WO2016082742A1 - Composition dentaire anti-sensibilité - Google Patents

Composition dentaire anti-sensibilité Download PDF

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Publication number
WO2016082742A1
WO2016082742A1 PCT/CN2015/095412 CN2015095412W WO2016082742A1 WO 2016082742 A1 WO2016082742 A1 WO 2016082742A1 CN 2015095412 W CN2015095412 W CN 2015095412W WO 2016082742 A1 WO2016082742 A1 WO 2016082742A1
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hydroxyapatite
soluble calcium
oral care
care composition
polycarboxylic compound
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PCT/CN2015/095412
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English (en)
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Honglei YUE
Yanxiao LI
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Hawley & Hazel Chemical Co. (Zhongshan) Ltd.
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Publication of WO2016082742A1 publication Critical patent/WO2016082742A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the present disclosure relates to the field of oral care.
  • the present disclosure relates to a composition for blocking a dentinal tubule, a method for manufacturing the composition and uses thereof.
  • Dental hypersensitiveness is a very common and frequent oral condition, and is also one of the common causes of clinical tooth pain.
  • the pathogenesis of dental hypersensitiveness remains unclear, however, the hydrodynamical theory proposed by Brannstrom and Astrom (Brannstrom M, and Astrom A, The hydrodynamics of the dentine; its possible relationship to dentinal pain. Int Dent J, 1972, 22 (2) : 219 ⁇ 227) is currently widely accepted.
  • the hydrodynamical theory when a dentinal tubule is wide-open and over-exposed due to different causes such as gingival atrophy or dental erosion, dentinal tubule fluid which is found inside the dentinal tubule can overflow inward or outward in response to external stimuli (such as temperature, chemical stimulus, mechanical stimulus, etc.
  • J Clin Periodontol, 1987, 14 (5) : 280-284) revealed that the number of open dentinal tubules as well as the average diameter thereof within a unit area on a sensitive dentin surface are multiple-fold of those on an insensitive dentin surface, and consequently the flow speed of dentinal tubule fluid in a sensitive dentin is more than 100-fold higher than that in an insensitive dentin. Therefore, an essential solution to treat dental hypersensitiveness requires blocking a dentinal tubule and reducing permeability of dentin so as to reduce the fluid flow inside the dentin.
  • HAP Hydroxyapatite
  • Nanohydroxyapatite Nano HAP
  • whose nanoscale size effect imparts better adsorption and re-mineralization performance has been considered as a promising de-sensitizing material and attracted considerable attention in the field of dentistry and oral care in international community.
  • Citrate plays an important role in inhibiting the growth of HAP and controlling HAP size (Baoquan Xie and George H. Nancollas, How to control the size and morphology of apatite nanocrystals in bone. PNAS 2010, 107 (52) : 22369-22370) .
  • Citrate also has relatively good biocompatibility with human body, and is important to the growth and re-mineralization of hydroxyapatite. To date, however, no blocking method has been found to enable deep infiltration of hydroxyapatite into a dentinal tubule.
  • the present disclosure relates to compositions for infiltrating into a dentinal tubule to block the dentinal tubule, methods for manufacturing the compositions and uses thereof.
  • the present disclosure provides oral care compositions, comprising hydroxyapatite, a polycarboxylic compound, soluble calcium and an orally acceptable carrier.
  • the hydroxyapatite of the oral care compositions is capable of infiltrating into a dentinal tubule.
  • the hydroxyapatite can infiltrate into the dentinal tubule to a depth of at least about 5 ⁇ m.
  • the polycarboxylic compound is selected from the group consisting of a citrate compound, such as potassium citrate, sodium citrate etc. ; polyaspartate, such as sodium polyaspartate, potassium polyaspartate etc.
  • iminidisuccinate such as tetrapotassium iminidisuccinate, tetrasodium iminidisuccinate etc.
  • 2-phosphonobutane-1, 2, 4-tricarboxylate such as tetrasodium 2-phosphonobutane-1, 2, 4-tricarboxylate etc.
  • polyacrylate such as sodium polyacrylate, potassium polyacrylate etc.
  • the soluble calcium has a concentration (ppm) ranging from about 7.34 ppm to about 800 ppm. In certain embodiments, the ratio of molar concentration (mol/L) of the soluble calcium to molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound ranges from about 0.00178 to about 0.361.
  • the oral care compositions are characterized in that 1) the percentage by mass (w/w) (by dry weight) of the hydroxyapatite in the composition ranges from about 0.01%to about 50%; 2) the percentage by mass (w/w) (by dry weight) of the polycarboxyl radical in the composition ranges from about 0.001%to about 30%; and 3) the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from about 1.238 to about 99.041.
  • the percentage by mass (w/w) of the hydroxyapatite in the oral care compositions ranges from about 0.1%to about 20%. In certain embodiments, the percentage by mass (w/w) of the polycarboxyl of the polycarboxylic compound in the oral care compositions ranges from about 0.01%to about 12%, preferably from about 0.0874%to about 6.995%.
  • the orally acceptable carrier comprises one or more of a thickener, an abrasive, a surfactant and a flavoring agent. In certain embodiments, the thickener comprises one or more of xanthan gum, carrageenan and carboxymethylcellulose sodium.
  • the flavoring agent comprises methyl salicylate and/or eugenol.
  • the oral care composition further comprises one or more active ingredients.
  • the active ingredient comprises an anti-caries agent, an anti-sensitive agent and/or an anti-bacterial agent.
  • the anti-caries agent comprises a source of fluoride.
  • the anti-sensitive agent comprises a source of potassium ions.
  • the composition is toothpaste, gel or mouthwash. In certain embodiments, the composition is tooth strip, oral spray and tooth powder.
  • the present disclosure provides methods for preparing the oral care composition comprising mixing a polycarboxylic compound, hydroxyapatite, and soluble calcium with an orally acceptable carrier.
  • the present disclosure provides aqueous mixtures comprising hydroxyapatite, a polycarboxylic compound and soluble calcium.
  • the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound ranges from about 0.00178 to about 0.361.
  • the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from about 1.238 to about 99.041.
  • the hydroxyapatite has a particle size ranging from about 10 nm to about 100 nm, preferably from about 20 nm to about 50 nm.
  • the aqueous mixtures have a pH from about 7 to about 14.
  • the aqueous mixtures further comprise a metal ion, such as copper ion, zinc ion, silver ion, or any combination thereof.
  • the metal ion is capable of interacting with the carboxyl radical of the polycarboxylic compound.
  • the present disclosure provides methods for preparing the oral care compositions comprising mixing the aqueous mixture with an orally acceptable carrier.
  • the present disclosure provides methods for filling a dentinal tubule comprising contacting a dentin with the oral care composition according to the disclosure to allow the hydroxyapatite to infiltrate into the dentinal tubule.
  • the oral care compositions are toothpaste, and the methods comprise brushing a tooth with the toothpaste to allow the hydroxyapatite to infiltrate into the dentinal tubule.
  • the oral care compositions are gel, and the methods comprise brushing a tooth with the gel or contacting a tooth with the gel to allow the hydroxyapatite to infiltrate into the dentinal tubule.
  • the oral care compositions are mouthwash, and the methods comprise contacting a tooth with the mouthwash to allow the hydroxyapatite to infiltrate into the dentinal tubule.
  • the present disclosure provides dental materials having a dentinal tubule, wherein the dentinal tubule is infiltrated with hydroxyapatite.
  • the dental materials are tooth.
  • the dentinal tubule is infiltrated with the hydroxyapatite to a depth of at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, at least about 20 ⁇ m, at least about 30 ⁇ m, at least about 40 ⁇ m, at least about 50 ⁇ m, at least about 60 ⁇ m, or at least about 70 ⁇ m.
  • the diameter of the dentinal tubule is about 1 ⁇ m to about 4 ⁇ m, such as at least about 1 ⁇ m, at least about 2 ⁇ m, at least about 3 ⁇ m, at least about 4 ⁇ m.
  • the present disclosure provides use of the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium in the manufacture of an oral care composition for relieving or preventing tooth sensitivity.
  • the present disclosure provides uses of the aqueous mixtures comprising hydroxyapatite, a polycarboxylic compound and soluble calcium in the manufacture of an oral care composition for infiltrating a dentinal tubule of a tooth.
  • the present disclosure provides methods for preparing the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium, comprising mixing the hydroxyapatite, the polycarboxylic compound and the soluble calcium in an aqueous solution.
  • the polycarboxylic compound is selected from the group consisting of a citrate compound, polyaspartate, iminodisuccinate, 2-phosphonobutane-1, 2, 4-tricarboxylate, and polyacrylate.
  • Figure 1 illustrates a scanning electron microscope (SEM) image of the Nano HAP raw material with a rod-like shape (raw material 1) .
  • Figure 2 illustrates a scanning electron microscope (SEM) image of the Nano HAP raw material with needle-like shape (raw material 2) .
  • Figure 3 illustrates the Zeta potential of the suspensions of Nano HAP (raw material 1) -potassium citrate-soluble calcium (suspension 1-I ⁇ 1-VIII) , wherein the ratio of the Nano HAP to potassium citrate is 1.25: 0, 1.25: 0.05, 1.25: 0.5, 1.25: 1, 1.25: 2, 1.25: 4, 1.25: 8 and 1.25: 16, respectively.
  • Figure 4 illustrates the Zeta potential of the suspensions of Nano HAP (raw material 2) -potassium citrate-soluble calcium (suspension 2-IV ⁇ 2-XI) , wherein the ratio of the Nano HAP to potassium citrate is 1.25: 0, 1.25: 0.05, 1.25: 0.5, 1.25: 1, 1.25: 2, 1.25: 4, 1.25: 8 and 1.25: 16, respectively.
