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    公开号:BR112014004760B1
    申请号:R112014004760-0
    申请日:2012-08-17
    公开日:2018-11-06
    发明作者:Yan Deng；Li Li；Qinghong Hu；Ruikang Tang
    申请人:Unilever N.V.；
    IPC主号:
    专利说明:

    (54) Title: DENTIFICATION COMPOSITION, METHOD OF REMINERALIZATION AND / OR TOOTH WHITENING (73) Holder: UNILEVER N.V., Dutch Company. Address: WEENA 455, NL-3013 AL ROTEERDAM., NETHERLANDS (NL) (72) Inventor: YAN DENG; LILI; QINGHONG HU; RUIKANG TANG.
    Validity Term: 20 (twenty) years from 08/17/2012, subject to legal conditions
    Issued on: 11/06/2018
    Digitally signed by:
    Liane Elizabeth Caldeira Lage
    Director of Patents, Computer Programs and Topographies of Integrated Circuits
    1/29 “DENTIFICATION COMPOSITION, METHOD OF REMINERALIZATION AND / OR TOOTH WHITENING”
    Field of the Invention Technique [001] The present invention relates to toothpastes such as toothpaste and mouthwash products. In particular, the present invention relates to toothpaste compositions that have a specific pH and comprise a source of insoluble and / or slightly soluble calcium in water and organic acid. The invention also relates to the use of such dentifrices for remineralization and / or teeth whitening.
    Background of the Invention [002] Products that are appreciated by consumers, unfortunately, often have a negative impact on teeth. Sour and sweet drinks, for example, can result in tooth erosion attacking the enamel that lines and protects your teeth. In addition, tobacco products as well as drinks such as coffee and tea can stain your teeth and thus result in a smile that is often unattractive.
    [003] In addition to what is consumed, the natural balance between tooth hydroxyapatite (PAH) that is dissolved from tooth enamel and PAH that is formed on or in the teeth of substances that occur naturally in saliva is continually displaced. Such a displacement can yield unattractive teeth with cariogenic conditions. Products targeting tooth decay and / or whitening, however, have been developed. Conventional products often comprise peroxides, coarse abrasives, or both.
    [004] The International Patent Application published as WO on s
    2007/066837 (LG HOUSEHOLD AND HEALTH CARE LTD) reveals a liquid delivery system for a liquid bleaching ingredient. O
    2/29 bleaching agent can be selected from peroxides, perborates, percarbonates, peroxyacids, persulfates and metal chlorides.
    [005] These types of products are not often desired as they can cause damage to teeth and gums if used inappropriately. Furthermore, such products can be costly and are not attractive to low-income consumers in need of remineralization of teeth.
    [006] Cement-like restorative compositions have also been developed for use as tooth fillers or that otherwise solidify on or around teeth. Such compositions remain in contact with teeth for extended periods and are said to aid mineralization and / or whitening.
    [007] International patent application published as WO 2010/042754 on s (MED COLLEGE GEORGIA RES INST) discloses systems, methods, compositions and kits for mineralization of tissue, particularly dental tissue. The methods, compositions and kits can be used to strengthen and prevent tissue weakening. For example, methods, compositions and kits can be used to treat and fill cavities in teeth caused by tooth decay.
    [008] The patent application published under n are JP 11-116421 A (LION CORP) discloses compositions with the ability to easily remove stains and operatively, bleaching teeth and also prevent the teeth become brittle including a phosphate compound self-healing calcium, a fluorine compound, a peroxide and a specific acid.
    [009] Unfortunately, such compositions may still require the use of aggressive oxidizing agents, such as peroxides, and / or require that the entire solid composition remain in contact with the teeth for extended periods of time. Thus, such compositions may not be
    3/29 suitable for use in a daily consumer routine to clean your teeth for a few minutes with toothpaste.
    [010] Therefore, the present inventors have recognized that there is a need to develop an oral hygiene product that is suitable for whitening and remineralizing teeth while being delicate to use and / or accessible to a wide range of consumers and / or effective when used as part of daily teeth cleaning or mouthwashing routines. This invention, therefore, is directed to a toothpaste composition as well as a method for remineralization and / or teeth whitening.
    Tests and Definitions
    Toothpaste [011] Toothpaste, for the purposes of the present invention, means a paste, powder, liquid, gum or other preparation to clean teeth or other surfaces in the oral cavity.
    Toothpaste [012] "Toothpaste", for the purposes of the present invention, means a toothpaste paste or gel for use with a toothpaste. Especially preferred are toothpastes suitable for cleaning teeth by brushing for about two minutes.
    Mouthwash [013] "Mouthwash" for the purposes of the present invention means toothpaste liquid for use in mouth rinsing. Especially preferred are mouthwash products suitable for rinsing the mouth by mouthwash and / or gargle for about half a minute before expectoration.
    SOLUBILITY [014] “Soluble” and “insoluble”, as used in this document, refers to the solubility of a source (for example, as salts of
    4/29 calcium) in water at 25 S C and atmospheric pressure. “Soluble” means a source that dissolves in water to give a solution with a concentration of at least 0.1 moles per liter. “Insoluble” means a source that dissolves in water to give a solution with a concentration less than 0.001 moles per liter. “Slightly soluble”, therefore, is defined to mean a source that dissolves in water to give a solution with a concentration greater than 0.001 rols per liter and less than 0.1 rols per liter.
    Particle size [015] “Particle size” as used in this document means diameter size and reported as a mass average diameter. “Diameter” means the largest measurable length in any dimension in the event that the particle is not a perfect sphere. The particle size can be measured, for example, by means of dynamic light scattering (DLS).
