles and 80% by weight of water was mixed with glycerin to form a homogeneous mixture having a dry weight ratio of particles to glycerin of 2:3. The mixture was then dried in a forced convection oven at 80°C to remove water, and mechanically homogenized to form a smooth, viscous composition, according to step 6 in Figure 6 . The composition had a dry content of 98% by weight.

[0098] The particles formed are spherical in shape and consist of a porous shell and a hollow interior. The diameter of a single sphere ranges from 100nm to 300nm, while the diameter of clusters and composites of fused spheres ranges from 200nm to 500nm. Representative scanning electron microscopy (SEM) images of the particles are shown in Figure 2. Figure 1 shown.

[0099] XRD analysis of the particles showed that they were amorphous. There was no characteristic peak, only a large increase in intensity around 2θ = 30°, indicating the presence of amorphous calcium phosphate, see Figure 2 .

[0100] The elemental analysis of the particles was determined by inductively coupled plasma optical emission spectroscopy (ICP-OES) and confirmed the contents shown in Table 1. Assuming that all P is present in the form of PO4, the calculated PO4 content and the Ca / P and (Ca+Mg) / P molar ratios are also shown in the table. The measured values ​​of Ca and Mg combined with the calculated values ​​of PO4 total 86 wt%, resulting in approximately 14 wt% bound HO. Based on the data in the examples, the balanced chemical formula of the particles is proposed:

[0101] Ca 2.7 Mg 1.3 H(PO4)3*4H2O

[0102] Table 1. ICP-OES elemental analysis results of the formed particles.

[0103]

[0104] wt% means weight%.

[0105] The formed particles were suspended in ethanol and the aggregated particles were dispersed using ultrasound, and the particle size distribution was determined by DLS. The z-average particle size was 370 nm, and its number distribution was as follows Figure 3 shown.

[0106] The surface area of ​​the material, measured according to the BET method using nitrogen, is 24 m 2 / g.

[0107] Example 2

[0108] A first aqueous solution (pH 7.4) was prepared from the concentrates of 500 mM NaCl, 640 mM Na2HPO4, and 119 mM KH2PO4. A second aqueous solution was prepared from the concentrates of 500 mM NaCl, 100 mM CaCl2, and 60 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to the Figure 1The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0109] Example 3

[0110] A first aqueous solution (pH 7.4) was prepared using 100 mM NaCl, 128 mM Na2HPO4, and 24 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 70°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0111] Example 4

[0112] A first aqueous solution (pH 7.4) was prepared using 100 mM NaCl, 128 mM Na2HPO4, and 24 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 80°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0113] Example 5

[0114] A first aqueous solution (pH 7.4) was prepared using 100 mM NaCl, 128 mM Na2HPO4, and 24 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 90°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0115] Example 6

[0116] A first aqueous solution (pH 7.4) was prepared with 160 mM Na2HPO4 and 30 mM KH2PO4. A second aqueous solution was prepared with 50 mM CaCl2 and 30 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0117] Example 7

[0118] A first aqueous solution (pH 4.7) was prepared using 100 mM NaCl and 150 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed using SEM and XRD. The precipitated particles were round, but not spherical. The particles had a rough surface and did not appear to be hollow. XRD analysis showed that the particles were crystalline white phosphate, a magnesium ion-substituted form of tricalcium phosphate (TCP).

[0119] Example 8

[0120] A first aqueous solution (pH 6.4) was prepared using 100 mM NaCl, 75 mM Na2HPO4, and 75 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0121] Example 9

[0122] A first aqueous solution (pH 8.1) was prepared using 100 mM NaCl, 145 mM Na2HPO4, and 4.8 mM KH2PO4. A second aqueous solution was prepared using 100 mM NaCl, 20 mM CaCl2, and 12 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0123] Example 10

[0124] A first aqueous solution (pH 9.3) was prepared using 75 mM Na2HPO4. A second aqueous solution was prepared using 20 mM CaCl2 and 12 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0125] Example 11

[0126] A first aqueous solution (pH 9.4) was prepared using 190 mM Na2HPO4. A second aqueous solution was prepared using 50 mM CaCl2 and 30 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 Spectrum shown.