  • Figure 5 illustrates scanning electron microscope (SEM) images of a model observed from a cross section perpendicular to the dentinal tubules (Model A) with different magnification scales, in which figure 5 (a) is a SEM image of Model A with 500X magnification and Figure 5 (b) is a SEM image of Model A with 5000X magnification.
  • SEM scanning electron microscope
  • Figure 6 illustrates scanning electron microscope (SEM) images of a model observed from a cross section parallel to the dentinal tubules (Model B) with different magnifications scales, in which Figure 6 (a) is a SEM image of Model B with 1000X magnification and Figure 6 (b) is a SEM image of Model B with 10000X magnification.
  • SEM scanning electron microscope
  • Figure 7 illustrates scanning electron microscope (SEM) images of dentinal tubule models (Model A) treated respectively by two commercially available Nano HAPs, in which Figure 7 (a) and Figure 7 (b) correspond to the two Nano HAPs of Figures 1 and 2, respectively.
  • SEM scanning electron microscope
  • Figure 8 illustrates scanning electron microscope (SEM) images of dentinal tubule models (Model A) treated respectively by two commercially available Nano HAPs that were modified by citrate and soluble calcium, in which Figure 8 (a) and Figure 8 (b) correspond to the two Nano HAPs of Figures 1 and 2, respectively.
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • SEM scanning electron microscope
  • Figure 16 illustrates a paste manufactured by the preparation process according to the present disclosure.
  • the present disclosure relates to compositions capable of infiltrating into a dentinal tubule to block the dentinal tubule, methods for manufacturing the compositions and the uses thereof.
  • Dentin is an essential component of teeth. Distributed within dentin are dentinal tubules radiating from the dental pulp to the enamel border. Generally, when the openings of the dentinal tubules at the surface of dentin are exposed to stimuli such as cold, heat, acid, sweet, mechanical or chemical stimuli, the dental pulp nerve endings would be excited to generate transient pain which is a symptom of dentine hypersensitivity. It is reported that there are more open dentinal tubules with larger average diameter in individuals with dentine hypersensitivity than those without. Accordingly, dental hypersensitivity can be relieved or treated by blocking the dentinal tubules to decrease dentin permeability.
  • Dentin is mainly composed of hydroxyapatite, or HAP for short.
  • HAP is well biocompatible and can be used to block dentinal tubules.
  • the blockade efficiency is unsatisfactory, and therefore greatly limits the use of HAP in blocking the dentinal tubules.
  • the present disclosure modifies the surface properties of HAP in such a way to increase the affinity between HAP and the dentin surface, thereby enabling HAP to infiltrate deep into the dentinal tubules. This remarkably improves the efficacy of HAP as a de-sensitizing material and eventually achieves long-lasting anti-sensitive effects.
  • compositions comprising HAP, a polycarboxylic compound and soluble calcium, which are capable of promoting deep infiltration of HAP into dentinal tubules.
  • the polycarboxylic compound is physiologically biocompatible and plays an important role in the growth and re-mineralization of HAP. Since calcium is an ion which contributes to the zeta potential of HAP, it has an important impact on the surface chemical structure and the surface electrical property of HAP.
  • Our studies have demonstrated that a composition comprising the three components is capable of promoting deep infiltration of HAP into dentinal tubules, thereby providing possibility of curing dental hypersensitiveness.
  • the present disclosure provides oral care compositions comprising hydroxyapatite, a polycarboxylic compound, soluble calcium and an orally acceptable carrier.
  • the hydroxyapatite in the oral care composition is capable of infiltrating into a dentinal tubule.
  • the hydroxyapatite can infiltrate into a dentinal tubule to a depth of at least about 5 ⁇ m.
  • infiltrate means that the hydroxyapatite enters into a dentinal tubule to a depth of at least about 5 ⁇ m, such as at least about 10 ⁇ m, at least about 20 ⁇ m, at least about 25 ⁇ m, at least about 30 ⁇ m, at least about 35 ⁇ m, at least about 40 ⁇ m, at least about 50 ⁇ m, etc.
  • the hydroxyapatite infiltrated into a dentinal tubule is capable of effectively decreasing the permeability of the dentin and reducing fluid flow inside the dentin. It is typically recognized that, compared to deposition on the surface of a dentinal tubule, blockade by infiltration inside a dentinal tubule has more remarkable and persistent effects, thereby can provide more effective treatment of dental hypersensitiveness.
  • a polycarboxylic compound and soluble calcium are capable of modifying hydroxyapatite surface to improve the interaction between hydroxyapatite and a tooth, dentin or a dentinal tubule, thereby not only facilitating deposition of hydroxyapatite on the dentin surface but also enabling deep infiltration of hydroxyapatite into a dentinal tubule.
  • a polycarboxylic compound and soluble calcium are capable of modifying the surface of hydroxyapatite to enable dispersion in a more evenly manner, which results in not only effective blockade of the opening of a dentinal tubule but also deep infiltration into the dentinal tubule. Even for hydroxyapatites that are unsuitable to provide blocking effects due to their poor physical properties, they can be modified to effectively block a dentinal tubule and infiltrate deeply into the dentinal tubule after treatment with a polycarboxylic compound and soluble calcium.
  • the hydroxyapatite according to the present disclosure is nanohydroxyapatite.
  • Nanohydroxyapatite due to its small size effect, can provide better adsorption and re-mineralization, and more effectively block the opening of a dentinal tubule and is capable of infiltrate deeply into the dentinal tubule.
  • “Nanohydroxyapatite” as used in the present disclosure denotes hydroxyapatite with a particle size less than 1 ⁇ m.
  • the hydroxyapatite in the oral care composition has a particle size ranging from about 10 nm to about 100 nm.
  • the hydroxyapatite particle in the oral care composition can be observed and counted under an electron microscope.
  • the oral care composition can be diluted in water or in other suitable solvent (s) , and the hydroxyapatite can be separated from micron-sized abrasives or from other micron-sized insoluble solids using different centrifugal speeds or other approaches well-known in the art, and is dried afterwards.
  • Suitable amount of sample is placed on a sample platform and observed under an electron microscope.
  • the total number of hydroxyapatite particles and the number of hydroxyapatite particles within a predetermined particle size are both counted, and the percentage of the hydroxyapatite particles with predetermined particle size in the total particle number is calculated.
  • At least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles in the oral care composition has a particle size no more than 100 nm; or at least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles have a particle size no more than 90 nm; or at least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles have a particle size no more than 80 nm; or at least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles have a particle size ranging between about 10 nm and about 100 nm; or at least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles have a particle size ranging between about 20 nm and about 100 nm; or at least about 50%, about 60%, about 70%, about 80%or about 90%of the hydroxyapatite particles have a particle size
  • the percentage by mass (w/w) of the hydroxyapatite in the oral care composition ranges from about 0.01%to about 50%, more preferably from about 0.1%to about 20%.
  • the percentage by mass (w/w) of the hydroxyapatite in the oral care composition can range from about 0.01%to about 40%, from about 0.01%to about 30%, from about 0.01%to about 20%, from about 0.01%to about 15%, from about 0.01%to about 10%, from about 0.01%to about 5%, from about 0.1%to about 20%, from about 0.1%to about 15%, from about 0.1%to about 10%, from about 0.1%to about 5%, from about 0.1%to about 4.5%, from about 0.75%to about 4.5%, from about 0.75%to about 5%, from about 0.75%to about 10%, from about 0.75%to about 15%, from about 0.75%to about 20%, from about 1%to about 4.5%, from about 1.25%to about 4.5%, from about 1.5%to about 4.5%, from
  • the percentage by mass (w/w) of the hydroxyapatite in the oral care composition is about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.8%, about 2.25%, about 4.5%, or is within a range defined by any two of the above-mentioned values as endpoints, as if each of the ranges has been individually listed in the present disclosure.
  • the amount of the hydroxyapatite in the oral care composition can be calculated based on the formula of the oral care composition.
  • Soluble calcium denotes the calcium which exists in a form other than precipitates in a solvent (e.g. water) or medium (e.g. toothpaste) .
  • Soluble calcium can include those which after being dispersed in a solvent or medium, are present in the form of ions, complexes or chelates, and dispersible conjugates (e.g. calcium conjugated with a protein) .
  • Soluble calcium mainly contrasts to calcium which exists as part of an insoluble component, such as calcium existed in hydroxyapatite crystal. Soluble calcium can be obtained by appropriate approaches in the art.
  • soluble calcium derives from impurities in the raw material of hydroxyapatite, for example, the residual soluble calcium due to incomplete reaction in the course of hydroxyapatite preparation.
  • soluble calcium derives from decomposition product of hydroxyapatite.
  • soluble calcium can be produced from hydroxyapatite decomposition under an acidic condition or in the presence of some chelating agents or as a result of action of both factors.
  • soluble calcium derives from an exogenous calcium-containing compound.
  • a soluble calcium-containing compound can be dispersed in a solvent, preferably in water or in an aqueous solution, to produce soluble calcium.
  • the solid soluble calcium-containing compound can be in any solid form that is suitable for dispersion and dissolution, for example, powder, crystal and the like.
  • the concentration of soluble calcium can be determined by methods well known to a person skilled in the art, such as atomic absorption spectrum or inductively coupled plasma atomic emission spectroscopy.
  • the concentration of soluble calcium is tested by inductively coupled plasma atomic emission spectroscopy (ICP-AES) .
  • ICP-AES inductively coupled plasma atomic emission spectroscopy
  • the test solution flows through an atomization device and forms an aerosol, which is sprayed from a quartz tube into a plasma torch, where the sample is decomposed into excited atoms and ions which, when returning to the stable basal state, are capable of emitting energy shown as a spectrum of certain wavelengths.
  • the species and quantity of the elements contained in the sample can be determined.