    Remineralization and Whitening [016] “Remineralization”, as used in this document, means in situ generation (ie, in the oral cavity) of hydroxyapatite (PAH) in teeth (including layers in teeth from 10 nm to 20 microns and preferably 75 nm to 10 microns and more preferably, 150 nm to 5 microns in thickness including all ranges covered in it) to reduce the likelihood of tooth sensitivity, tooth decay, regenerate enamel and / or improve the appearance of teeth by whitening generation of such a new PAH. The new PAH, which includes layers in it, typically covers at least 30 percent and preferably, at least 45 percent and most preferably 48 to 100 percent of the clean tooth surface with the toothpaste composition of this invention and that includes all the ranges covered in it. “Laundering” also
    5/29 may include physical teeth whitening by the adhesion of calcium based salts and other opacifiers temporarily to the teeth surface.
    pH [017] When referring to the pH of a composition, this means the pH measured when 1 part by weight of the composition is uniformly dispersed and / or dissolved in 20 parts by weight of pure water at 25 S C. In particular, the pH can be measured by manually mixing 1 g of toothpaste with 20 ml of water for 30 seconds, then immediately testing the pH with indicator paper or a pH meter.
    Oxidative bleaching compound [018] “Oxidizing bleaching compound”, as used herein, means one or more of peroxides, perborates, percarbonates, peroxyacids, persulfates and metal chlorides.
    Substantially free [019] “Substantially free of”, as used herein, means less than 1.5% and preferably less than 1.0% and more preferably, less than 0.75% and even more preferably, less than 0.5% and more preferably from 0.0 to 0.1% by weight, based on the total weight of the toothpaste composition, including all ranges covered therein.
    Viscosity [020] Viscosity of a toothpaste is the value taken at room temperature (25 S C) with a Brookfield Viscometer spindle, N s 4 and at a speed of 5 rpm. Values are quoted in centipoises (cP = mPa.s) unless otherwise specified.
    Miscellaneous [021] Except in the examples or where otherwise explicitly indicated, all numbers in this description that indicate
    6/29 amounts of material or reaction conditions, physical properties of materials and / or use can optionally be understood as modified by the words "about".
    [022] All quantities are by weight of the final toothpaste composition, unless otherwise specified.
    [023] It should be noted that when specifying any range of values, any particular higher value can be associated with any particular higher value.
    [024] For the avoidance of doubt, the word "understand" is meant to mean "include", but not necessarily "consist of" or "composed (a) of". In other words, the steps or options listed need not be exhaustive.
    [025] The disclosure of the invention, as found in this document, should be considered to cover all achievements, as found in the claims as being multiply dependent on each other regardless of the fact that the claims can be verified without multiple dependency or redundancy.
    [026] Where a feature is revealed in relation to a particular aspect of the invention (for example, a composition of the invention), such disclosure should also be considered to apply to any other aspect of the invention (for example, a method of the invention) mutatis mutandis.
    Brief Description of the Invention [027] The present invention provides a toothpaste composition comprising:
    (a) source of calcium insoluble and / or slightly soluble in water, where the source of calcium comprises
    i. A component capable of reacting with phosphate ions to produce calcium phosphate in situ,
    7/29 ii. hydroxyapatite (PAH) and / or amorphous calcium phosphate (ACP) which has a mass average diameter of 5 microns or less, or iii. both; and (b) at least 0.1% by weight of organic acid having 1 to 3 groups of carboxylic acid or its physiologically acceptable salt or a combination thereof;
    wherein the toothpaste composition has a pH greater than 6.0.
    [028] The composition is found to be surprisingly effective in remineralizing dental tissue, such as enamel and / or dentin when, in normal use, as a toothpaste and without any special procedure or implantation. Thus, additional aspects of the invention relate to methods and uses that employ the composition to remineralize and / or whiten an individual's teeth.
    Brief Description of the Figures [029] Certain embodiments of the invention are illustrated by the Figures, in which:
    Figure 1 is an SEM image of a native acid-etched enamel surface prior to incubation;
    Figure 2 is an SEM image of the enamel surface after incubation in simulated body fluid (SBF) containing calcium silicate particles;
    Figure 3 is an SEM image of the enamel surface after incubation in SBF containing particles of calcium silicate and 100 mM glutamic acid;
    Figure 4 is a SEM image of a cross-section of an enamel block after brushing with anhydrous toothpaste containing calcium silicate particles for two weeks;
    8/29
    Figure 5 is a SEM image of a cross-section of an enamel block after brushing for two weeks with the same anhydrous toothpaste as the sample in Figure 4, but which additionally contains 1% glutamic acid;
    Figure 6 is a SEM image of a cross section of an enamel block after brushing for two weeks with the same anhydrous toothpaste as the sample in Figure 4, but which additionally contains 2% glutamic acid;
    Figure 7 is a SEM image of a cross section of an enamel block after brushing for two weeks with the same anhydrous toothpaste as the sample in Figure 4, but which additionally contains 1% glycine;
    Figure 8 is a SEM image of a cross section of an enamel block after brushing for two weeks with the same anhydrous toothpaste as the sample in Figure 4, but which additionally contains 1% citric acid;
    Figure 9 is a SEM image of a cross-section of an enamel block after brushing with water toothpaste containing calcium silicate particles for four weeks;
    Figure 10 is a SEM image of a cross section of an enamel block after brushing for four weeks with the same water toothpaste as the sample in Figure 9, but which additionally contains 1% glycine; and
    Figure 11 is a SEM image of a cross section of an enamel block after brushing for four weeks with the same water toothpaste as the sample in Figure 9, but which additionally contains 2% glutamic acid.
    Detailed Description [030] The composition of the present invention comprises a source of calcium insoluble and / or slightly soluble in water. The use of a
    9/29 source of insoluble and / or slightly water-soluble calcium allows substantial contact time between the source and a user's teeth during cleaning.