[0127] Example 12

[0128] A first aqueous solution (pH 9.3) was prepared with 60 mM Na2HPO4. A second aqueous solution was prepared with 50 mM CaCl2 and 30 mM MgCl2. The two solutions were heated to 85°C separately and then mixed in a volume ratio of 1:1 to form a precipitate. The precipitate was collected by filtration, washed and analyzed by SEM and XRD. The collected particles were not spherical or hollow, but consisted of irregular and seemingly dense particles with rough surfaces. XRD analysis of the material showed that the crystalline phase was white phosphate calcium phosphate. This result is consistent with the type of particles formed at low pH as confirmed in Example 7. The difference from this embodiment is that the initial pH of the phosphate solution is higher and that HPO4 2- No excess of Ca 2+ and Mg 2+ The content causes the following reactions:

[0129] 3-xCa 2+ +xMg 2+ +2HPO4 2- →Ca 3-x Mg x(PO4)2+2H +

[0130] No excess HPO4 2- , the system will lose its buffering capacity, and the product H + This will lower the pH and cause the formation of TCP crystalline particles having a higher Ca / P ratio than the particles formed and characterized in Example 1.

[0131] Example 13

[0132] A first aqueous solution (pH 9.4) was prepared using 220 mM Na2HPO4. A second aqueous solution was prepared using 60 mM CaCl2 and 36 mM MgCl2. The two solutions were heated to 85°C and then mixed in a 1:1 volume ratio to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to those of the Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 The pH of the filtrate is 7.0, indicating that HPO4 2- The excess is sufficient to maintain neutral pH.

[0133] This example produced particles with twice the mass of particles produced in Example 1.

[0134] Table 2: Summary of process parameters and compositions used to synthesize particles in Examples 1 to 13.

[0135]

[0136] In the result column: Spher.part indicates spherical particles, Amorph. indicates amorphous.

[0137] Example 14

[0138] A first aqueous solution was prepared using 0.5 mM KCl, 200 mM NaCl, 16 mM Na2HPO4, and 3 mM KH2PO4. A second aqueous solution was prepared using 0.5 mM KCl, 200 mM NaCl, 2.5 mM CaCl2, and 1.5 mM MgCl2.

[0139] In the first experiment, the two solutions were heated separately to 45°C. Then equal volumes of the first solution (phosphate) and the second solution (calcium and magnesium) were mixed to form a precipitate, i.e. Figure 1 and 5 The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were a mixture of spherical particles and microcrystals, and were identified as brushite (CaHPO4*2H2O) by XRD.

[0140] In the second experiment, the two solutions were heated to 65°C separately. Then, equal volumes of the first solution (phosphate) and the second solution (calcium and magnesium) were mixed to form a precipitate. The precipitate was collected by filtration, washed, and analyzed by SEM and XRD. The particles formed were similar in shape, size, and appearance to the first solution. Figure 2 The particles shown are similar and are XRD amorphous, similar to Figure 4 Spectrum shown.

[0141] In the third experiment, the two solutions were heated separately to 85°C. Then, equal volumes of the first solution (phosphate) and the second solution (calcium and magnesium) were mixed to form a precipitate. The precipitate was collected by filtration, washed, and analyzed using SEM and XRD. The particles formed were similar in shape, size, and appearance to the first solution. Figure 1 The particles shown are similar and are XRD amorphous, similar to Figure 2 The mass yield of the reaction performed at 85 °C was increased compared to the experiment performed at 65 °C.

[0142] This series of experiments showed that there is a preferred temperature window in which the precipitation reaction is stable and efficient in terms of consistency in shape, size, appearance and mass yield.

[0143] Example 15

[0144] Use 0.5mM KCl, 200mM NaCl, 16mM Na HPO and 3mM KH PO to prepare the first aqueous solution (pH 7.4). Use 0.5mM KCl, 200mM NaCl, 2.5mM CaCl and 0.75mM MgCl to prepare the second aqueous solution. Both solutions are heated to 85 ℃ respectively. Then the first solution (phosphate) and the second solution (calcium and magnesium) are mixed in equal volumes to form a precipitate. The precipitate is collected by filtration, washed and analyzed with SEM and XRD. There is no spherical particle, but a poor crystalline phase identified as white patite in XRD is formed.