  • the method typically comprises the following steps: a certain amount of a sample of an oral care composition (such as toothpaste, gel or mouthwash) is accurately weighed and dissolved in water, after centrifugation the supernatant is collected and subjected to digest treatment to completely slake the organic substances therein, the emission spectral line and intensity of the calcium element in the obtained digested product are measured and compared with the standard curve of a calcium ion standard solution, thereby extrapolating the calcium concentration of the sample .
  • an oral care composition such as toothpaste, gel or mouthwash
  • Suitable digestion methods well-known in the art include but not limited to, digestion treament using high-purity concentrated nitric acid or microwave, so long the organic substances in the supernatant is completely slaked without introducing contamination of other calcium source.
  • the soluble calcium in the oral care composition has a concentration (ppm) ranging from about 7.34 ppm to about 800 ppm.
  • the soluble calcium has a concentration (ppm) ranging from about 7.34 ppm to about 739 ppm, from about 8.33 ppm to about 739 ppm, from about 8.92 ppm to about 739 ppm, from about 13.25 ppm to about 739 ppm, from about 14.4 ppm to about 739 ppm, from about 14.84 ppm to about 739 ppm, from about 28.4 ppm to about 739 ppm, from about 33.8 ppm to about 739 ppm, from about 43 ppm to about 739 ppm, from about 48.5 ppm to about 739 ppm, from about 48.71 ppm to about 739 ppm, from about 50.0 ppm to about 739 ppm, from about 56.97 ppm to about 739 ppm, from about 65.13 ppm to about 739 ppm, from about 76.5 ppm to about 739 ppm, from about 87.75 ppm
  • the soluble calcium has a concentration (ppm) ranging from about 7.34 ppm to about 600 ppm, from about 7.34 ppm to about 395.80 ppm, from about 7.34 ppm to about 185.34 ppm, from about 7.34 ppm to about 87.88 ppm, from about 7.34 ppm to about 65.13 ppm, from about 7.34 ppm to about 48.71 ppm, from about 7.34 ppm to about 14.84 ppm, from about 7.34 ppm to about 13.25 ppm, from about 7.34 ppm to about 8.92 ppm.
  • concentration ppm
  • the soluble calcium has a concentration (ppm) ranging from about 87.88 ppm to about 395.80 ppm, from about 87.88 ppm to about 185.34 ppm, from about 185.34 ppm to about 395.80 ppm.
  • Polycarboxylic compound denotes a compound having at least two carboxyl groups in its chemical structure, or more preferably with three or more carboxyl groups.
  • a polycarboxylic compound can be ionized to produce polycarboxylate radical when dissolved in water.
  • the polycarboxylic compound is citrate compound, i.e. a compound which can be ionized to produce citrate radical when dissolved in water.
  • the citrate compound is a citrate, such as potassium citrate or sodium citrate.
  • the polycarboxylic compound is polyaspartate, such as sodium polyaspartate (for example, having a molecular weight of 3000-5000 or 5000-8000) .
  • the polycarboxylic compound is 2-phosphonobutane-1, 2, 4-tricarboxylate, such as tetrasodium 2-phosphonobutane-1, 2, 4-tricarboxylate (PBTCA-Na 4 ) .
  • the polycarboxylic compound is iminidisuccinate, such as tetrasodium iminidisuccinate, tetrapotassium iminidisuccinate.
  • the polycarboxylic compound is a polyacrylate, such as sodium polyacrylate (for example, having a molecular weight of 3000-5000) .
  • the polycarboxylic compound has one of the following structures:
  • the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound ranges from about 0.00178 to about 0.361.
  • the molar concentration of the carboxyl radical of this polycarboxylic compound is considered as N mol/L when 1 molar of this polycarboxylic compound is prepared into 1L aqueous solution.
  • the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound ranges from about 0.00199 to about 0.169, from about 0.00542 to about 0.169, from about 0.0121 to about 0.169, from about 0.0247 to about 0.169, from about 0.0378 to about 0.169, from about 0.0414 to about 0.169, from about 0.0555 to about 0.169, from about 0.0619 to about 0.169, from about 0.0662 to about 0.169, from about 0.0676 to about 0.169, from about 0.0704 to about 0.169, from about 0.0715 to about 0.169, from about 0.0745 to about 0.169, from about 0.0747 to about 0.169, from about 0.0784 to about 0.169, from about 0.0902 to about 0.169, from about 0.0941 to about 0.169, from about 0.101 to about 0.169, from about 0.106 to about 0.169, from about 0.113 to about 0.169, from about 0.00199 to about
  • the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound ranges from about 0.00403 to about 0.334, from about 0.00667 to about 0.334, from about 0.0219 to about 0.334, from about 0.0293 to about 0.334, from about 0.0396 to about 0.334, from about 0.0597 to about 0.334, from about 0.0835 to about 0.334, from about 0.178 to about 0.334, from about 0.271 to about 0.334, from about 0.00228 to about 0.216, from about 0.00403 to about 0.361, from about 0.00667 to about 0.361, from about 0.0219 to about 0.361, from about 0.0293 to about 0.361, from about 0.0396 to about 0.361, from about 0.0597 to about 0.361, from about 0.0835 to about 0.361, from about 0.178 to about 0.361, from about 0.271
  • the polycarboxylic compound is a citrate compound, and the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the citrate compound also meets any of the above-mentioned ratio ranges.
  • the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the citrate ranges from about 0.00178 to about 0.271, from about 0.00178 to about 0.178, from about 0.00178 to about 0.0835, from about 0.00178 to about 0.0396, from about 0.00178 to about 0.0219, from about 0.00178 to about 0.00667. In certain embodiments, the ratio of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the citrate ranges from about 0.0396 to about 0.178, from about 0.0396 to about 0.0835, from about 0.0835 to about 0.178.
  • the percentage by mass (w/w) of the polycarboxyl radical of the polycarboxylic compound in the oral care composition ranges from about 0.001%to about 30%, such as from about 0.01%to about 30%, from about 0.01%to about 25%, from about 0.01%to about 20%, from about 0.01%to about 15%, from about 0.01%to about 10%, from about 0.05%to about 16%, from about 0.05%to about 12%, from about 0.05%to about 8%, from about 0.05%to about 4%, from about 0.05%to about 2.73%, from about 0.05%to about 2.68%, from about 0.05%to about 2.64%, from about 0.05%to about 2.25%, from about 0.05%to about 2%, from about 0.05%to about 1.2%, from about 0.05%to about 1%, from about 0.05%to about 0.742%, from about 0.05%to about 0.65%, from about 0.05%to about 0.6%, from about 0.05%to about 0.571%, from about 0.05%to
  • the amount of the polycarboxyl radical in the oral care composition can be determined by methods well-known in the art, such as high performance liquid chromatography, spectrophotometry (for example, see Zhu Jun-li, Quantitative Determination of Citrate by Spectrophotometry Method, Chinese Journal of Analysis Laboratory, No. 2, 2012) .
  • the percentage by mass of the polycarboxyl radical can be determined by ultraviolet spectrophotometry, a method useful for qualitatively and quantitatively analyzing the polycarboxyl radical based on the measurement of the absorbance or luminous intensity of a polycarboxyl radical at a specific wavelength or within a certain wavelength range.
  • the method typically comprises the following steps: standard solutions of different concentrations of polycarboxyl radical are obtained and the respective absorbance at the characteristic wavelength of the polycarboxyl radical (for example, the specific absorbance wavelength of citrate is 490 nm) is measured with a UV spectrophotometer whose basal level has been adjusted with a blank solution, and a standard curve is drawn; a certain amount of a sample oral care composition (such as toothpaste, gel or mouthwash) is accurately weighed and dissolved in water, after centrifugation the supernatant is collected and subjected to proper filteration and dilution to provide the testing sample, whose absorbance is measured, and the equivalent amount of the polycarboxyl radical is extrapolated based on the standard curve.
  • a sample oral care composition such as toothpaste, gel or mouthwash
  • the polycarboxylic compound is a citrate compound.
  • the percentage by mass of the citrate compound in the oral care composition can be determined by a high performance liquid chromatography.
  • the method typically comprises the following steps: a certain amount of an oral care composition (such as toothpaste, gel or mouthwash) is accurately weighed and dissolved in water, after centrifugation the supernatant is collected and subjected to proper filteration and dilution, followed by analysis by high performance liquid chromatography, and the concentration of the citrate compound in the sample can be obtained by referring to a standard curve of the citrate standard solution, and the percentage by mass of the citrate radical can be then calculated based on the factor of dilution.
  • an oral care composition such as toothpaste, gel or mouthwash
  • the range of the percentage by mass (w/w) of citrate radical of the citrate compound in the oral care composition also meets any of the above-mentioned ratio ranges of the percentage by mass (w/w) of the polycarboxyl radical of the polycarboxylic compound in the oral care composition.
  • the polycarboxylic compound and the hydroxyapatite can be mixed within a wide ratio range. Without being bound by theory, it is believed that in the mixture formed by the hydroxyapatite and polycarboxylic compound of the present disclosure, the polycarboxylic compound is mainly distributed on the surface of the hydroxyapatite, thereby leading to surface modification which makes the mixture different from hydroxyapatite itself in many aspects.
  • the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from about 1.238 to about 99.041, such as from about 1.238 to about 71.676, from about 1.238 to about 63.712, from about 1.238 to about 55.748, from about 1.238 to about 47.784, from about 1.238 to about 39.820, from about 1.238 to about 31.856, from about 1.238 to about 23.892, from about 1.238 to about 15.928, from about 1.238 to about 7.964, from about 15.928 to about 79.640, from about 23.892 to about 79.640, from about 31.856 to about 79.640, from about 39.820 to about 79.640, from about 47.784 to about 79.640, from about 55.748 to about 79.640, from about 63.712 to about 79.640, from about 79.640
  • the polycarboxylic compound is a citrate compound.
  • the ratio range of the molar concentration (mol/L) of the carboxyl radical of the citrate compound to the molar concentration (mol/L) of the hydroxyapatite also meets any of the above-mentioned ratio range of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite.