    [031] It is possible that the calcium source of the present invention is provided in the form of a calcium phosphate. However, crystalline forms of calcium phosphate in addition to hydroxyapatite (PAH) may not be suitable precursors for the formation of PAH. On the other hand, it was found that amorphous calcium phosphate (ACP) is an excellent precursor for PAH formation when used as small particles. In addition, since PAH itself is supplied in the form of small particles, it was found that they have the ability to be arranged together on crystalline rods similar to enamel in situ. Thus, if the calcium source of the present invention is calcium phosphate, then it is supplied in the form of HAP and / or ACP which has a mass average diameter of 5 microns or less (also referred to herein as “ Micronized HAP / ACP ”). Preferably, the particle size of HAP and / or ACP is less than 2 microns, more preferably, less than 1 micron, even more preferably, less than 0.5 micron and more preferably, in the range 0.01 to 0, 1 micron.
    [032] Although the calcium source of the present invention, when present as calcium phosphate, is HAP and / or ACP with the particle size specified above, it does not eliminate the presence of other calcium phosphate salts and / or particles greater PAH or ACP. Preferably, however, at least 50% by weight of calcium phosphate in the composition is composed of micronized HAP / ACP. More preferably, the micronized PAH / ACP makes up at least 75% of the total amount of calcium phosphate in the composition, even more preferably, at least 85% and most preferably the amount is in the range of 90 to 100%.
    10/29 [033] Additionally or alternatively, the calcium source comprises a component capable of reacting with phosphate ions to produce a calcium phosphate in situ. Illustrative examples of the types of calcium sources that can be used in this invention include, for example, calcium oxide, calcium silicate, calcium carbonate, calcium hydroxide, calcium sulfate, calcium carboxymethylcellulose, calcium alginate, bioactive glass , mixtures of the same or similar. In a preferred embodiment, the calcium source is calcium silicate and / or bioactive glass. In a more preferred embodiment, the calcium silicate used is CaSiO3 in which it is made commercially available under the name Microcal ET from PQ, Huber, Weifang Hongyuan Chemical Co. Ltd.
    [034] In yet another preferred embodiment, the calcium source is insoluble calcium silicate, present as the oxide composite cálciosílica (CaO-SiO 2) as described in International patent application published as WO 2008/015117 on s (Unilever) .
    [035] When a composite material calcium silicate is used, the ratio of calcium to silicon (Ca: Si) can be from 1:10 to 3: 1. The Ca: Si Ratio is preferably from 1: 5 to 2: 1, and more preferably from 1: 3 to 2: 1 and most preferably from about 1: 2 to 2: 1. Calcium silicate can comprise monocalcium silicate, bicalcium silicate or tricalcium silicate in which the calcium to silicon (Ca: Si) ratios must be understood to be atom ratios.
    [036] The calcium source employed in this invention can be in a crystalline or amorphous state and preferably, it is in an amorphous state. In an often preferred embodiment, the source of calcium is in a mesoporous state, that is, the source is a material that has pores with diameters from 1 nm to 50 microns. Mesoporous calcium silicate (MCS) is often preferred.
    11/29 [037] The MCS that can be used in this invention can be made, for example, by combining a calcium salt, a silica precursor such as silicate and a structure targeting agent to yield a solid suitable for calcination. A more detailed description of the process can be conducted to create an MCS suitable for use herein is described in the aforementioned International Application, published under WO 2008/015117 are on and which is hereby incorporated by reference in its entirety.
    [038] The bioactive glass that can be used as the calcium source in the present invention comprises calcium and optionally phosphate ions. Suitable bioactive glasses are described, for example, in the documents Nos WO 2010/041073 (BIOFILM LTD), 9 No WO 2009/158564 (amikacin TECHNOLOGY INC), 9 No WO 99/13852 (UNIV MARYLAND) n 9 WO2005 / 063185 (NOVAMIN TECHNOLOGY INC), No. 9 WO 96/10985 (BIOXID OY) and / or No. 9 WO 97/27148 (UNIV MARYLAND) of which all international patent applications are incorporated by reference in this document. integrity.
    [039] Typically, the toothpaste composition of the present invention comprises 0.1 to 60% by weight of the calcium source, more preferably 0.2 to 50%. Even more preferably, the toothpaste composition comprises the calcium source in an amount of at least 0.3% by weight, even more preferably at least 0.5% or even at least 1%. In a more preferred embodiment the toothpaste composition comprises the calcium source in an amount of at least 5% by weight and, ideally, in the range of 10 to 40% by weight.
    [040] Where the toothpaste is a toothpaste or powder, larger amounts of the calcium source are preferred. This is due to the fact that toothpaste is typically applied, only in smaller volumes (for example, about 2 ml) per consumer use. Additionally, folders
    12/29 tooth are typically opaque and therefore allow the incorporation of high levels of insoluble or slightly soluble calcium sources, without affecting the appearance expected by the consumer. Thus, in one embodiment, the toothpaste is a toothpaste or powder and comprises the calcium source in an amount of at least 5% by weight, more preferably at least 7% by weight and most preferably in the range of 10 to 40 % by weight.
    [041] Where toothpaste is a mouthwash product, smaller amounts of the calcium source are preferred. This is due to the fact that mouthwash products are typically used in larger volumes (for example, about 20 ml) per consumer use than toothpaste. Additionally, mouthwash products are typically transparent and, therefore, the incorporation of high levels of insoluble or slightly soluble calcium sources can negatively affect the appearance expected by the consumer. Thus, in one embodiment, the toothpaste is a mouthwash product and comprises the calcium source in an amount of at least 0.2% by weight, more preferably at least 0.5% by weight and more preferably from 1 to 10% by weight.