[0145] In the second experiment, a first aqueous solution was prepared using 0.5 mM KCl, 200 mM NaCl, 16 mM Na HPO and 3 mM KH PO. A second aqueous solution was prepared using 0.5 mM KCl, 200 mM NaCl and 2.5 mM CaCl. The two solutions were heated to 85°C respectively. The first solution (phosphate) and the second solution (calcium and magnesium) were then mixed in equal volumes to form a precipitate. The precipitate was collected by filtration, washed and analyzed using SEM and XRD. No spherical particles were present, but plate-like crystals were formed that were identified as tricalcium phosphate (TCP) in XRD.

[0146] These experiments indicate that magnesium ions act as stabilizers for the amorphous phase and that a sufficient degree of magnesium ion substitution is required to maintain the amorphous phase.

[0147] Example 16

[0148] A microwave synthesizer was used to evaluate alternative heating methods and an extended process temperature range. For these experiments, a single solution was prepared with 0.5 mM KCl, 200 mM NaCl, 16 mM Na2HPO4, 3 mM KH2PO4, 2.5 mM CaCl2, and 1.5 mM MgCl2. In different experiments, the solution was placed in a sealed glass vial and heated rapidly (< 2 minutes) from room temperature (23°C) to 50°C, 70°C, 90°C, 100°C, 120°C, or 140°C using microwave-assisted heating. The obtained precipitates were analyzed by SEM, which showed that in all cases spherical and hollow particles were formed, which was consistent with the results of the experiment. Figure 1 The particles shown are comparable. At temperatures of 100°C or above, the particles have a slightly rougher surface character and show signs of crystallization.

[0149] These experiments demonstrate that particles can be synthesized using alternative heating regimes and that particles can be synthesized over a wide temperature window depending on the heating regime.

[0150] Example 17

[0151] The pH buffering capacity of a composition containing 40% by weight of spherical and hollow calcium magnesium phosphate particles and 60% by weight of glycerol according to the present invention was evaluated by mixing with deionized water. In the experiment, 0.5 g of the composition was added to 500 mL of water to obtain a concentration of 0.1% by weight. The pH of the solution was monitored for the first 30 minutes of dissolution of the composition, and the results were shown in FIG. Figure 2 By adding the composition, the pH of the solution increased dramatically from about 7.5 to 9.5 within 5 minutes and remained stable thereafter.

[0152] This rapid release of ions is an important feature of certain dental materials and products because the local increase in pH promotes the nucleation and growth of hydroxyapatite, which benefits the remineralization of enamel and dentin.

[0153] Example 18

[0154] The desensitizing gel of the present invention containing 7.5 wt% of spherical and hollow calcium magnesium phosphate particles was mixed into aqueous solutions of pH 4 and pH 7.9 at a concentration of 0.1 wt%. The pH of the starting solution was adjusted with 0.1 M HCl and 0.1 M NaOH, respectively. The pH of the solution was monitored for 30 minutes before the gel dissolved. The results showed that Figure 1In both cases, the gels were found to increase pH, from 4.0 to 8.6 and from 7.9 to 9.3, respectively. Similar experiments with corresponding gels in which inert glass particles were substituted for the calcium magnesium phosphate produced no pH change, indicating that the particles were responsible for the effect.

[0155] The desensitizing gel is intended as a treatment option for dentin hypersensitivity by remineralizing exposed dentinal tubules. The increase in pH caused by the particles will promote the nucleation and growth of hydroxyapatite mineral on the dentin surface and within the exposed dentinal tubules.

[0156] Example 19

[0157] The spherical and hollow calcium magnesium phosphate particles of 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 release of calcium ions, magnesium ions, and phosphate ions from the particles was monitored by filtering the particles and analyzing the filtrate using ICP-OES. The filtrate was diluted before analysis. The results are shown in Figure 7 The release was characterized by an initial burst followed by a decrease in ion concentration, most notably for Ca. The initial burst of ion release would promote a rapid mineralization process, and the subsequent decrease in the calcium content in the filtrate indicates that calcium phosphate reprecipitated from solution, but at a higher Ca / P ratio than that of the original particles, i.e., calcium phosphate with a Ca / P ratio closer to that of hydroxyapatite was formed.

[0158] Example 20

[0159] A gel containing 5 wt% of the spherical, hollow calcium magnesium phosphate particles of the present invention was prepared and used to evaluate dentin occlusion and remineralization properties. A similar gel containing 5 wt% of hollow calcium phosphate particles according to a previous invention (WO 2014 / 148997 A1) was also prepared and tested in parallel to compare the results.