  • the formula of a hydroxyapatite molecule is Ca 10 (PO 4 ) 6 (OH) 2 with a molecular weight of 1004. Accordingly, the molar concentration of hydroxyapatite molecule can be calculated by dividing the mass of hydroxyapatite by its molecular weight (i.e. 1004) , and then by the volume of the test solution.
  • the oral care composition of the present disclosure can be in any suitable form for oral care known in the art, such as, but not limited to, toothpaste, gel, mouthwash, dental floss, dentifrice such as paste, powder, tablet or liquid formula used for cleaning the oral surface, gel, tooth strip, oral spray, tooth powder, foam, bubble gum, lipstick, sponge, collutory, chewing gum, or dental prosthesis products, etc.
  • dentifrice such as paste, powder, tablet or liquid formula used for cleaning the oral surface, gel, tooth strip, oral spray, tooth powder, foam, bubble gum, lipstick, sponge, collutory, chewing gum, or dental prosthesis products, etc.
  • the oral care composition is toothpaste, wherein the percentage by mass of hydroxyapatite is from 0.5%to 10%, the percentage by mass of polycarboxyl radical is from 0.0874%to 6.995%, the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from 1.238 to 54.155, and the concentration of the soluble calcium is 7.34-800 ppm.
  • the oral care composition is mouthwash, wherein the percentage by mass of hydroxyapatite is from 0.5%to 5%, the percentage by mass of polycarboxyl radical is from 0.0874%to 6.995%, the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from 1.238 to 54.155, and the concentration of the soluble calcium is 7.34-800 ppm.
  • the oral care composition is gel, wherein the percentage by mass of hydroxyapatite is from 0.5%to 10%, the percentage by mass of polycarboxyl radical is from 0.0874%to 6.995%, the ratio of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite ranges from 1.238 to 54.155, and the concentration of the soluble calcium is 7.34-800 ppm.
  • an “orally acceptable carrier” is a carrier which can be used as an ingredient of the oral care composition and is compatible with the oral physiological environment without any excessive side effects to the mouth.
  • the carrier can include suitable cosmetic and/or therapeutically active substances.
  • the orally acceptable carrier is compatible with the hydroxyapatite, the polycarboxylic compound and the soluble calcium of the present disclosure without excessively affects the blocking activity of the hydroxyapatite on a dentinal tubule.
  • orally acceptable carriers well known in the art can be used, such as, but not limited to, a thickener, an abrasive, a surfactant and a flavoring agent.
  • a “thickener” is a substance which increases the viscosity of a solution or liquid/solid mixture but does not substantially alter its properties.
  • the purpose of adding a thickener is to provide a framework, liquidity and stability to the product.
  • Examples of a thickener include but not limited to one or more of hydroxyethyl cellulose, carboxymethylcellulose and salts thereof (such as carboxymethylcellulose sodium) , carrageenan, carboxy vinyl polymer, xanthan gum, carrageenan, gelatin, amylopectin, sodium alginate, etc.
  • the thickener comprises one or more of xanthan gum, carrageenan or carboxymethylcellulose sodium.
  • an “abrasive” is a main ingredient for cleaning in a toothpaste.
  • the hardness, size, shape and amount of the abrasive should be comprehensively considered to ensure effective cleaning without abrasion of the teeth.
  • examples of an abrasive include but not limited to calcium carbonate, calcium hydrophosphate, calcium pyrophosphate, tricalcium phosphate, silicon dioxide, aluminium silicate, aluminum hydroxide, aluminium oxide, zeolite, titanium oxide, or zirconium silicate, etc.
  • the abrasive comprises silicon dioxide.
  • a “surfactant” is provided to emulsify the flavor and form foam in the toothpaste. To certain extent, it also facilitates sufficient and complete dispersion of the complex of hydroxyapatite-polycarboxylic compound.
  • a surfactant include, but not limited to, anionic surfactant, such as sodium dodecyl sulfonate; amphoteric surfactant, such as betaine; amino acid surfactant such as sodium lauryl sarcosinate and nonionic surfactant, such as polyoxyethylene and polyoxy propylene copolymer, polyethylene glycol, etc.
  • flavoring agent is an agent useful to improve sensory properties of the oral care composition.
  • a flavoring agent include, but not limited to, sodium saccharin, flavoring oil, such as spearmint oil, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage oil, eucalyptus oil, cinnamon oil, lemon oil and orange oil, methyl salicylate and eugenol.
  • the flavoring agent comprises methyl salicylate and/or eugenol.
  • the oral care composition further comprises one or more active ingredients.
  • An “active ingredient” is an ingredient capable of treating or relieving oral condition or disease.
  • the active ingredient comprises an anti-caries agent, an anti-sensitive agent and/or an anti-bacterial agent.
  • an “anti-caries agent” is an agent with inhibitory effects on caries.
  • it can be an agent which enhances the ability of anti-caries of a tooth by reducing the solubility of hydroxyapatite in the dental enamel, or an agent which controls the plaques or inhibits the growth of bacteria.
  • an anti-caries agent examples include, but not limited to, fluoride ion sources, such as sodium fluoride, potassium fluoride, calcium fluoride, magnesium fluoride, stannous fluoride, ammonium fluoride, sodium monofluorophosphate, potassium monofluorophosphate, fluosilicate, etc; phosphorus containing agents, such as calcium phosphate, sodium trimetaphosphate, magnesium glycerophosphate, phytate, calcium lactophosphate, sodium caseinate, etc, and arginine and its derivatives, etc.
  • the anti-caries agent comprises fluoride ion sources.
  • an “anti-sensitive agent” is a substance that can prevent or treat dental hypersensitiveness by inhibiting nerve impulse, blocking a dentinal tubule or reducing permeability thereof.
  • an anti-sensitive agent include, but not limited to, potassium ion sources, such as dipotassium glycyrrhizinate, potassium fluoride, potassium nitrate and potassium chloride, etc.
  • the anti-sensitive agent comprises potassium ion sources.
  • an “anti-bacterial agent” is a chemical substance that inhibits the growth or proliferation of certain microorganisms in the oral care composition below necessary level within a period of time.
  • examples of an anti-bacterial agent include, but not limited to, zinc oxide, stannous chloride, tetrahydrocurcuminoid, cetylpyridinium chloride, and triclosan, etc.
  • the oral care composition provided in the present disclosure can be prepared by mixing a polycarboxylic compound, hydroxyapatite, and soluble calcium with an orally acceptable carrier.
  • the polycarboxylic compound, hydroxyapatite, soluble calcium and orally acceptable carrier can be formulated according to the above-mentioned amounts and ratios, and mixed by appropriate orders and manners.
  • compositions comprising a polycarboxylic compound, hydroxyapatite and soluble calcium
  • the present disclosure further provides a composition comprising hydroxyapatite, a polycarboxylic compound and soluble calcium.
  • the hydroxyapatite can be nanohydroxyapatite
  • the polycarboxylic compound can be any polycarboxylic compound described in the present disclosure (such as a citrate compound) .
  • the composition can be dispersed in water and forms an aqueous mixture described in the present disclosure.
  • the ratio range of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound can be any of the above-mentioned ratio ranges of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound in the oral care composition.
  • the ratio range of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite can be any of the above-mentioned ratio ranges of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite in the oral care composition.
  • Aqueous mixtures comprising a polycarboxylic compound, hydroxyapatite and soluble calcium
  • the present disclosure further provides an aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium.
  • the “aqueous mixture” denotes that a majority, such as at least 50%, 70%, 80%, 90%, 95%and 100%, of the solvent in the aqueous mixture is composed of water.
  • the solvent of the aqueous mixture is water or an aqueous solution of a buffer salt.
  • the aqueous mixture is substantively composed of hydroxyapatite, a polycarboxylic compound, soluble calcium, water and a buffer salt.
  • the ratio range of the molar concentration (mol/L) of the soluble calcium to molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound could be any of the above-mentioned ratio ranges of the molar concentration (mol/L) of the soluble calcium to the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound in the oral care composition.
  • the ratio range of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite could be any of the above-mentioned ratio ranges of the molar concentration (mol/L) of the carboxyl radical of the polycarboxylic compound to the molar concentration (mol/L) of the hydroxyapatite in the oral care composition.
  • the concentrations of hydroxyapatite, polycarboxylic compound and soluble calcium can be adjusted as needed, as long as the concentrations are suitable for preparing the aqueous mixture and/or can be used to prepare the oral care composition of the present disclosure.
  • the aqueous mixture can be mixed with other ingredients such as an orally accepted carrier, the mixing process of which may dilute the amounts of each ingredient in the aqueous mixture. Therefore, the concentration of each ingredient of the aqueous mixture may vary depending on the possible fold of dilution during the preparation of the oral care composition.
  • the concentration may be, for example, 1.5 folds, 2 folds, 2.5 folds, 3 folds, 5 folds, 8 folds, 10 folds, 20 folds, etc, higher than that of the corresponding ingredient in the oral care composition of the present disclosure.
  • the percentage by mass of the hydroxyapatite in the aqueous mixture or the percentage by mass of the hydroxyapatite in the aqueous mixture when diluted by 1.5 folds, 2 folds, 2.5 folds, 3 folds, 5 folds, 8 folds, 10 folds, or 20 folds could be within any of the above-mentioned ranges of the percentage by mass (w/w) of the hydroxyapatite in the oral care composition.
  • the percentage by mass (w/w) of the polycarboxyl radicalin the aqueous mixture or the percentage by mass of the polycarboxyl radical of the aqueous mixture when diluted by 1.5 folds, 2 folds, 2.5 folds, 3 folds, 5 folds, 8 folds, 10 folds, or 20 folds could be within any of the above-mentioned ranges of the percentage by mass (w/w) of the polycarboxyl radicalin the oral care composition.