    [042] Preferably the calcium source has a mass average diameter of five (5) microns or less and preferably from 10 to 100% and especially from 25 to 100% and more especially from 70 to 100% by weight of the source of calcium used in this invention has a particle size of 0.1 to 1.5 microns.
    [043] Additional examples of calcium salts suitable for use in this invention are commercially available and often commercially sold from suppliers such as Cole-Parmer, Great Lakes Calcium and Fujian Sannong Calcium Carbonate Co. Ltd.
    [044] The present inventors have surprisingly found that certain organic acids and their salts, that is, organic acid that
    13/29 has 1 to 3 carboxylic acid groups that intensify the generation of enamel-like PAH crystals on tooth surfaces. Without wishing to be bound by theory, the present inventors believe that the calcium source of this invention allows the formation of nanoparticles in PAH on the surface of teeth and that organic acid promotes and regulates the aggregation and crystallization of nanoparticles absorbed in crystals that have the shape and orientation of native enamel. Furthermore, it is believed that the organic acid carboxylate group is the main reason required for the interaction with PAH nanoparticles. Thus, it is preferred that the organic acid has at least 2 carboxylic acid groups. Many carboxylate groups can, however, cause organic acid to chelate calcium ions and thereby inhibit the formation and / or aggregation of PAH. Thus, organic acid has no more than 3 groups of carboxylic acid.
    [045] The toothpaste composition comprises at least 0.1% by weight of organic acid which has 1 to 3 groups of carboxylic acid or its physiologically acceptable salt or a mixture thereof. Preferably, the composition comprises organic acid or its physiologically acceptable salt or a mixture thereof in an amount in the range of 0.2 to 20% by weight, more preferably from 0.5 to 10% and more preferably from 1 to 5% .
    [046] Organic acid can be, for example, an acidic amino acid, neutral acidic amino acid or a mixture thereof, suitable amino acids, therefore, include glutamic acid, glycine, aspartic acid, asparagine, alanine, leucine or a mixture thereof. Most preferred are glutamic acid, aspartic acid, glycine or a mixture thereof. Even more preferred are acidic amino acids, especially glutamic acid, aspartic acid or a mixture thereof and the most preferred is glutamic acid.
    14/29 [047] Other preferred acids are non-amino acids that can be used as an alternative to or in combination with amino acids. Suitable organic acids, therefore, include formic acid, acetic acid, benzoic acid, lactic acid, glycolic acid, gluconic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pyelic acid, maleic acid, fumaric acid, malic acid, citric acid or mixtures thereof. The most preferred is citric acid.
    [048] Suitable physiologically acceptable salts of organic acid include those in which the counter ion is selected from the group consisting of Na + , K + , NH4 + , Ca 2+ , Mg 2+ , Ál 3+ , Zn 2+ and combinations thereof. Preferably, the counterion is not calcium as it may affect the organic acid's ability to interact with PAH. Thus, more preferably the counter-ion is selected from the group consisting of Na + , K + , NH4 + , Mg 2+ , Al 3+ , Zn 2+ and combinations thereof. Even more preferred are salts with monovalent ions as they tend to be very soluble in water. Thus, more preferably, the counter-ion is selected from the group consisting of Na + , K + , NH 4 + and combinations thereof.
    [049] It should be noted that where organic acid is mentioned in the present disclosure, it also includes the corresponding physiologically acceptable salts thereof, also where it is not explicitly stated.
    [050] The most preferred organic acids of the present invention are highly soluble in water. In particular, organic acids with a molar mass of less than 500 g mol ' 1 are preferred. More preferably, the molar mass is in the range of 70 to 250 g mol ' 1 . Where
    15/29 molar masses are declared, these do not include the mass of any counterions or hydration water.
    [051] It is found that the composition of the present invention has the ability to remineralize teeth in situ without the inclusion of a phosphate source in the composition itself. Without wishing to be bound by theory, the present inventors believe that this may be due to the fact that the calcium source in the composition of the invention reacts with phosphate ions in saliva.
    [052] Thus, in one embodiment the composition can be substantially free of phosphate source. This is especially preferred when the composition is a single-phase water composition (i.e., greater than 1.5% water, preferably more than 5% water, more preferably more than 10% water and more preferably 20 to 90% % water by weight of the composition). The presence of both calcium and phosphate sources in a single-phase water formulation can induce the premature reaction of calcium and phosphate and product instability.
    [053] For certain compositions, especially anhydrous compositions (that is, compositions substantially free of water) or double phase water compositions, it is preferable to compose a phosphate source in the composition to aid in situ generation of calcium phosphate.
    [054] The source of phosphate that can be used in this invention is limited only to the extent that it can be used in a composition suitable for use in an oral cavity. Illustrative examples of the types of phosphate source suitable for use in this invention include monosodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium pyrophosphate, tetrasodium pyrophosphate, sodium hexametaphosphate, monopotassium phosphate, potassium hydrogen phosphate, potassium hydrogen phosphate, potassium hydrogen phosphate trisodium phosphate, tripotassium phosphate, mixtures thereof or
    16/29 similar. The phosphate source is preferably one that is soluble in water.
    [055] Typically, the phosphate source comprises from 0.5 to 15% and more preferably from 2 to 12% and most preferably from 4 to 9% by weight of the toothpaste composition, based on the total weight of the toothpaste composition and which includes all the tracks covered in it. In a more preferred embodiment, the phosphate source used is trisodium phosphate and monosodium dihydrogen phosphate in a weight ratio of trisodium phosphate to monosodium dihydrogen phosphate from 1: 4 to 4: 1, preferably 1: 3 to 3: 1 and more preferably, from 1: 2 to 2: 1, which include all the relationships covered therein.