[0160] In this study, 1 mm thin dentin specimens were cut from extracted permanent molars of human origin and etched in phosphoric acid to expose the tubules. The gel was applied to the exposed dentin surface twice daily for up to 7 days by brushing with a soft-bristled toothbrush. The dentin specimens were stored in artificial saliva at 37°C between brushings. After the final gel application, the specimens were dried and prepared for evaluation in the SEM. The appearance of the dentin surface after 4 and 7 days of treatment with the gel is shown in Figure 8 and Figure 9Compared to particles prepared according to WO 2014 / 148997, the particles according to the present invention caused faster and more complete tubule occlusion. This was attributed to the smaller average diameter of the spherical particles, which made it easier for them to penetrate the tubules, and the amorphous nature of the particles, which made them dissolve more quickly and release the bioactive ions that mineralized the surface.

[0161] Example 21

[0162] The dentin occlusive and remineralizing properties of a desensitizing gel formulated with 7.5 wt.% of the present invention's spherical, hollow calcium magnesium phosphate particles were evaluated. In this study, 1 mm thin dentin specimens were cut from extracted permanent molars of human origin and etched in phosphoric acid to expose the tubules. The dentin specimens were then brushed with the gel twice daily for one minute per side for 14 days. After each brushing event, the specimens were rinsed with deionized water and stored in artificial saliva at 37°C until the next brushing event. After treatment, the specimens were vacuum dried and evaluated in a SEM.

[0163] The processing results are shown in Figure 10 In the study, complete occlusion of exposed dentinal tubules was demonstrated. Evaluation of cross-sections revealed that mineralization occurred deep within the tubules (>60 μm). The degree of occlusion achieved by treatment reliably and completely eliminated fluid movement within the tubules, providing effective pain relief for hypersensitive teeth.

[0164] Example 22

[0165] The dentin occlusive and remineralizing properties of a desensitizing gel formulated with 7.5 wt. % of the present invention's spherical and hollow calcium magnesium phosphate particles were evaluated when applied in conjunction with a fluoride toothpaste. In this study, 1 mm thin dentin specimens were cut from extracted permanent molars of human origin and etched in phosphoric acid to expose the tubules. The dentin specimens were first brushed with a standard fluoride toothpaste and then with the desensitizing gel. This event was repeated four times daily over four days. The dentin specimens were stored in artificial saliva at 37°C between brushings. After treatment, the specimens were vacuum dried and evaluated in a SEM.

[0166] The processing results are shown in Figure 11 In the dentine specimens, the exposed tubules were completely occluded by a dense mineralized layer. Cross-sectional evaluation of dentin samples showed that the mineral deposited within the tubules was composed of microcrystals with high aspect ratios, and many tubules were completely occluded at a distance of more than 20 μm from the dentin surface.

[0167] Example 23

[0168] The spherical and hollow calcium magnesium phosphate particles of the present invention were stored in municipal tap water and artificial saliva at 37° C. for up to 28 days. The aim was to characterize the degradation and crystallization of the particles in different media over this time period.

[0169] Particle samples were removed after 7, 14 and 28 days for evaluation in SEM and after 28 days for XRD evaluation.

[0170] The results for tap water are shown in Figure 12 In artificial saliva, the particles began to degrade and recrystallize within a week, see Figure 13 After two weeks, no spherical particles remained, and after four weeks, larger plate-like crystals formed. The crystalline phases were identified as hydroxyapatite and leucomorphite, both naturally occurring minerals in human hard tissues.

[0171] Example 24

[0172] A composition according to the present invention containing 40 wt% spherical and hollow calcium magnesium phosphate particles, 55 wt% glycerol and 5 wt% free water was stored in a sealed container at room temperature (20°C to 23°C) for up to 18 months, after which the characteristics of the composition and the particles were evaluated to determine the stability of the particles.

[0173] It was found that the characteristics of the composition were maintained and key properties of the particles such as morphology, crystallinity, particle size and chemical composition were retained. SEM and XRD data are available at Figure 14 The results show that the composition containing particles and glycerol according to the present invention is stable and has a shelf life of at least 18 months.