  • the concentration (ppm) of the soluble calcium in the aqueous mixture or the concentration of the soluble calcium in the aqueous mixture when diluted by 1.5 folds, 2 folds, 2.5 folds, 3 folds, 5 folds, 8 folds, 10 folds, or 20 folds could be within any of the above-mentioned ranges of the concentration (ppm) of the soluble calcium in the oral care composition.
  • the hydroxyapatite particles in the aqueous mixture that have a particle size larger than 100 nm is no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, or no more than about 10%.
  • the dispersity of the hydroxyapatite in the aqueous solution can be improved after the hydroxyapatite is mixed with a polycarboxylic compound and soluble calcium.
  • a hydroxyapatite aqueous solution to which a polycarboxylic compound and soluble calcium are added can remain well-dispersed for an extended period of time before sedimentation and stratification of the hydroxyapatite, in comparison with a hydroxyapatite solution with the same concentration and the same volume.
  • the well-dispersed period can be extended from 2 hours to 12 hours or even longer.
  • the absolute value of Zeta potential of the hydroxyapatite aqueous solution is increased.
  • the dispersity of the hydroxyapatite aqueous solution can be characterized by methods known in the art, such as dynamic light scattering, particle size distribution, etc.
  • the improvement of the dispersity of the hydroxyapatite is advantageous in many aspects.
  • the improvement of the dispersity could imporve the blocking effect of the hydroxyapatite on a dentinal tubule.
  • the commercial hydroxyapatite in Figure 2 hardly blocks a dentinal tubule when used in the experiment for blocking a dentinal tubule, as shown in Figure7 (b) .
  • the same commercial hydroxyapatite showed much improved dispersity and blocking effect on a dentinal tubule after being mixed with a polycarboxylic compound and soluble calcium, as shown in Figure 8 (b) .
  • the improved dispersity can also be helpful in the preparation of the oral care composition.
  • the present disclosure further provides a method for improving the dispersity of the hydroxyapatite in a solution, comprising mixing the hydroxyapatite, a polycarboxylic compound and soluble calcium.
  • the method further comprises dispersing the mixure of the hydroxyapatite, the polycarboxylic compound and soluble calcium in a solution or a medium.
  • the hydroxyapatite in the aqueous mixture is capable of infiltrating into a dentinal tubule.
  • the hydroxyapatite can infiltrate into the dentinal tubule to a depth of, at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, at least about 20 ⁇ m, at least about 25 ⁇ m, at least about 30 ⁇ m, at least about 35 ⁇ m, at least about 40 ⁇ m, at least about 50 ⁇ m, at least about 55 ⁇ m, at least about 60 ⁇ m, at least about 65 ⁇ m, at least about 70 ⁇ m, at least about 75 ⁇ m, at least about 80 ⁇ m, etc.
  • the aqueous mixture that comprises hydroxyapatite, a polycarboxylic compound and soluble calcium has a Zeta potential of negative value.
  • the polycarboxylic compound and soluble calcium could alter the electrical property of the hydroxyapatite surface, thereby allowing accumulation of negatively charged carboxyl radicals on the hydroxyapatite surface.
  • the Zeta potential of the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium ranges from about -38 to about -20mV. It is known in the art that instrumental measurement usually could have certain measurement errors, and the measurement errors within the above-mentioned range can be understood and accepted by a person skilled in the art.
  • the Zeta potential of the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium ranges from about -38 to about -20mV.
  • the surface of hydroxyapatite and soluble calcium is positively charged at certain pH value and thus the aqueous solution thereof has a positive Zeta potential, for example, the potential could be at about +30mV at certain concentrations.
  • Zeta potential also known as electric potential or electrokinetic potential ( ⁇ -potential or ⁇ -electric potential) , refers to the potential of a shear plane, which is an important index to characterize the colloidal dispersion stability.
  • Zeta potential could be determined by a technique and/or instrument known in the art, such as an electrophoresis method, an electro-osmosis method, a streaming potentiometry and an ultrasonic method, etc.
  • Zeta potential could be determined by a streaming potentiometry, for example, the potential of the mixture could be determined by a suitable potential analyzer (such as Malvern Zetasizer Nano ZS potential analyzer) .
  • the dispersity and surface modification of the hydroxyapatite could be determined by measuring Zeta potential, so as to provide assessment of the infiltration ability of the hydroxyapatite in the aqueous mixture into a dentinal tubule.
  • the pH value of the aqueous mixture ranges from about 7 to about 14.
  • the pH value of the aqueous mixture is within a range which is orally and physiologically acceptable; that is to say, when administrated to mouth, the mixture will not cause excessive stimulation or injury to an oral tissue (eg. a tooth, muscle, mucosa, etc) .
  • the pH value of the aqueous mixture ranges from about 7 to about 10, from about 7 to about 9, or from about 7 to about 8.
  • the pH value of the aqueous mixture could be adjusted by a known method in the art.
  • the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium could be prepared using an appropriate buffer solution, and/or adjusted to a desired pH range by a suitable acid or alkali.
  • the aqueous mixture further comprises a metal ion.
  • the metal ion is capable of interacting with the carboxyl radical of the polycarboxylic compound, for example forming a metal salt or complex with the carboxyl radical.
  • the examples of a metal ion comprises, for instance, copper ion, zinc ion, silver ion, or any combination thereof.
  • the metal ion is beneficial to the oral health.
  • the copper ion can prevent dental plaque and has whitening effect;
  • the zinc ion is able to inhibit the formation of dental plaque and dental calculus, thus preventing various pigments, such as a korron, spots of tea, etc, from adhering and depositing on the surface of a tooth, thus removing stains;
  • the silver ion has extraordinarily robust antibacterial ability and a broad-spectrum of antibacterial performance.
  • the aqueous mixture comprising hydroxyapatite, a polycarboxylic compound and soluble calcium of the present disclosure could be prepared by appropriate methods.
  • the method comprises mixing the polycarboxylic compound, dispersed hydroxyapatite and soluble calcium in an aqueous solution.
  • the “dispersed hydroxyapatite” denotes the hydroxyapatite dispersed in a solvent.
  • the hydroxyapatite is dispersed in water or aqueous solution which may contain necessary solute, such as, but not limited to, a buffer salt for adjusting the pH.
  • the dispersed hydroxyapatite may have appropriate dispersion density so as to form a complex with a polycarboxylic compound in a better manner.
  • any suitable mixing approaches can be used to mix the polycarboxylic compound, hydroxyapatite and soluble calcium.
  • the polycarboxylic compound and soluble calcium can be added to the dispersed hydroxyapatite and then mixed well.
  • the polycarboxylic compound is selected from citrate compound such as potassium citrate, sodium citrate, etc; polyaspartate, such as sodium polyaspartate, potassium polyaspartate, etc; iminodisuccinate, such as potassium iminodisuccinate, sodium iminodisuccinate, etc; 2-phosphonobutane-1, 2, 4-tricarboxylate, such as tetrasodium 2-phosphonobutane-1, 2, 4-tricarboxylate, etc; and polyacrylate, such as sodium polyacrylate, potassium polyacrylate, etc.
  • a salt without any side effect to mouth is selected.
  • the solid polycarboxylic compound could be added to the dispersed hydroxyapatite.
  • the solid polycarboxylic compound could be the solid forms of polycarboxylic compound powder, crystal and the like that are suitable for dispersion.
  • the soluble calcium exists in the form of calcium ions.
  • the soluble calcium-containing compound could be dispersed in a solvent, preferably in water or aqueous solution, to form soluble calcium.
  • the solid form of the soluble calcium-containing compound can be powder, crystal and the like that are suitable for dispersion and dissolution.
  • the soluable calcium-containing compound is added to the dispersed hydroxyapatite solution and then forms a mixture with the polycarboxylic compound.
  • the soluble calcium is derived from unreacted calcium ions during the preparation of hydroxyapatite which is not removed by methods known in the art such as centrifugation and washing.
  • the unreacted calcium ions are from soluable calcium sources used during preparation of the hydroxyapatite, such as calcium chloride, calcium nitrate, etc.
  • the soluable calcium is derived from calcium ions disassociated from the hydroxyapatite in the presence of a chelating agent or under acidic condition, or from bound calcium which is complexed with a chelating agent.
  • the chelating agent is, for example, EDTA, etc
  • the acid is, for example, citric acid, etc.
  • a solution comprising the soluble calcium and polycarboxylic compound could be added to the dispersed hydroxyapatite.
  • concentration of the solution comprising the soluble calcium and polycarboxylic compound and the amount of dispersed hydroxyapatite could be appropriately selected, so that the obtained aqueous solution upon mixture has a desired concentration and content. All of these are well-known routine experimental procedures for a person skilled in the art.
  • the present disclosure provides a method for filling a dentinal tubule, comprising contacting the dentin with an oral care composition of the present disclosure to allow the hydroxyapatite to infiltrate into the dentinal tubule.
  • the hydroxyapatite of the oral care composition provided by the present disclosure is capable of infiltrating into a dentinal tubule.
  • the hydroxyapatite can infiltrate into the dentinal tubule to a depth of at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, at least about 20 ⁇ m, at least about 30 ⁇ m, at least about 40 ⁇ m, at least about 50 ⁇ m, at least about 60 ⁇ m, or at least about 70 ⁇ m.
  • the depth of the hydroxyapatite infiltrated into a dentinal tubule could be determined by appropriate experimental methods.
  • the oral care composition is contacted with a tooth sample, such as an animal tooth sample. After a period of time (such as 10-120 minutes) , the tooth sample is collected, a longitudinal section plane of the dentinal tubules is prepared and the depth of the hydroxyapatite infiltration can be observed and measured by an electron microscope.