    [056] The toothpaste composition has a pH greater than 6.0. If the pH of the composition is too low, then it can lower the pH in the oral cavity so that the generation of calcium phosphate in situ is delayed. In addition, the stability of the calcium source in very low pH compositions can be compromised. Therefore, it is preferred that the pH is in the range 7.0 to 11.0, more preferably, 8.0 to 10.5 and most preferably 8.5 to 10.0.
    [057] Surprisingly, the present inventors have also found that the effectiveness of organic acid in facilitating the development guidance of newly formed apatite crystals can be further enhanced by the presence of a fluoride source. Thus, in a preferred embodiment the toothpaste composition comprises the source of fluoride. Suitable sources of fluoride include sodium fluoride, stannous fluoride, sodium monofluorophosphate, zinc ammonium fluoride, tin ammonium fluoride, calcium fluoride, cobalt ammonium fluoride or mixtures thereof. The composition preferably comprises the source of fluoride in an amount of at least 0.001% and preferably, of
    17/29
    0.01 to 12% and more preferably, from 0.1 to 5% by weight of the toothpaste composition, based on the total weight of the toothpaste composition and which includes all ranges covered therein.
    [058] The composition of the present invention is a toothpaste. Typically, dentifrices comprise at least a surfactant, thickening agent, humidifier or a combination thereof.
    [059] Preferably the toothpaste composition comprises a surfactant. Preferably, the composition comprises at least 0.01% surfactant by weight of the composition, more preferably at least 0.1% and most preferably 0.5 to 7%. Suitable surfactants include anionic surfactants, such as sodium, magnesium, ammonium or ethanolamine salts of Cs-Cis alkyl sulfates (eg, sodium lauryl sulfate), Cs-Cis alkyl sulfosuccinates (eg, sodium sulfosuccinate dioctyl), Cs-Cis alkyl sulfoacetates (such as sodium lauryl sulfoacetate), Cs-Cis alkyl sarcosinates (such as sodium lauryl sarcosinate), Cs-Cis alkyl phosphates (which can optionally comprise up to 10 units ethylene oxide and / or propylene oxide) and sulfated monoglycerides. Other suitable surfactants include non-ionic surfactants, such as optionally polyethoxylated fatty acid sorbitan esters, ethoxylated fatty acids, polyethylene glycol esters, fatty acid monoglyceride ethoxylates and ethylene oxide / ethylene oxide / propylene block polymer oxide. Other suitable surfactants include amphoteric surfactants, such as betaines or sulfobetaines. Mixtures of any of the materials described above can also be used. More preferably, the surfactant comprises or is an anionic surfactant. The preferred anionic surfactants are sodium lauryl sulfate and / or sodium dodecylbenzene sulfonate. Most preferably, the surfactant is sodium lauryl sulfate.
    18/29 [060] The thickening agent can also be used in this invention and is limited only to the extent that it can be added to a composition suitable for use in the mouth. Illustrative examples of the types of thickening agents that can be used in this invention include sodium carboxymethyl cellulose (SCMC), hydroxyl ethyl cellulose, methyl cellulose, ethyl cellulose, tragacanth gum, arabic gum, karaya gum, sodium alginate, carrageenan, guar, xanthan gum, orange moss, starch, modified starch, silica-based thickening agents including silica aerogels, magnesium aluminum silicate (ie Goma see), carbomers (crosslinked acrylates) and mixtures thereof.
    [061] Typically, sodium carboxymethyl cellulose and / or a Carbomer is / are preferred. When a Carbomer is used, those that have a molecular weight of at least 700,000 are desired and preferably, those that have a molecular weight of at least 1,200,000 and more preferably, those that have a molecular weight of at least about 2,500 .000 are desired. Carbomer mixtures can also be used in this document.
    [062] In an especially preferred embodiment, the Carbomer is Synthalen PNC, Synthalen KP or a mixture thereof. It has been described as a high molecular weight and cross-linked polyacrylic acid and identified by CAS number 9063-87-0. These types of materials are commercially available from suppliers such as Sigma.
    [063] In another especially preferred embodiment, the sodium methyl carboxy cellulose (SCMC) used is SCMC 9H. It has been described as a sodium salt of a cellulose derived with carboxymethyl groups linked to hydroxy groups of major glucopyranose monomers and identified by CAS number 9004-32-4.0, which is available from suppliers such as Alfa Chem.
    19/29 [064] The thickening agent typically comprises from 0.01 to about 10% and preferably from 0.1 to 8% and more preferably, from 1.5 to 6% by weight of the toothpaste composition, based in total weight of the composition and that includes all the bands covered in it.
    [065] When the toothpaste composition of this invention is a toothpaste or gel, it typically has a viscosity of about 50,000 to 180,000 centipoise and preferably, 60,000 to 170,000 centipoise and more preferably, 65,000 to 165,000 centipoise.
    [066] Suitable humidifiers are preferably used in the oral hygiene composition of the present invention and they include, for example, glycerin, sorbitol, propylene glycol, dipropylene glycol, diglycerol, triacetin, mineral oil, polyethylene glycol (preferably, PEG-400 ), alkane diols such as butane diol and hexanediol, ethanol, pentylene glycol or a mixture thereof. Glycerin, polyethylene glycol, sorbitol or mixtures thereof are the preferred humidifiers.
    [067] The humidifier can be present in the range of 10 to 90% by weight of the toothpaste composition. Preferably, the carrier humidifier comprises from 25 to 80% and more preferably, from 45 to 70% by weight of the toothpaste composition, based on the total weight of the composition and which includes all the ranges covered therein.