[0174] Example 25

[0175] Chemical reactions and phase changes, such as degradation or crystallization of amorphous calcium phosphate, are accelerated at elevated temperatures. Stability under accelerated conditions was evaluated by storing a composition according to the present invention containing 40% by weight of spherical and hollow calcium magnesium phosphate particles, 55% by weight of glycerol, and 5% by weight of free water in a sealed container at 40°C for up to 12 months. The composition and particle characteristics were then evaluated to determine stability.

[0176] It was found that the characteristics of the composition were maintained and key properties of the particles such as morphology, crystallinity, particle size and chemical composition were retained. SEM and XRD data are available at Figure 15 Using a conservative acceleration factor of 3 for storage conditions at 40°C, the results indicate that the composition according to the invention having particles and glycerol is stable and has an expected shelf life of 36 months.

[0177] Example 26

[0178] The desensitizing gel containing particles and additives according to the present invention was stored in LDPE tubes suitable for the product at ambient conditions (20°C to 23°C) for up to 18 months, during which time product properties such as water content, consistency and appearance of particles were evaluated. Figure 16 It was found that the performance of the product being evaluated was maintained and it was concluded that the product stability of the desensitizing gel was at least 18 months.

[0179] Example 27

[0180] The desensitizing gel containing particles and additives according to the present invention was stored under accelerated conditions (40°C, >90% rH) in LDPE tubes suitable for the product for up to 12 months, after which product properties such as moisture content, consistency and appearance of the particles were evaluated. Figure 17 The tube weight and gel water content increased slightly due to storage at relatively high humidity, but the particle appearance and gel consistency were largely maintained. Using a conservative acceleration factor of 3 for storage conditions, the tentative shelf life of the desensitized gel was estimated to be 36 months.

[0181] Example 28

[0182] To demonstrate the stability of compositions containing particles and glycerol made according to the present invention, even in compositions containing excess free water (which would normally promote ACP crystallization), compositions containing 40 wt% spherical and hollow calcium magnesium phosphate particles, 55 wt% glycerol, and 5 wt% free water according to the present invention were mixed with water to form mixtures containing 5 wt% to 50 wt% excess free water. These mixtures were stored at ambient conditions (20°C to 23°C) for up to 20 weeks, after which the particles were analyzed by SEM and XRD to record any significant changes in appearance and crystallinity, see Figure 18 and Figure 19 The results in [ 1 ] confirmed that the particles remained spherical and amorphous in mixtures containing 5% to 10% excess water by weight over the study period (20 weeks). In mixtures containing 30% and 50% excess free water by weight, there was a slight change in particle appearance after 20 weeks of storage, but most particles retained their characteristic spherical shape. After 8 weeks of storage, an increase in crystallinity was first noted in the 50% excess free water sample.

[0183] Example 29

[0184] A prototype whitening gel according to the present invention containing 16% by weight of carbamide peroxide and 7.5% by weight of spherical and hollow calcium magnesium phosphate particles was applied to tooth enamel specimens for 6 hours per day for 3 days, with storage in artificial saliva at 37° C. A control whitening gel containing 16% by weight of carbamide peroxide but without particles was evaluated in parallel on tooth enamel specimens from the same teeth.

[0185] Chromatic evaluation after treatment with the different gels confirmed similar whitening effects, indicating that the particles according to the present invention had no adverse effect on the whitening process. Vickers hardness evaluation (300 gf, 10 s) of the enamel samples before and after treatment, based on a two-tailed paired t-test (significance level of 0.05), confirmed a significant increase in hardness for the samples treated with the whitening gel containing the particles, while the hardness of the samples treated with the control gel did not change significantly (see Table 3). The observed increase in hardness for the samples treated with the whitening gel containing the particles indicates that the particles induced mineralization of the surface enamel, thereby strengthening the teeth.

[0186] Table 3. Results of tooth enamel hardness evaluation before and after three days of whitening treatment with gels containing or without particles of the present invention. *Significant difference

[0187] Figure 20 Figure 21 Enamel samples Treatment Vickers hardness (± SD) before treatment 1A Vickers hardness (± SD) after treatment 313.5±11.6 357.5±21.9 <0.01* 1B p value 318.2±9.1 334.9±17.5 0.19 2A Granular gel 294.3±10.4 343.6±22.2 0.02* 2B Control gel 294.8±17.0 296.6±12.3 0.73 2C Granular gel 298.3±23.6 298.2±8.5 0.99

[0188] Example 30

[0189] The amorphous calcium phosphate particles according to the present invention are stabilized by magnesium substitution, but still crystallize over time under ambient conditions. The composition having particles and a pasting compound according to the present invention is formed in part to achieve long-term stability of the particles.