  • the hydroxyapatite infiltrated into a dentinal tubule plays an important role for blocking the dentinal tubule, which not only blocks the opening of the dentinal tubule, but also persistently maintains the dentinal tubule in a sealing state to achieve a better and long-lasting effect of anti-dental hypersensitiveness.
  • the oral care composition could be any suitable oral care composition provided in the present disclosure, such as, but not limited to, toothpaste, mouthwash, gel, dental floss, dentifrice such as paste, powder, tablet or liquid formula used for cleaning the oral surface, gel, tooth strip, oral spray, tooth powder, foam, bubble gum, lipstick, sponge, collutory, chewing gum, or dental prosthesis products, etc.
  • Oral care, especially tooth care, using the oral care composition provided in the present disclosure could effectively facilitate the hydroxyapatite to infiltrate into the dentinal tubules.
  • the oral care composition is toothpaste and the method comprises brushing a tooth with the toothpaste to allow the hydroxyapatite to infiltrate into the dentinal tubules.
  • the oral care composition is gel, and the method comprises brushing a tooth with the gel or contacting a tooth with the gel to allow the hydroxyapatite to infiltrate into the dentinal tubules.
  • the oral care composition is mouthwash, and the method comprises contacting a tooth with the mouthwash to allow the hydroxyapatite to infiltrate into the dentinal tubules.
  • the aqueous mixture comprisng the hydroxyapatite, polycarboxylic compound and soluble calcium provided in the present disclosure can be used to prepare the oral care composition for relieving or preventing dental hypersensitiveness.
  • Dental hypersensitiveness is a common oral discomfort, and the major pathogenesis is that the flow change of the fluid inside a dentinal tubule stimulates the dental pulp nerve endings, thus generating impulse and conducting pain.
  • the major symptom is stimulation pain during toothbrushing. When having hard, sour, sweet, cold or hot food, all of these stimulations cause soreness, especially the cold stimulation.
  • the hydroxyapatite provided in the present disclosure is capable of infiltrating deeply into and blocking a dentinal tubule, thereby reducing the external stimulation to the dentin and/or dental nerve and thus relieving or preventing tooth sensitivity.
  • the aqueous mixture comprisng the hydroxyapatite, polycarboxylic compound and soluble calcium provided in the present disclosure can be used to prepare the oral care composition for filling a dentinal tubule of a tooth.
  • the hydroxyapatite is capable of filling a dentinal tubule and infiltrating into a certain depth, as shown in the present disclosure.
  • the present disclosure provides a dental material having dentinal tubules, wherein the dentinal tubules are infiltrated with hydroxyapatite.
  • the dental material is a tooth.
  • the hydroxyapatite is capable of infiltrating deeply into the dentinal tubules, forming a dental material, such as a tooth, that has the dentinal tubules infiltrated with the hydroxyapatite.
  • the dentinal tubules are infiltrated with the hydroxyapatite to a depth of at least about 5 ⁇ m, at least about 10 ⁇ m, at least about 15 ⁇ m, at least about 20 ⁇ m, at least about 30 ⁇ m, at least about 40 ⁇ m, at least about 50 ⁇ m, at least about 60 ⁇ m, or at least about 70 ⁇ m.
  • the diameter of the dentinal tubules is about 1-4 ⁇ m.
  • Example 1 Preparing an aqueous mixture comprising hydroxyapatite, citrate and soluble calcium
  • Raw material 1 The nanohydroxyapatite (Nano HAP) was commercially available (purchased from Fluidinova Inc., Portugal) , which is an aqueous solution of about 15%Nano HAP containing about 1053ppm soluble calcium.
  • the soluble calcium was from a soluble calcium source calcium chloride which did not react completely during the preparation of hydroxyapatite and was not removed by methods commonly known in the art.
  • Raw material 2 The nanohydroxyapatite (Nano HAP) was commercially available (purchased from Shanghai Zilin Biotechnology Inc. ) and is the dry powder of Nano HAP. It was prepared into a 15%Nano HAP aqueous solution. The concentration of soluble calcium was about 4ppm. As the solubility of Nano HAP was very low, the soluble calcium produced due to dissolution of Nano HAP was negligible.
  • Figures 1 and 2 The shapes and sizes of the two types of Nano HAPs are shown in Figures 1 and 2, where Figure 1 shows a 20nm-50nm short rod shape and Figure 2 shows a 20nm-50nm needle-like shape.
  • the potassium citrate is a raw material of food grade.
  • Zeta potential analyzer (Malvern Zetasizer Nano ZS) ; scanning electron microscope (HITACHI S-4800) .
  • the raw material 1 was used as the source of the Nano HAP and soluble calcium.
  • the raw material 1 was diluted with deionized water and mixed well. Then, different doses of potassium citrate were added to make the different ratios as shown in the Table 1 below, and mixed well to make suspensions 1-I ⁇ 1-VIII.
  • the Nano HAP in each group was dispersed in water according to the ratio in Table 1 and the potassium citrate was then dispersed to the solution to formulate suspensions 1-I ⁇ 1-VIII.
  • the Zeta potential of suspensions 1-I ⁇ 1-VIII was measured by a Zeta potential analyzer, respectively, to characterize the effect of various doses of potassium citrate on the electrical property on the Nano HAP surface.
  • the results of Zeta potential measurement of suspensions 1-I ⁇ 1-VIII were shown in Figure 3.
  • the surface of the raw material Nano HAP was strongly positively charged after interaction with soluble calcium, and the Zeta potential of the aqueous suspension was at +34.3mV.
  • Various doses of potassium citrate were added to form Nano HAP-citrate complex, and despite of the difference in dose, citrate treatment resulted strong negative charges on the surface of Nano HAP, and the Zeta potential of the aqueous suspension was between -30 mV and -38 mV. This result indicates that the negatively charged citrate was adsorbed to the surface of Nano HAP and converted the strong positive charges on the surface into strong negative charges.
  • citrate was successfully adsorbed to the surface of the Nano HAP and modified the surface of Nano HAP in suspensions 1-I ⁇ 1-VIII.
  • the raw material 2 was used as a source of Nano HAP and was diluted with deionized water, followed by addition of CaCl 2 ⁇ 2H 2 O to introduce soluble calcium.
  • the change of Zeta potential is shown in Table 2.
  • the addition of the soluble calcium converted the electrical properties of Nano HAP surface.
  • the surface of Nano HAP was slightly negatively charged before the addition of the soluble calcium; however, after adding a small amount of soluble calcium ions, the electrical properties of Nano HAP surface was converted from negatively charged to positively charged.
  • As a structure-potential ion for Nano HAP calcium ion is essential for surface chemical structure and surface electrical property of Nano HAP.
  • Potassium citrate was added according to Table 3 after the addition of the soluble calcium.
  • the charges on the surface of Nano HAP were converted to negative charges with an increased absolute value of Zeta potential, as shown in Figure 4. This result illustrates that the dispersion of the nanohydroxyapatite was remarkably improved.
  • Example 2 Nanohydroxyapatite blocks and infiltrates into a dentinal tubule
  • Bovine incisors were used to prepare the model, and a 2mm-thick disc was cut off perpendicularly to the longitudinal axis of the Bovine incisors, at about 3mm below the junction of the crown and the root.
  • the disc was then sanded by abrasive papers with 600, 1200 and 2000 grit paper discs, respectively, to obtain a 2mm x 6mm smooth observation plane. After polishing, it was etched by 6 wt%citric acid for 5 minutes to expose the dentinal tubules, and was then washed in an ultrasonic cleaner for 3 times, 15 minutes of each time, to obtain Model A, of which the observation plane is perpendicular to the dentinal tubule. The observation of Model A under SEM was shown in Figure 5, in which the opened dentinal tubules were clearly observed.
  • Model A that is perpendicular to the dentinal tubules was obtained according to method (A) and was then treated with a test sample. After the treatment, the model was dried in an oven at 40°C for 24 hours and was then cut open by a scalpel along the direction parallel to the dentinal tubules. The resulted section that was parallel to the dentinal tubule was Model B, of which the observation plane was parallel to the dentinal tubule. The observation of Model B under SEM was shown in Figure 6, in which the walls of the dentinal tubules were smooth without sediments and some fibrous substance could be observed.
  • Raw material 1 The nanohydroxyapatite (Nano HAP) was commercially available (purchased from Fluidinova Inc., Portugal) , which is a 15%Nano HAP aqueous solution containing about 1053ppm soluble calcium.
  • the soluble calcium was from a soluble calcium source (calcium chloride) which did not react completely in the preparation of hydroxyapatite and was not removed by methods commonly known for a person skilled in the art.
  • Raw material 2 The nanohydroxyapatite (Nano HAP) was commercially available (purchased from Shanghai Zilin Biotechnology Inc. ) and is the dry powder of Nano HAP. It was prepared into a 15%Nano HAP solution and the concentration of the soluble calcium was about 4ppm. Because the solubility of the Nano HAP was very low, the soluble calcium produced due to dissolution of Nano HAP in water was negligible.
  • Nano HAP nanohydroxyapatite
  • Figures 1 and 2 The shapes and sizes of the two Nano HAPs are shown in Figures 1 and 2, wherein Figure 1 shows a 20nm-50nm short rod shape and Figure 2 shows a 20nm-50nm needle-like shape.
  • the potassium citrate is a raw material of food grade.
  • Model A was treated for 2 minutes, and then washed and dried. The blocking effect of the surface of model A was observed under SEM, as shown in Figure 7.
  • the two Nano HAPs were independently mixed with the potassium citrate and soluble calcium according to the ratio in Table 4.
  • group 1’ -I raw material 1 was used and the soluble calcium was derived from the residual soluble calcium source due to incomplete reaction during the preparation of Nano HAP.
  • group 2’ -II raw material 2 was used and the soluble calcium source was derived from the added CaCl 2 ⁇ 2H 2 O.