    [068] The toothpaste compositions described in this document may comprise optional ingredients that are common in the art. These ingredients include antimicrobial agents, anti-inflammatory agents, anti-caries agents, plaque buffers, vitamins, plant extracts, desensitizing agents, anti-calculating agents, biomolecules, flavors, proteinaceous materials, preservatives, opacifying agents (especially titanium dioxide), coloring agents, pH adjustment agents, sweetening agents, particulate abrasive materials, compounds
    20/29 polymeric, buffers and salts to buffer the pH and ionic strength of the compositions and mixtures thereof. Such ingredients typically and collectively make up less than 20% by weight of the toothpaste composition described herein and preferably from 0.0 to 15% by weight and more preferably from 0.01 to 12% by weight of the composition, including all the tracks covered in it.
    [069] The dentifrice composition of the present invention can be effective in teeth whitening even in the absence of oxidative bleaching compound and, in a preferred embodiment the composition, is substantially free of oxidative bleaching compound.
    [070] The toothpaste composition of this invention can be used in a method of remineralizing and / or whitening an individual's teeth which comprises the step of contacting one or more of the individual's teeth with the toothpaste composition. In addition or alternatively, the composition can be used in a method for the manufacture of a medicament for remineralization and / or whitening teeth of an individual comprising the step of contacting one or more teeth of the individual with the toothpaste composition.
    [071] Typically, the composition can be packaged. In the form of toothpaste or gel, the composition is packaged in a conventional plastic laminate, metal tube or a single dispenser compartment. The same can be applied to dental surfaces by any physical means, such as a toothpaste, fingertip or by an applicator directly on the sensitive area. In the form of a liquid mouthwash product, the composition can be packaged in a bottle, sachet or other convenient container.
    21/29 [072] The composition can be effective even when used in an individual's daily oral hygiene routine. For example, the composition can be brushed on the teeth and / or rinsed around the inside of the individual's mouth. The composition can, for example, be brought into contact with the teeth for a period of time from one second to 20 hours. More preferably, from 10 s to 10 hours, even more preferably from 30 s to 1 hour and more preferably from 1 minute to 5 minutes. The composition can be used daily, for example, for use by an individual once, twice or three times a day.
    Examples
    Example 1 [073] This example demonstrates the effect of glutamic acid on enamel remineralization with hydroxyapatite nanoparticles (PAH).
    Experimental Section [074] All reagents were analytical grade and used without further purification. CO 2 free triple distilled water was used in the experiments. All solutions were filtered through 0.22 pm of Millipore films before use.
    [075] Human third molars extracted without caries were used in this study. They were used in a thymol solution after its roots and pulps were removed and were sectioned perpendicular to the dental crown using a low speed diamond saw. The surfaces of each sample were polished with the use of silicon carbide paper in order to remove the bacterial stain and pigment and marked in 37% by weight of phosphoric acid for 10 s. These specimens were then washed with deionized water and air dried.
    [076] Apatite nanoparticles (-20-30 nm) were synthesized as described in Tao et al (J. Phys. Chem. B 2007, 111,
    22/29
    13410-13418). Then 0.1% by weight of aqueous dispersion of the nanoparticle was prepared for further applications.
    [077] The simulated body fluid (SBF) was prepared simplified dissolving NaCl, KCl, 2 Κ ΗΡΟ4 3Η 2 · Ο, MgCl 2 6H 2 O, CaCl 2 in deionized water. The SBF composition is shown in Table 1 (values are given in mM). The fluid was buffered at pH = 7.40 ± 0.05 in 37 S C with NaOH and HCI. No precipitation was observed during fluid preparation. When used, the concentration of glumatic acid (Glu) in SBF was 100 mM. The pH of these solutions was 7.40 ± 0.05. All solutions were kept in a water bath for 1 h at 37 S C.
    TABLE 1
    Na + K + Ca 2+ Mg 2+ cr HPO4 2 'HCO 3 2 ' SO4 2 ' SBF 142.0 5.0 2.5 1.5 147.8 1.0 4.2 0.5
    [078] The above 3 μ volume apatite nanoparticle dispersion was carefully poured onto the enamel surfaces and the sample was air dried at 25 S C. The enamel was additionally washed with 10 ml of ethanol to remove particles weakly absorbed and air dried at 25 S C. Then these samples were immersed in SBF or SBF with glutamic acid for 72 h at 37 S C. Equivalent experiments were performed in the absence of PAH nanoparticles.
    [079] Scanning electron microscopy (SEM) was performed using an S-4800 field emission scanning electron microscope (HITACHI, Japan) at an acceleration voltage of 5 kV.
    [080] The phase and orientation of the newly formed layer was examined by X'PERT PRO X-ray diffractometer (PANalytical, Netherlands) with K a Cu radiation with thin film mode.
    23/29 [081] FTIR spectra (Nicolet, Nexus670, USA) were used for crystallinity and identification of absorbed organic species.
    [082] The measurement of mechanical properties was performed by means of a nanoindentator (Nanoindentador, XP, MTS, USA) with Berkovich tip (tip radius of about 20 nm).
    Results [083] Table 2 summarizes the results of the various tests.
    TABLE2
    Substrate Means ofimmersion New layer visible in SEM after immersion Structural orientation of new SEM & XRD layer. Stiffness after immersion (GPa) * Enamel SBF Yes Random 2.2 ± 0.4 Nail Polish +PAH nanoparticles SBF Yes Random Not measured Enamel SBF + Glu NotNot measuredNail Polish +PAH nanoparticles SBF + Glu Yes Similar toenamel 4.7 ± 0.2
    * Native enamel stiffness was 4.2 ± 0.2 GPa.