[0190] The particles according to the invention were stored in a closed container in the form of a dry fine powder under ambient conditions for 11 months to evaluate their stability. It was found that some particles retained their spherical shape but showed signs of degradation and crystallization. Other particles had completely transformed. XRD evaluation showed an increase in crystallinity, see Control gel No Figure 22 .

[0191] Compared to the particle stability in the compositions containing glycerol (Examples 24 and 25), the degradation / crystallization of the powder particles was significant.

Claims

1. A composition comprising a paste-forming compound and XRD amorphous calcium magnesium phosphate spherical particles having a hollow core and a shell, wherein the spherical particles are XRD amorphous, and wherein the shell of the spherical particles comprises 15 to 30 wt % calcium, 50 to 70 wt % phosphate, 5 to 11 wt % magnesium, and 1 to 20 wt % bound water, and wherein the Ca / P molar ratio is in the range of 0.70 to 1.20, and wherein the (Ca+Mg) / P molar ratio is in the range of 1.00 to 1.70, and wherein the spherical particles have an average particle size in the range of 100 nm to 500 nm, and wherein the amount of spherical particles in the composition is 35 to 50 wt %; wherein the composition is prepared by the following method, wherein the method comprises: a. providing a first aqueous solution having a pH of 6 to 10 and a first temperature, wherein the first aqueous solution contains dihydrogen phosphate ions and / or hydrogen phosphate ions, and one or more counter ions; b. providing a second aqueous solution having a second temperature, wherein the second aqueous solution contains calcium ions and magnesium ions and one or more counter ions; and wherein the amount of calcium is in molar excess over magnesium; c. heating the first aqueous solution and the second aqueous solution to a first elevated temperature and a second elevated temperature, respectively, wherein the first elevated temperature and the second elevated temperature are each at least 60°C; d. bringing the first aqueous solution and the second aqueous solution into contact with each other to obtain a third aqueous solution having a third temperature, wherein the amount of phosphate in the third aqueous solution is in molar excess over the total amount of calcium and magnesium; e. forming spherical particles; f. collecting the formed spherical particles; g. washing the separated spherical particles with a solvent; h. dehydrating the washed spherical particles at a fifth temperature until a slurry comprising 70% to 95% by weight of free water is obtained; i. mixing the spherical particles with a paste compound, wherein the amount of the spherical particles in the composition is 35% to 50% by weight; j at a seventh temperature so that the mixture of spherical particles and paste compound dehydration; and k. Optionally, homogenizing the mixture of the spherical particles and the paste-forming compound to obtain a composition.

2. The composition according to claim 1, wherein The first aqueous solution contains one or more counterions selected from sodium and / or potassium.

3. The composition according to claim 1, wherein The second aqueous solution contains one or more counterions selected from chloride, sodium and / or potassium.

4. The composition according to claim 1, wherein The washed spherical particles are dewatered at a fifth temperature until a slurry comprising 75 to 85 wt% free water is obtained.

5. The composition according to claim 1, wherein The amount of spherical particles in the composition was 40% by weight.

6. The composition according to claim 1, wherein The paste-forming compound is selected from glycerol, triglycerides, polyethylene glycol, propylene glycol, polypropylene glycol, polyvinyl alcohol, mineral oil or liquid paraffin.

7. The composition according to claim 1, wherein The paste-forming compound is glycerin.

8. The composition according to any one of claims 1 to 7, wherein The spherical particles have a porous shell.

9. The composition according to any one of claims 1 to 7, wherein The spherical particles are long-range amorphous.

10. The composition according to any one of claims 1 to 7, wherein The average particle size of the spherical particles is 150 nm to 450 nm.

11. The composition according to any one of claims 1 to 7, wherein The average particle size of the spherical particles is 250 nm to 350 nm.

12. The composition according to any one of claims 1 to 7, wherein The spherical particles include 12 to 16 wt % of bound water.