  • Model A was treated by 1’ -I and 2’ -II for 2 minutes, respectively, and then washed and dried. The blocking effect of the surface of model A was observed under SEM, as shown in Figure 8.
  • Raw material 1 which originally provided modest blocking effects (as shown in Figure 1) , showed different morphologies of the sediment layer on the surface of the dentinal tubule before and after the treatment with potassium citrate and soluble calcium.
  • the blocking layer of the Nano HAP after the treatment of potassium citrate and soluble calcium was relatively solid and firm (as shown in Figures 8 (a) ) , indicating that the introduction of potassium citrate and soluble calcium improved the interaction between the Nano HAP and the dentin.
  • Suspensions 1” -I, 1” -II, 1” -III and 1” -IV were prepared according to the different ratios in Table 5, where the Nano HAP raw material of Figure 1 (i.e. raw material 1) was used. 2 dentin pieces of Model A were added to 10ml of each suspension respectively. The models were immersed for 40 minutes and shaked simultaneously on a shaker to make sure that the suspensions were mixed well. Next, the observation surfaces of the dentins of Model A were washed using 100ml deionized water for 30 seconds, and dried at 40°C. One of the 2 dentin pieces of Model A in each group of the suspensions was subject to make Model B according to section 2.1. Pieces of Model A and Model B after the treatment of suspensions 1” -I, 1” -II, 1” -III and 1” -IV respectively were observed under SEM, and the results were shown in Figures 9-12.
  • the raw material 2 was used and different concentrations of soluble calcium were added into the raw material to test whether it can infiltrate into the dentinal tubules. The results were shown in Table 6.
  • Model A a layer of Nano HAP (unmodified by citrate) was deposited on the surface of Model A (as shown in Figure 9 (a) and 9 (b) ) .
  • Model B Nano HAP only deposited on the surface of the dentin and did not infiltrate into dentinal tubules, that is to say, the dentinal tubules were infiltrated with the Nano HAP to a depth of 0 ⁇ m.
  • the walls of the dentinal tubules were smooth, and certain fibrous substance could be observed (as shown in Figure 9 (c) and 9 (d)) .
  • the dentinal tubules were infiltrated with the Nano HAP to a depth of 5 ⁇ m, even up to 100 ⁇ m (as shown in Figure 10 (c) , Figure 10 (d) , Figure 11 (c) , Figure 11 (d) , Figure 12 (c) and Figure 12 (d) ) .
  • the Nano HAP suspension that contains potassium citrate but very low level of soluble calcium (i.e.
  • Model A was deposited with Nano HAP (as shown in Figure 13 (a) ) ; as seen in Model B, however, the layer of Nano HAP merely deposited on the surface of the dentin and did not infiltrate into the dentinal tubules. The walls of the dentinal tubules were smooth, and certain fibrous substance could be observed (as shown in Figure 13 (b)) .
  • the blocking layer deposited on the surface of the dentin tends to be gradually brushed away and would not provide long-lasting anti-sensitive effects.
  • the blocking substance that enters into the dentinal tubules can last long.
  • Example 3 Use of the nanohydroxyapatite, citrate and soluble calcium in the formula of toothpaste and mouthwash
  • Raw material 1 A 15%Nano HAP solution containing 1053ppm unreacted soluble calcium. The raw material was commercially available and was purchased from Fluidinova Inc., Portugal.
  • Raw material 2 Dry powder of Nano HAP was prepared into a 15%Nano HAP solution. The solution contains about 4ppm soluble calcium which was released from the Nano HAP. The raw material was commercially available and was purchased from Shanghai Zilin Biotechnology Inc.
  • Raw material 3 A 15%Nano HAP solution. The synthetic process was the same as that of raw material 1, but most of the unreacted soluble calcium was removed by repeated centrifugations and washings. The soluble calcium in the raw material was about 43ppm. The raw material was commercially available and was purchased from Fluidinova Inc., Portugal.
  • formulas 1, 2, 3 and 4 The components of formulas 1, 2, 3 and 4 are shown in Table 7.
  • Formulas 1, 3 and 4 used raw material 1, wherein formulas 3 and 4 were added with trisodium phosphate docecahydrate to adjust the concentration of the calcium ions.
  • Trisodium phosphate dodecahydrate serves as an adsorbent for calcium and can precipitate a portion of the soluble calcium in the formulas in the form of calcium phosphate, thereby adjusting the amount of the soluble calcium in the formulas.
  • Formula 2 used raw material 2 and the soluble calcium was added.
  • a Nano HAP aqueous suspension was prepared and the amount of the soluble calcium was adjusted, where necessary, by optionally adding soluble calcium.
  • the preparation ratio was chosen as appropriate according to the water amount and the amount of added Nano HAP in the formula.
  • a 15%Nano HAP aqueous solution was prepared in the present Example.
  • step 2 The suspension of step 1 was mixed evenly with humectant sorbitol by sonication. Potassium citrate was added and sonicated to allow mixing. Trisodium phosphate docecahydrate was added, dissolved and mixed evenly.
  • Titanium dioxide and Sodium saccharin were added to the suspension of Step 2 and mixed evenly.
  • Step 4 The mixture of Step 4 was added to the mixture of Step 3, and heated to provide a mixed composition.
  • the silicon dioxide was added to the composition prepared in Step 5, followed by mixing and vacuum treatment.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the results are shown in Table 8 as below.
  • Formulas 5, 6, 7, 8 and 9 used raw material 1.
  • the soluble calcium was derived from the residual soluble calcium which were left due to incomplete reaction in the preparation of raw material.
  • Trisodium phosphate docecahydrate was added to formulas 8 and 9 to adjust the concentration of soluble calcium.
  • Trisodium phosphate dodecahydrate serves as an adsorbent for calcium and can form calcium phosphate precipitation with a portion of the soluble calcium in the formulas, thereby adjusting the content of the soluble calcium in the formula.
  • Formulas 6 and 7 used raw material 3 and the soluble calcium was added.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the results are shown in Table 10 as below.
  • Raw material 1 was used and the soluble calcium was derived from the residual soluble calcium which was left due to incomplete reaction in the preparation of raw material.
  • Formula 10 is shown in Table 11 as below.
  • Raw material Percentage/wt% Sorbitol 30 Polyethylene glycol 1 Xanthan gum 0.8 Glycerol 15 Aqueous suspension containing 15%Nano-HAP 15 Potassium citrate 0.6 Silicon dioxide (thickening-type) 8 Silicon dioxide (abrasive-type) 12 Sodium Lauryl Sulfate 1.5 Cocamidopropyl betaine 1.25 Sodium saccharin 0.15 Titanium dioxide 0.3 Flavor 1.2 Deionized water 16.7 Water loss -0.5 Total amount 100
  • the preparation process was identical to Section 3.1.1 and the toothpaste was fine and smooth as well.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the result were shown in Table 12 as below.
  • Raw material 1 was used, and the soluble calcium was from the residual soluble calcium left unreacted in the raw material.
  • Raw material Percentage/wt% Sorbitol 30 Polyethylene glycol 1 Xanthan gum 0.8 Glycerol 18 Aqueous suspension containing 15%Nano-HAP 6.7 Potassium citrate 0.27 Silicon dioxide (thickening-type) 10 Silicon dioxide (abrasive-type) 12 Sodium Lauryl Sulfate 2 Sodium saccharin 0.15 Titanium dioxide 0.3 Flavor 1.2
  • the preparation process was identical to 3.1.1 and the toothpaste was fine and smooth as well.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the results are shown in Table 14 as below.
  • Toothpaste slurry was prepared by mixing the toothpaste prepared by the process of Sections 3.1.1-3.1.4 and deionized water at a ratio of 1: 3. Model B was immersed in the toothpaste slurry for 40 minutes and then washed and dried and was observed under SEM.
  • the toothpaste formulas containing nanohydroxyapatite, citrate and soluble calcium can block the dentinal tubules effectively, infiltrate into the dentinal tubules and have a long-lasting anti-sensitive effect.
  • Nanohydroxyapatite in the formulas containing different concentrations of soluble calcium could infiltrate into the dentinal tubules to different depths.
  • the raw material 3 was used and different ratios of soluble calcium were added.
  • Formula 12 is shown in Table 16 as below.
  • Xanthan gum was added into the glycerol and mixed for 10 minutes;
  • Nano HAP aqueous suspension was prepared and combined with soluble calcium. This step can be skipped if the purchased raw material contains appropriate amount of soluble calcium. The preparation ratio was chosen as appropriate according to the water amount and the amount of added Nano HAP in the formula. A 15%Nano HAP aqueous solution was prepared in the present Example.
  • Step 1 was added into the suspension of nanohydroxyapatite of Step 4, and heated to obtain the composition.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the results are shown in Table 17 as below.
  • Raw material 3 was used and soluble calcium of different ratios was added.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the results are shown in Table 19 as below.
  • the raw material 3 was used and soluble calcium of different ratios was added.
  • Formula 17 is shown in Table 20 as below.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the result is shown in Table 21 as below.
  • Raw material 3 was used and soluble calcium of different ratios was added.
  • Formula 18 is shown in Table 22 as below.
  • the soluble calcium and citrate was measured by the method for measuring soluble calcium and citrate according to the present disclosure, and the result is shown in Table 23 as below.
  • the mouthwash prepared by the process of Sections 3.2.1-3.2.4 was used to conduct immersion experiment with Model A. Model A was immersed in the mouthwash for 10 minutes and was then washed and dried, and observed under SEM.
  • Model B was immersed in the mouthwash for 40 minutes, and then washed and dried and observed under SEM.
  • a double blind, parallel, randomized and controlled clinic trial lasting for 2 weeks was performed in the center of clinic trial to further confirm the effect of the present invention for the practical application.
  • 40 subjects were selected according to the following criteria and were divided into a trial group and a control group randomly so that each group has 20 subjects.