    [084] As can be seen from the data in
    Table 2, emerging enamel for 72 hours in SBF resulted in the formation of a new layer on the enamel surface, however, the structure of the crystals
    24/29 deposited was similar to flakes and not crystals similar to native enamel rods. In addition, flake-like crystals had poor mechanical properties. The inclusion of glutamic acid in the SBF did not actually result in any deposition of a new crystalline layer on the enamel surface. In fact, only when both PAH nanoparticles and glutamic acid were present, enamel-like crystals could be formed on the enamel surface. Additionally, this new enamel-like layer was 0.5-1 microns thick and was at least as rigid as native enamel.
    Example 2 [085] This example demonstrates the effect of glutamic acid on remineralization of enamel with calcium silicate (CS) particles.
    Experimental Section [086] The enamel blocks were incubated for 24 hours in SBF at 37 S C. CS was added to the SBF in an amount of 1 mg / ml. For some samples, 100 mM of glutamic acid was also added to the SBF. Other conditions were similar to those described in Example 1.
    Results [087] Figures 2 and 3 show SEM images of the enamel surface morphology after incubation with or without CS. The exposed enamel rods (Figure 1) were covered with newly formed calcium phosphate particles. For samples incubated without CS (Figure 2), the calcium phosphate particles deposited on the enamel surface were small, similar to spheres and randomly distributed on the surface. However, for enamel blocks incubated with CS and 100 mM of Glu (Figure 3), the morphology of the newly formed apatitis was different. This layer was formed from small rod-like particles, firmly arranged on the surface and similar to the morphology of
    25/29 native enamel surface. In this way, glutamic acid and calcium silicate can cooperatively remineralize the enamel.
    Example 3 [088] This example demonstrates the effect of glutamic acid and fluoride on remineralization of enamel with calcium silicate (CS) particles.
    Experimental Section [089] The enamel blocks were brushed with a double phase calcium silicate and phosphate toothpaste which have the composition shown in Table 3.
    TABLE 3
    Double stage toothpaste CS phase Phosphate phase Component Content(% by weight) Composition Content (% by weight) Chlorinated water 35.89 Deionized water 3.768 Sweetener 0.2 PEG1500 2 Potassium nitrate 0.5 Sweetener 0.27 Sorbitol (70%) 20.00 NaH 2 PO 4 6.41 Benz alcohol. 0.5 Na 3 PO 4 7.64 Calcium silicate 30 Sorbitol (70%) 55 Abrasive Silica 4 Abrasive Silica 12.00 SCMC 0.3 Thickener Silica 3.5
    26/29
    Double stage toothpaste CS phase Phosphate phase Component Content(% by weight) Composition Content (% by weight) Sodium monofluorophosphate 1.11 Sodium lauryl sulfate 6.6 Flavor 0.9 Flavor 1.20 Sodium lauryl sulfate 6.6 SCMC 0.5 Sodium monofluorophosphate 1.11 Color 0.002
    [090] 3 g of toothpaste were prepared by mixing 1.5 g of each phase. 6 g of water was then added and permeated with the toothpaste as quickly as possible by mixing manually (within 15 s). Immediately after preparation, the aqueous paste was added within 5 s to the enamel blocks. Then, the blocks were brushed manually for 1 min before incubation in the aqueous paste for another 1 minute.
    [091] After brushing, the aqueous paste was quickly removed from the blocks. The brushed blocks were washed with distilled water twice using 15 ml of distilled water each time. Between the brushes, the samples of rinsed teeth were incubated in a stunning bath in 37 ° C shaking in 2 ml of SBF. The SBF contained in
    100 mM glutamic acid, with or without 0.01 mM sodium fluoride.
    27/29
    Results [092] After incubation with SBF containing glutamic acid for 4 days, apatite stems similar to enamel formed on the enamel surface. For enamel blocks incubated with SBF and 100 mM glutamic acid, but without fluoride, the newly formed apatite on the surface was in the form of randomly arranged stem crystals. For samples incubated with glutamic acid and 0.01 mM fluoride in SBF, the apatite rods formed on the surface were more oriented and the new layer was more ordered. Thus, there was a cooperative effect of amino acid and fluoride in guiding the development of apatite crystals (newly formed from CS) that was better than the amino acid alone.
    Example 4 [093] This example demonstrates the effect of toothpaste containing calcium silicate and various organic acids on remineralization of teeth.
    Experimental Section [094] Anhydrous and water monophasic toothpaste formulations were prepared as shown in Table 4.
    TABLE 4
    Component (% w / w) Anhydrous toothpaste Water toothpaste Glycerin up to 100 - PEG 400 10.50 - Flavor 1.20 1.00 Trisodium phosphate 3.80 - Calcium silicate 15.00 30.00
    28/29
    Component (% w / w) Anhydrous toothpaste Water toothpaste Monofluorophosphatesodium 1.11 1.11 Sweetener 0.20 0.20 Organic acid 0, 1.00 or 2.00 0, 1.00 or 2.00 Monosodium phosphate 3.20 - PEG 3000 1.75 - Pigment 0.05 - Abrasive silica 7.00 - Sodium lauryl sulfate 2.00 2.20 Sorbitol (70%) - 20.0 Water - up to 100 Benz alcohol. - 0.50 Potassium nitrate - 0.50 Thickened silica - 1.00 SCMC - 0.30
    [095] In treatment, the teeth (blocks of bovine enamel) were brushed by hand with diluted toothpaste (toothpaste: water, 3 g: 6 g) for 1 min and incubated in watery toothpaste-water paste for 1 min after brushing. During the next rinse stage, each
    29/29 sample was rinsed with deionized water twice (15 ml each rinse). Brushing was performed 3 times a day for four weeks and samples between brushes were stored in SBF.
    [096] The organic acids tested were glutamic acid, glycine and citric acid. All toothpastes had a pH of about 9 regardless of the presence of organic acid.