13. The composition according to any one of claims 1 to 7, wherein The spherical particles include 20 to 26 wt% calcium, 52 to 64 wt% phosphate, 5 to 9 wt% magnesium, and 12 to 16 wt% bound water, and wherein the Ca / P ratio is 0.80 to 1.00 and the (Ca+Mg) / P ratio is 1.15 to 1.

45.

14. The composition according to any one of claims 1 to 7, wherein The spherical particles further include at least one ion selected from the group consisting of sodium, potassium, silicon, zinc, and fluorine.

15. The composition according to any one of claims 1 to 7, wherein The spherical particles have a diameter of 10 m 2 / g to 40m 2 / g of BET average surface area.

16. The composition according to any one of claims 1 to 7, wherein The spherical particles have a diameter of 15m 2 / g to 35m 2 / g of BET average surface area.

17. The composition according to any one of claims 1 to 7, wherein The spherical particles have a 20m 2 / g to 30m 2 / g of BET average surface area.

18. The composition according to any one of claims 1 to 7, wherein The amount of the paste-forming compound is at least 50% by weight.

19. The composition according to any one of claims 1 to 7, wherein The amount of the paste-forming compound is at least 55% by weight.

20. The composition according to any one of claims 1 to 7, wherein The amount of the paste-forming compound was 60% by weight.

21. The composition according to any one of claims 1 to 7, wherein The composition comprises no more than 10% by weight of free water.

22. The composition according to any one of claims 1 to 7, wherein The composition comprises no more than 8% by weight of free water.

23. The composition according to any one of claims 1 to 7, wherein The composition includes 5% by weight or less of free water.

24. The composition according to claim 21, wherein The composition includes 1 wt% or more of free water.

25. The composition according to claim 21, wherein The composition includes 2% by weight or more of free water.

26. The composition according to claim 21, wherein The composition includes 3 wt% or more free water.

27. The composition according to any one of claims 1 to 7, wherein The composition comprises 35 to 45 wt% of spherical particles, at least 55 wt% of a paste-forming compound and less than 8 wt% of free water.

28. A method of preparing a composition according to any one of the preceding claims, wherein the method comprises: a. providing a first aqueous solution having a pH of 6 to 10 and a first temperature, wherein the first aqueous solution contains dihydrogen phosphate ions and / or hydrogen phosphate ions and one or more counter ions; b. providing a second aqueous solution having a second temperature, wherein the second aqueous solution contains calcium ions and magnesium ions and one or more counter ions; and wherein the amount of calcium is in molar excess over magnesium; c. heating the first aqueous solution and the second aqueous solution to a first elevated temperature and a second elevated temperature, respectively, wherein the first elevated temperature and the second elevated temperature are each at least 60°C; d. bringing the first aqueous solution and the second aqueous solution into contact with each other to obtain a third aqueous solution having a third temperature, wherein the amount of phosphate in the third aqueous solution is in molar excess over the total amount of calcium and magnesium; e. To form spherical particles; f. collecting the formed spherical particles; g. Optionally, washing the separated spherical particles with a solvent; h. Optionally, dehydrating the washed spherical particles at a fifth temperature until a slurry comprising 70% to 90% by weight of free water is obtained; i. mixing the spherical particles with a paste compound, wherein the amount of the spherical particles in the composition is 35% to 50% by weight; j at a seventh temperature so that the mixture of spherical particles and paste compound dehydration; and k. Optionally, homogenizing the mixture of the spherical particles and the paste-forming compound to obtain a composition.

29. The method according to claim 28, wherein The first aqueous solution contains one or more counterions selected from sodium and / or potassium.

30. The method of claim 28, wherein The second aqueous solution contains one or more counterions selected from chloride, sodium and / or potassium.

31. The method of claim 28, wherein The washed spherical particles are dewatered at a fifth temperature until a slurry comprising 75 to 85 wt% free water is obtained.

32. The method of claim 28, wherein: The paste-forming compound is glycerin.

33. The method of claim 28, wherein: The third temperature is 70°C to 95°C.

34. The method according to any one of claims 28 to 33, wherein The temperature difference between the first temperature and the first elevated temperature and the second temperature and the second elevated temperature is at least 40°C.

35. The method according to any one of claims 28 to 33, wherein The temperature difference between the first temperature and the first elevated temperature and the second temperature and the second elevated temperature is 40°C to 80°C.