  • the subjects were healthy male and female adults who met the criteria of inclusion and exclusion respectively.
  • the clinical trial was randomized, double blind and parallel.
  • the subjects in the trial group used the toothpaste of Formula 1 of Example 3.1.1 in the present disclosure (trial toothpaste)
  • the subjects in the control group used the control toothpaste, which was a placebo formula in which the Nano HAP in the formula of Example 3.1 was substituted for the same amount of water.
  • the subjects brushed their teeth twice each day in the morning and evening using the toothpaste and the toothbrush provided.
  • the toothpaste was applied on the entire head of the tooth brush and the brushing process lasted for 1 minute.
  • the subjects were subjected to the oral soft tissue (OST) examination, cold air blowing sensitivity evaluation and touch/pressure sensitivity evaluation.
  • OST oral soft tissue
  • the therapeutic efficacy was evaluated by cold air blowing sensitivity evaluation and touch/pressure sensitivity evaluation.
  • the cold air blowing sensitivity evaluation served as a primary evaluation index and the touch/pressure sensitivity evaluation served as the secondary evaluation index in the experiment.
  • the sensitive tooth was blown by an air gun of the dental unit for 1 second from a distance of 1 cm, with a pressure of the air compressor at 60p.s.i. ( ⁇ 5 p.s.i. ) and a blow temperature at 19-21°C. When blowing, the adjacent teeth were covered by fingers to avoid affecting the result accuracy.
  • the Schiff cold air sensitivity index was used for evaluation using the scores set forth as below:
  • a low score of the Schiff cold air sensitivity index indicates a low sensitivity of the dentin.
  • a calibrated Yeaple electrical pressure sensitivity probe was used to quantitatively determine the pressure (in gram) imposed on the surface of a tooth.
  • the probe When determining the sensitivity, the probe contacted with the exposed dentin on the buccal surface of the selected tooth and was placed at the enamel-dentin border for detection.
  • the probing force was initially set at 10 gram, and then increased each time by 10 gram until the subject felt uncomfortable.
  • the maximal probing force was 80 gram. A high value of the probing force indicates a low sensitivity of the dentin.
  • the cold air blowing sensitivity evaluation scores for the baseline and 1 week treatment of the subjects in the study are shown in Table 25.
  • the mean score of the cold air blowing sensitivity for the subjects in the trial group is 0.6, and the control group is 1.75.
  • the scores were decreased by 54.1%and 23.9%, respectively, and the scores were significantly different within each group (P ⁇ 0.05) .
  • the cold air sensitivity score for the trial group after 1 week of use was decreased by 44.3%, and the difference is significant (P ⁇ 0.05) .
  • Table 25 Summary of the cold air blowing sensitivity scores for the baseline and 1 week treatment
  • Paired t-test is used to compare the significant difference between the scores of the baseline and the 1 week treatment.
  • the difference between the trial group and the control group after 1 week treatment is indicated by a percentage relative to the mean sensitivity scores of the control group after 1 week treatment. A positive value indicates that the sensitivity of the trial group was improved relative to the control group.
  • the scores of the touch/pressure sensitivity evaluations for the baseline and 1 week treatment of the subjects in the study are shown in Table 26.
  • the mean score of the touch/pressure sensitivity after 1 week use of the test toothpaste was 25.75g, and the control group was 19.25g.
  • the scores were increased by 134%and 71%, respectively, in comparison with the baseline, and the scores are significantly different within each group (P ⁇ 0.05) .
  • the score of the trial group was increased by 33.76%, and the difference is significant (P ⁇ 0.05) .
  • Paired t-test is used to compare the significant difference between the scores of the baseline and the 1 week treatment.
  • the difference between the trial group and the control group after 1 week treatment is indicated by a percentage relative to the mean sensitivity scores of the control group after 1 week treatment. A positive value indicates that the sensitivity of the trial group was improved relative to the control group.
  • Example 5 Study on the effect of the citrate and soluble calcium to the infiltration of nanohydroxyapatite into the dentinal tubules
  • addition of the citrate and soluble calcium simultaneously can enhance the infiltration of the nanohydroxyapatite into the dentinal tubules, thus increasing the blocking effect to the dentinal tubules.
  • the following experiments were performed to determine whether the enhanced infiltration effect is caused by the citrate alone, the soluble calcium alone or a synergistic effect of both citrate and soluble calcium.
  • Raw material 1 A 15%Nano HAP solution purchased from Portugal, wherein the percentage by mass of the nanohydroxyapatite is 15%and the concentration of the soluble calcium is 1053ppm.
  • the NanoXIM was diluted by 6.67 folds using deionized water, i.e. the percentage by mass of the nanohydroxyapatite was 2.25%, and the concentration of the soluble calcium was 157.87 ppm. Whether the nanohydroxyapatite infiltrated into the dentinal tubules in the presence or absence of citrate was then determined. The result is shown in Table 27.
  • the nanohydroxyapatite can not infiltrate into the dentinal tubules in the presence of soluble calcium alone and without citrate.
  • Raw material 1 was used and different amounts of potassium citrate were added into the raw material to determine whether the nanohydroxyapatite infiltrated into the dentinal tubules. The result is shown in Table 28.
  • the citrate was effective within a broad ratio range. However, too high or too low of the amount of citrate could not facilitate the nanohydroxyapatite to infiltrate into the dentinal tubules, suggesting that the ratio relationship between the citrate and the soluble calcium is effective within a certain range.
  • Raw material 1 A 15%Nano HAP solution containing 1053ppm residual unreacted soluble calcium. The raw material was commercially available and was purchased from Fluidinova Inc., Portugal.
  • Raw material 2 Dry powder of Nano HAP was prepared into a 15%Nano HAP solution. The soluble calcium released from the Nano HAP was about 4ppm and was negligible. The raw material was purchased from Shanghai Zilin Biotechnology Inc.
  • Raw material 3 A 15%Nano HAP solution. The synthetic process was the same as that for raw material 1, but most of the unreacted soluble calcium was removed by repeated centrifugations and washings. The soluble calcium in the raw material was about 43ppm. The raw material was commercially available and was purchased from Fluidinova Inc., Portugal.
  • the percentage by mass of the nanohydroxyapatite and the potassium citrate in each paste were the same, but the concentrations of the soluble calcium were different. As the concentration of soluble calcium increased, more nanohydroxyapatite infiltrated into the dentinal tubule. When the concentration of soluble calcium was very low, for example 4ppm, the nanohydroxyapatite can not infiltrate into the dentinal tubules despite the presence of the citrate. This result suggests that the soluble calcium was essential for the infiltration of the nanohydroxyapatite into the dentinal tubules.
  • Raw material 3 was used and different concentrations of soluble calcium was added into the raw material to determine whether the nanohydroxyapatite could infiltrate into the dentinal tubules. The results were shown in Table 31.
  • Example 6 Suspensions prepared by nanohydroxyapatite, other polycarboxylic compounds and soluble calcium
  • Suspensions 3-I, 3-II, 3-III, 3-IV and 3-V were prepared according to the different ratios shown in the following Table 32.
  • the Nano HAP of Figure 1 was used, and the pH value of tetrasodium 2-phosphonobutane-1, 2, 4-tricarboxylate (PBTCA-Na 4 ) was adjusted to 8.0 by NaOH.
  • the Model Bs treated by the suspensions 3-I, 3-II, 3-III, 3-IV and 3-V were observed under the SEM.

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Abstract

L'invention concerne une composition de soins bucco-dentaires comprenant de l'hydroxyapatite, un composé polycarboxylique, du calcium soluble et un véhicule oralement acceptable, et l'utilisation de cette composition pour soulager ou prévenir la sensibilité des dents. La composition de soins bucco-dentaires peut être préparée en mélangeant le mélange aqueux au véhicule oralement acceptable.
PCT/CN2015/095412 2014-11-24 2015-11-24 Composition dentaire anti-sensibilité WO2016082742A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019034377A1 (fr) * 2017-08-18 2019-02-21 Unilever N.V. Composition de soin bucco-dentaire
RU2799030C1 (ru) * 2022-10-14 2023-07-03 Федеральное государственное бюджетное образовательное учреждение высшего образования "Уральский государственный медицинский университет" Министерства здравоохранения Российской Федерации Стоматологический гель для реминерализации твердых тканей зубов

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Publication number Priority date Publication date Assignee Title
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1743027A (zh) * 2004-09-02 2006-03-08 深圳市清华源兴生物医药科技有限公司 含银口腔清洁用品
WO2007106295A2 (fr) * 2006-03-01 2007-09-20 Dentech, Inc. Produits pour l'hygiene buccale et leurs procedes d'utilisation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4177258A (en) * 1978-10-13 1979-12-04 Colgate Palmolive Company Dentifrice for dental remineralization
KR101262293B1 (ko) * 2011-01-18 2013-05-08 주식회사 바이오알파 중성에서 안정한 고농도 인산칼슘 수용액의 제조방법
CN102133154B (zh) * 2011-03-09 2012-09-19 东南大学 牙根根尖充填材料及其制备方法
CN103120623B (zh) * 2012-12-01 2014-10-01 云南白药集团股份有限公司 抗牙本质敏感口腔清洁护理制剂

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1743027A (zh) * 2004-09-02 2006-03-08 深圳市清华源兴生物医药科技有限公司 含银口腔清洁用品
WO2007106295A2 (fr) * 2006-03-01 2007-09-20 Dentech, Inc. Produits pour l'hygiene buccale et leurs procedes d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019034377A1 (fr) * 2017-08-18 2019-02-21 Unilever N.V. Composition de soin bucco-dentaire
RU2799030C1 (ru) * 2022-10-14 2023-07-03 Федеральное государственное бюджетное образовательное учреждение высшего образования "Уральский государственный медицинский университет" Министерства здравоохранения Российской Федерации Стоматологический гель для реминерализации твердых тканей зубов

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