    Results [097] The Figures. 4-8 show representative SEM images of the enamel blocks after two weeks of brushing with anhydrous toothpaste. The location of any remineralized layer is indicated by a white arrow. A new layer was visible for blocks brushed with toothpaste without organic acid (Figure 4). However, 1% glutamic acid (Figure 5), glycine (Figure 7) or citric acid (Figure 8) improved the thickness of the layer. The best coverage and thickness were apparent in samples brushed with toothpaste containing glutamic acid. Increasing the organic acid content of toothpaste to 2% provided even better remineralization (Figure 6).
    [098] The Figures. 9 to 11 show representative SEM images of enamel blocks after four weeks of brushing with water toothpaste. The deposited particles were apparent on the surface of the enamel blocks brushed with toothpaste without organic acid (Figure 9). Brushing with toothpaste containing organic acids glycine (Figure 10) or glutamic acid (Figure 11) produced a thicker layer.
    1/3
    权利要求:
    Claims (14)
    [1]
    Claims
    1. DENTIFICATION COMPOSITION, characterized by comprising:
    (a) source of calcium insoluble and / or slightly soluble in water, where the source of calcium comprises
    1. a component capable of reacting with phosphate ions to produce calcium phosphate in situ, ii. hydroxyapatite and / or amorphous calcium phosphate having a mass average diameter of 5 microns or less, or iii. a combination of them;
    (b) at least 0.1% by weight of organic acid having 1 to 3 groups of carboxylic acid, or its physiologically acceptable salt, or a combination thereof, wherein the organic acid is an acidic amino acid; and (c) surfactant, thickening agent, humidifier or a combination thereof;
    where the toothpaste composition has a pH greater than 6.0, and where the component capable of reacting with phosphate ions to produce a calcium phosphate in situ comprises calcium oxide, calcium silicate, calcium carbonate, hydroxide calcium, calcium sulfate, calcium carboxymethylcellulose, calcium alginate, bioactive glass or a mixture thereof.
    [2]
    2. COMPOSITION according to claim 1, characterized in that the composition comprises a surfactant.
    [3]
    3. COMPOSITION, according to any of the
    Petition 870180073005, of 08/20/2018, p. 12/14
    2/3 claims 1 or 2, characterized in that the calcium source is insoluble in water, preferably the calcium source is calcium silicate, bioactive glass or a combination thereof.
    [4]
    4. COMPOSITION, according to claim 3 characterized by the calcium source being calcium silicate which has a Ca: Si ratio in the range of 1:10 to 3: 1.
    [5]
    COMPOSITION according to any one of claims 1 to 4, characterized in that the composition comprises the calcium source in an amount of 0.1 to 50% by weight.
    [6]
    6. COMPOSITION according to claim 5, characterized in that the toothpaste is a toothpaste or powder and comprises the source of calcium in an amount of at least 5% by weight.
    [7]
    7. COMPOSITION according to claim 5, characterized in that the toothpaste is a mouthwash product and comprises the source of calcium in an amount of at least 0.5% by weight.
    [8]
    COMPOSITION according to any one of claims 1 to 7, characterized in that the organic acid is glutamic acid, aspartic acid or a mixture thereof.
    [9]
    COMPOSITION according to any one of claims 1 to 8, characterized in that the organic acid has 2 or 3 groups of carboxylic acid, preferably the organic acid is glutamic acid.
    [10]
    COMPOSITION according to any one of claims 1 to 9, characterized in that the organic acid has a molar mass less than 500 g mol · 1 .
    Petition 870180073005, of 08/20/2018, p. 13/14
    3/3
    [11]
    COMPOSITION according to any one of claims 1 to 10, characterized in that the composition comprises organic acid in an amount in the range of 0.2 to 20% by weight.
    [12]
    12. COMPOSITION according to any one of claims 1 to 11, characterized in that the composition comprises a phosphate source, preferably the phosphate source is monosodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium pyrophosphate, tetrasodium pyrophosphate, sodium hexametaphosphate, monopotassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate or a mixture thereof.
    [13]
    13. COMPOSITION according to any one of claims 1 to 12, characterized in that the pH is in the range of 7.0 to 11.0.
    [14]
    14. METHOD OF REMINERALIZING AND / OR WHITING an individual's TEETH, characterized by comprising the stage of contacting one or more teeth of the individual with the toothpaste composition, as defined in any one of claims 1 to 13.
    Petition 870180073005, of 08/20/2018, p. 14/14
    1/4
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    同族专利:
    公开号 | 公开日
    BR112014004760A2|2017-03-28|
    CN103764102B|2018-05-29|
    CN103764102A|2014-04-30|
    WO2013034421A3|2014-01-16|
    BR112014004760B8|2019-01-02|
    EP2753292A2|2014-07-16|
    WO2013034421A2|2013-03-14|
    EP2753292B1|2018-06-27|
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    法律状态:
    2017-08-29| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-05-22| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2018-10-09| B09A| Decision: intention to grant|
    2018-11-06| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/08/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    2019-01-02| B16C| Correction of notification of the grant|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 17/08/2012, OBSERVADAS AS CONDICOES LEGAIS. (CO) REF. RPI 2496 DE 06/11/2018 QUANTO AOS ITENS (73) ENDERECO E (30) PRIORIDADE UNIONISTA |
    2021-03-02| B25A| Requested transfer of rights approved|Owner name: UNILEVER IP HOLDINGS B.V. (PB) |
    优先权:
    申请号 | 申请日 | 专利标题
    CNPCT/CN2011/001519|2011-08-09|
    CN2011001519|2011-09-08|
    PCT/EP2012/066120|WO2013034421A2|2011-09-08|2012-08-17|Tooth remineralizing dentifrice|
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