36. A method according to any one of claims 28 to 33, wherein The temperature difference between the first temperature and the first elevated temperature and between the second temperature and the second elevated temperature is 50°C to 70°C.

37. A method according to any one of claims 28 to 33, wherein The first aqueous solution and the second aqueous solution are brought into contact with each other in a volume ratio of 2:1 to 1:

2.

38. The method according to any one of claims 28 to 33, wherein The first aqueous solution and the second aqueous solution are brought into contact with each other in a volume ratio of 1.10:1 to 1:1.

10.

39. The method according to any one of claims 28 to 33, wherein The first aqueous solution and the second aqueous solution are brought into contact with each other in a volume ratio of 1.05:1 to 1:1.

05.

40. The method according to any one of claims 28 to 33, wherein The first aqueous solution and the second aqueous solution were brought into contact with each other at a volume ratio of 1:

1.

41. The method of claim 37, wherein: The contacting is performed in a continuous manner.

42. The method of claim 37, wherein: The contacting is performed in a continuous flow manner.

43. The method according to any one of claims 28 to 33, wherein The formed and separated spherical particles are washed at a fourth temperature.

44. The method according to claim 43, wherein The fourth temperature is 50°C to 90°C.

45. The method of claim 43, wherein The fourth temperature is 70°C to 80°C.

46. ​​A method according to any one of claims 28 to 33, wherein The formed, separated and optionally washed spherical particles are partially dehydrated using centrifugation or reduced pressure and / or at a fifth temperature.

47. The method of claim 46, wherein The fifth temperature is 50°C to 150°C.

48. The method of claim 46, wherein The fifth temperature is 60°C to 110°C.

49. The method of claim 46, wherein The fifth temperature is 60°C to 80°C.

50. The method according to any one of claims 28 to 33, wherein The water in the first aqueous solution and the second aqueous solution is tap water or purified water.

51. The method according to any one of claims 28 to 33, wherein The water in the first aqueous solution and the second aqueous solution is deionized water, distilled water or ultrapure water.

52. The method according to any one of claims 28 to 33, wherein The solvent in the washing step g is purified water.

53. The method according to any one of claims 28 to 33, wherein The solvent in the washing step g is deionized water, distilled water or ultrapure water.

54. The method according to any one of claims 28 to 33, wherein The pH of the first aqueous solution is 7 to 10.

55. The method according to any one of claims 28 to 33, wherein In the first aqueous solution, the molar ratio of dihydrogen phosphate ions: hydrogen phosphate ions is in the range of 0-100:75-600.

56. The method according to any one of claims 28 to 33, wherein The total concentration of phosphate in the first aqueous solution is 60 mM to 800 mM.

57. The method according to any one of claims 28 to 33, wherein The spherical particles are suspended in a slurry before being mixed with the paste-forming compound, wherein the slurry includes 10 to 30 weight percent of the spherical particles and 70 to 90 weight percent of water.

58. The method according to any one of claims 28 to 33, wherein The spherical particles are suspended in a slurry before being mixed with the paste-forming compound, wherein the slurry includes 15 to 25 weight percent of the spherical particles and 75 to 85 weight percent of water.

59. The method according to any one of claims 28 to 33, wherein The formed, collected, optionally washed and / or dehydrated spherical particles are mixed with a paste-forming compound and dried at a seventh temperature and homogenized to form a uniform composition.

60. The method of claim 59, wherein The seventh temperature is in the range of 50°C to 150°C.

61. The method of claim 59, wherein: The seventh temperature is in the range of 60°C to 90°C.

62. The method of claim 59, wherein: Homogenization is performed by mechanical means to form a homogeneous composition.

63. Use of the composition according to any one of claims 1 to 27 as an ingredient in toothpaste, desensitizing gel, bleaching paste, dental varnish, dental polishing paste, pit and fissure sealant, tooth filling material, pulp capping material, mouthwash, interdental cleaning tool, or chewing gum.

64. A toothpaste, desensitizing gel, bleaching paste, pit and fissure sealant, dental varnish or dental polish comprising the composition according to any one of claims 1 to 27, wherein the amount of spherical particles is from 0.5% to 15% by weight.

65. A bleaching cream comprising the composition of any one of claims 1 to 27 and carbamide peroxide, wherein the amount of the spherical particles is 3% to 10% by weight and the amount of carbamide peroxide is 10% to 20% by weight.

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